Quetiapine Fumarate Prescribing Information
- 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.ScreeningPatientsforBipolarDisorderA 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.ScreeningPatientsforBipolarDisorderA 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 (
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.
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 mcg/L males; >26 mcg/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 D2receptors, 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 [see
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
CLINICALSTUDIES(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
CLINICALSTUDIES(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
CLINICALSTUDIES(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
CLINICALSTUDIES(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
CLINICALSTUDIES(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
CLINICALSTUDIES(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.
Indication | Initial Dose | Recommended Dose | Maximum Dose | ||||||||||||||||||||||||||||||||
| Schizophrenia-Adults ( 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1 and 14.2 )].
Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ( 14.2 )]. | 25 mg twice daily | 150 to 750 mg/day | 750 mg/day | ||||||||||||||||||||||||||||||||
| Schizophrenia-Adolescents (13 to 17 years) ( 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1 and 14.2 )].
Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ( 14.2 )]. | 25 mg twice daily | 400 to 800 mg/day | 800 mg/day | ||||||||||||||||||||||||||||||||
| Bipolar Mania- Adults Monotherapy or as an adjunct to lithium or divalproex ( 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1 and 14.2 )].
Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ( 14.2 )]. | 50 mg twice daily | 400 to 800 mg/day | 800 mg/day | ||||||||||||||||||||||||||||||||
| Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy ( 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1 and 14.2 )].
Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ( 14.2 )]. | 25 mg twice daily | 400 to 600 mg/day | 600 mg/day | ||||||||||||||||||||||||||||||||
| Bipolar Depression-Adults ( 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1 and 14.2 )].
Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ( 14.2 )]. | 50 mg once daily at bedtime | 300 mg/day | 300 mg/day |
- Geriatric Use:Consider a lower starting dose (50 mg/day), slower titration and careful monitoring during the initial dosing period in the elderly (,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
CLINICALPHARMACOLOGY(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 UseOf 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
CLINICALPHARMACOLOGY(12.3) andDOSAGEANDADMINISTRATION(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 ImpairmentSince 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
DOSAGEANDADMINISTRATION(2.4) andCLINICALPHARMACOLOGY(12.3)].)12.3 PharmacokineticsAdultsQuetiapine 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.
ChildrenandAdolescentsAt 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 Cmaxof the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmaxwere 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
USEINSPECIFICPOPULATIONS(8.4)].AbsorptionQuetiapine 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 Cmaxand AUC values increased by 25% and 15%, respectively.
DistributionQuetiapine 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 EliminationFollowing 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.
AgeOral 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
DOSAGEANDADMINISTRATION(2.3)].GenderThere is no gender effect on the pharmacokinetics of quetiapine.
RaceThere is no race effect on the pharmacokinetics of quetiapine.
SmokingSmoking has no effect on the oral clearance of quetiapine.
Renal InsufficiencyPatients with severe renal impairment (Clcr=10 to 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
USEINSPECIFICPOPULATIONS(8.6)].Hepatic InsufficiencyHepatically 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 Cmaxwere 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
DOSAGEANDADMINISTRATION(2.4) andUSEINSPECIFICPOPULATIONS(8.7)].Drug-Drug Interaction StudiesThe in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 17 [see
DOSAGEANDADMINISTRATION(2.5and2.6) andDRUGINTERACTIONS(7.1)].Table17:TheEffectofOtherDrugsonthePharmacokineticsofQuetiapine Coadministered DrugDose SchedulesEffect on Quetiapine PharmacokineticsCoadministered DrugQuetiapinePhenytoin 100 mg three times
daily250 mg three times
daily5 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 clearanceThioridazine 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
daily20% decrease in mean
oral clearanceKetoconazole (Potent CYP3A4 Inhibitor) 200 mg once daily
for 4 days25 mg single dose 84% decrease in oral
clearance resulting in a 6.2-
fold increase in AUC of quetiapineFluoxetine 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
DRUGINTERACTIONS(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 doses250 mg three times daily No effect on steady-state
pharmacokinetics of lithiumAntipyrine 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 (
3 DOSAGE FORMS AND STRENGTHSTablets: 25 mg, 50 mg, 100 mg and 200 mg
SPL UNCLASSIFIED- Quetiapine tablets USP, 25 mg (as quetiapine) are pink colored, round, biconvex, film-coated tablets, debossed "LU" on one side and "Y15" on the other side.
- Quetiapine tablets USP, 50 mg (as quetiapine) are white, round, biconvex, film-coated tablets, debossed "LU" on one side and "Y16" on the other side.
- Quetiapine tablets USP, 100 mg (as quetiapine) are yellow colored, round, biconvex, film-coated tablets, debossed "LU" on one side and "Y17" on the other side.
- Quetiapine tablets USP, 200 mg (as quetiapine) are white, round, biconvex, film-coated tablets, debossed "LU" on one side and "Y18" on the other side.
- 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 PregnancyPregnancy Exposure RegistryThere 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 SummaryNeonates exposed to antipsychotic drugs (including quetiapine) during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery
(seeCLINICAL 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(seeCLINICAL 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 ConsiderationsDisease-associated maternal and/or fetal riskThere 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 reactionsExtrapyramidal 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.
DataHuman DataPublished 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.
AnimalData: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 LactationRisk SummaryLimited 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 PotentialInfertilityFemalesBased 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
[seeWARNINGS AND PRECAUTIONS].8.4 Pediatric UseIn 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
WARNINGSANDPRECAUTIONS(5.7) andADVERSEREACTIONS(6.1)].SchizophreniaThe 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
INDICATIONSANDUSAGE(1.1),DOSAGEANDADMINISTRATION(2.2),ADVERSEREACTIONS(6.1), andCLINICALSTUDIES(14.1)].Safety and effectiveness of quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established.
MaintenanceThe 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 ManiaThe 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
INDICATIONSANDUSAGE(1.2),DOSAGEANDADMINISTRATION(2.3),ADVERSEREACTIONS(6.1), andCLINICALSTUDIES(14.2)].Safety and effectiveness of quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.
Bipolar DepressionSafety 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 Cmaxof 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
CLINICALPHARMACOLOGY(12.3)].8.5 Geriatric UseOf 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
CLINICALPHARMACOLOGY(12.3) andDOSAGEANDADMINISTRATION(2.3)].8.6 Renal ImpairmentClinical experience with quetiapine in patients with renal impairment is limited [see
CLINICALPHARMACOLOGY(12.3)].8.7 Hepatic ImpairmentSince 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
DOSAGEANDADMINISTRATION(2.4) andCLINICALPHARMACOLOGY(12.3)].