Seroquel Prescribing Information
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. SEROQUEL XR is not approved for the treatment of 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. SEROQUEL XR is not approved for the treatment of patients with dementia-related psychosis
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 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
|---|---|
Increases Compared to Placebo | |
<18 | 14 additional cases |
18-24 | 5 additional cases |
Decreases Compared to Placebo | |
25-64 | 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.
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.
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 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
|---|---|
Increases Compared to Placebo | |
<18 | 14 additional cases |
18-24 | 5 additional cases |
Decreases Compared to Placebo | |
25-64 | 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.
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.
Based on the pharmacologic action of quetiapine (D2 antagonism), treatment with SEROQUEL XR may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential
WARNINGS AND PRECAUTIONS (
Like other drugs that antagonize dopamine D2receptors, SEROQUEL XR 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
SEROQUEL XR is an atypical antipsychotic indicated for the treatment of:
• Schizophrenia1.1 SchizophreniaSEROQUEL XR is indicated for the treatment of schizophrenia. The efficacy of SEROQUEL XR in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13-17 years) treated with SEROQUEL
[see Clinical Studies (14.1)].• Bipolar I disorder, manic, or mixed episodes1.2 Bipolar DisorderSEROQUEL XR is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of SEROQUEL XR in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 - 17 years) with manic episodes associated with bipolar I disorder treated with SEROQUEL
[see Clinical Studies (14.2)].SEROQUEL XR is indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of SEROQUEL XR was established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with SEROQUEL
[see Clinical Studies (14.2)].SEROQUEL XR is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with SEROQUEL. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials
[see Clinical Studies (14.2)].• Bipolar disorder, depressive episodes1.2 Bipolar DisorderSEROQUEL XR is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of SEROQUEL XR in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 - 17 years) with manic episodes associated with bipolar I disorder treated with SEROQUEL
[see Clinical Studies (14.2)].SEROQUEL XR is indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of SEROQUEL XR was established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with SEROQUEL
[see Clinical Studies (14.2)].SEROQUEL XR is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with SEROQUEL. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials
[see Clinical Studies (14.2)].• Major depressive disorder, adjunctive therapy with antidepressants1.3 Adjunctive Treatment of Major Depressive Disorder (MDD)SEROQUEL XR is indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of SEROQUEL XR as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment
[see Clinical Studies (14.3)].
• Swallow tablets whole and do not split, chew or crush2.1 Important Administration InstructionsSEROQUEL XR tablets should be swallowed whole and not split, chewed, or crushed.
It is recommended that SEROQUEL XR be taken without food or with a light meal (approximately 300 calories)
[see Clinical Pharmacology (12.3)].SEROQUEL XR should be administered once daily, preferably in the evening.
• Take without food or with a light meal (approx. 300 calories)2.1 Important Administration InstructionsSEROQUEL XR tablets should be swallowed whole and not split, chewed, or crushed.
It is recommended that SEROQUEL XR be taken without food or with a light meal (approximately 300 calories)
[see Clinical Pharmacology (12.3)].SEROQUEL XR should be administered once daily, preferably in the evening.
• Administer once daily, preferably in the evening2.1 Important Administration InstructionsSEROQUEL XR tablets should be swallowed whole and not split, chewed, or crushed.
It is recommended that SEROQUEL XR be taken without food or with a light meal (approximately 300 calories)
[see Clinical Pharmacology (12.3)].SEROQUEL XR should be administered once daily, preferably in the evening.
• 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 PatientsConsideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions
[see Use in Specific Populations , andClinical Pharmacology (12.3)].When indicated, dose escalation should be performed with caution in these patients.Elderly patients should be started on SEROQUEL XR 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 UseSixty-eight patients in clinical studies with SEROQUEL XR were 65 years of age or over. In general, there was no indication of any different tolerability of SEROQUEL XR in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to SEROQUEL XR, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients
[see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)].• Hepatic Impairment:Lower starting dose (50 mg/day) and slower titration may be needed (,2.4 Dose Modifications in Hepatically Impaired PatientsPatients with hepatic impairment should be started on SEROQUEL XR 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
,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 50 mg/day is recommended and the dose may be increased in increments of 50 mg/day
[see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].)12.3 PharmacokineticsAdults
Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmaxand AUC of norquetiapine are about 21-27% and 46-56%, respectively, of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. SEROQUEL XR 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 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 Use in Specific Populations (8.4)].Absorption
Quetiapine reaches peak plasma concentrations approximately 6 hours following administration. SEROQUEL XR dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the SEROQUEL XR Cmaxand AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmaxor AUC of quetiapine. It is recommended that SEROQUEL XR be taken without food or with a light meal
[see Dosage and Administration (2.1)].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. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine.
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 vitrostudies 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 norquetiapine.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/1.73m2, n=8) had a 25% lower mean oral clearance than normal subjects (CLcr>80 mL/min/1.73m2, 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 2 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 Dosage and Administration (2.4)and Use in Specific Populations (8.7)].Drug-Drug Interaction Studies
The
in vivoassessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 24[see Dosage and Administration and Drug Interactions (7.1)].Table 24: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine CoadministeredDrugDose SchedulesEffect onQuetiapinePharmacokineticsCoadministeredDrugQuetiapinePhenytoin
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 vitroenzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect onin vivometabolism 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 25)[see Drug Interactions (7.2)].Table 25: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs Coadministered DrugDose SchedulesEffect on Other Drugs PharmacokineticsCoadministered DrugQuetiapineLorazepam
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 10-12%
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
Indication | Initial Dose | Recommended Dose | Maximum Dose | ||||||||||||||||||||||||||||||||||||
Schizophrenia - Adults The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ].
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 ]. | 300 mg/day | 400-800 mg/day | 800 mg/day | ||||||||||||||||||||||||||||||||||||
Schizophrenia - Adolescents (13 to 17 years) The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ].
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 ]. | 50 mg/day | 400-800 mg/day | 800 mg/day | ||||||||||||||||||||||||||||||||||||
Bipolar I Disorder manic or mixed - Acute monotherapy or adjunct to lithium or divalproex - Adults The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ].
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 ]. | 300 mg/day | 400-800 mg/day | 800 mg/day | ||||||||||||||||||||||||||||||||||||
Bipolar I Disorder, manic Acute monotherapy - Children and Adolescents (10 to 17 years) The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ].
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 ]. | 50 mg/day | 400-600 mg/day | 600 mg/day | ||||||||||||||||||||||||||||||||||||
Bipolar Disorder, Depressive Episodes - Adults The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ].
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 ]. | 50 mg/day | 300 mg/day | 300 mg/day | ||||||||||||||||||||||||||||||||||||
Major Depressive Disorder, Adjunctive Therapy with Antidepressants - Adults The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ].
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 ]. | 50 mg/day | 150-300 mg/day | 300 mg/day |
• 50 mg extended-release tablets are peach, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 50” on one side and plain on the other side• 150 mg extended-release tablets are white, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 150” on one side and plain on the other side• 200 mg extended-release tablets are yellow, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 200” on one side and plain on the other side• 300 mg extended-release tablets are pale yellow, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 300” on one side and plain on the other side• 400 mg extended-release tablets are white, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 400” on one side and plain on the other side
• 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 SEROQUEL XR, 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 SEROQUEL XR, 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, SEROQUEL XR 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 1-2 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 SEROQUEL XR, 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.
Animal DataWhen 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 at approximately 1-2 times the MRHD (all doses tested) in rabbits.
In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day based on mg/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.