Quetiapine Fumarate: Package Insert and Label Information

QUETIAPINE FUMARATE- quetiapine fumarate tablet, extended release
Lupin Pharmaceuticals, Inc.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS

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 [see WARNINGS AND PRECAUTIONS (5.1)]. Quetiapine fumarate extended-release tablet is not approved for the treatment of patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS (5.1)].

Suicidal Thoughts and Behavior

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS (5.2)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS (5.2)]

Quetiapine fumarate extended-release tablet is not approved for use in pediatric patients under ten years of age [see USE IN SPECIFIC POPULATIONS (8.4)].

1 INDICATIONS AND USAGE

1.1 Schizophrenia

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

1.2 Bipolar Disorder

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

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

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

1.3 Adjunctive Treatment of Major Depressive Disorder (MDD)

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

1.4 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

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

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

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

2.2 Recommended Dosing

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

Table 1: Recommended Dosing for Quetiapine Fumarate Extended-Release Tablet
Indication Initial Dose and Titration Recommended Dose Maximum Dose
Schizophrenia-Adults Day 1: 300 mg/day Dose increases can be made at intervals as short as 1 day and in increments of up to 300 mg/day 400 to 800 mg/day 800 mg/day
Schizophrenia-Adolescents (13 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 800 mg/day 800 mg/day
Schizophrenia Maintenance-Monotherapy-Adults Not applicable 400 to 800 mg/day 800 mg/day
Bipolar I Disorder manic or mixed-Acute monotherapy or adjunct to lithium or divalproex-Adults Day 1: 300 mg/day Day 2: 600 mg/day Day 3: between 400 and 800 mg/day 400 to 800 mg/day 800 mg/day
Bipolar I Disorder, manic -Acute monotherapy -Children and Adolescents (10 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 600 mg/day 600 mg/day
Bipolar Disorder, Depressive Episodes-Adults Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day 300 mg/day 300 mg/day
Bipolar I Disorder Maintenance-Adjunct to lithium or divalproex-Adults Not applicable 400 to 800 mg/day 800 mg/day
Major Depressive Disorder- Adjunctive Therapy with Antidepressants-Adults Day 1: 50 mg/day Day 2: 50 mg/day Day 3: 150 mg/day 150 to 300 mg/day 300 mg/day

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 (14.1, 14.2)].

2.3 Dose Modifications in Elderly Patients

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

Elderly patients should be started on quetiapine fumarate extended-release tablet 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.

2.4 Dose Modifications in Hepatically Impaired Patients

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

2.5 Dose Modifications when used with CYP3A4 Inhibitors

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

2.6 Dose Modifications when used with CYP3A4 Inducers

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

2.7 Re-initiation of Treatment in Patients Previously Discontinued

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

2.8 Switching Patients from Quetiapine Fumarate Tablets to Quetiapine Fumarate Extended-Release Tablets

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

2.9 Switching from Antipsychotics

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

3 DOSAGE FORMS AND STRENGTHS

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

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

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

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

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

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

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 fumarate extended-release tablet is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 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.

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 fumarate extended-release tablet 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 fumarate extended-release tablet, 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.

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