Seroquel XR

Coadministration of thioridazine (200 mg b.i.d.) with SEROQUEL (300 mg b.i.d.), increased the clearance of SEROQUEL by 65%.

SEROQUEL did not induce the hepatic enzyme systems involved in the metabolism of antipyrine.

Coadministration of SEROQUEL (150 mg bid) and divalproex (500 mg bid) increased the mean maximum plasma concentration of quetiapine by 17% without changing the mean oral clearance.

SEROQUEL (quetiapine, immediate-release formulation) potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with psychotic disorders. Alcoholic beverages should be avoided while taking SEROQUEL XR.

CYP 3A4 is the primary enzyme responsible for cytochrome P450-mediated metabolism of quetiapine. Thus, coadministration of compounds (such as ketoconazole, erythromycin, clarithromycin, diltiazem, verapamil, or nefazodone), which inhibit CYP 3A4, may increase the concentration of SEROQUEL XR. In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of SEROQUEL given before and during treatment with ketoconazole, coadministration of ketoconazole resulted in an increase in mean C_max and AUC of quetiapine of 235% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours, but the mean t_max was unchanged. Due to the potential for an interaction of a similar magnitude in a clinical setting, the dosage of SEROQUEL XR should be reduced during concomitant use of quetiapine and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors). Special consideration should be given in elderly and debilitated patients. The risk-benefit ratio needs to be considered on an individual basis in all patients.

The single dose pharmacokinetics of lithium were not altered when coadministered with SEROQUEL.

Amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine, addition of SEROQUEL XR (150 mg or 300 mg/day; for up to 4 weeks) did not appear to have a consistent overall effect on the trough or pre-dose plasma concentrations of the antidepressant.

Concomitant use of SEROQUEL XR with hepatic enzyme inducers such as carbamazepine may substantially decrease systemic exposure to quetiapine. In a multiple dose trial in patients to assess the pharmacokinetics of SEROQUEL given before and during treatment with carbamazepine (a known hepatic enzyme inducer), coadministration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, and hence, in each patient, consideration for a higher dose of SEROQUEL XR, depending on clinical response, should be considered. It should be noted that the recommended maximum daily dose of SEROQUEL XR is 800 mg/day and continued treatment at higher doses should only be considered as a result of careful consideration of the benefit risk assessment for an individual patient.

Coadministration of SEROQUEL and another microsomal enzyme inducer, phenytoin, caused five-fold increases in the clearance of quetiapine. Increased doses of SEROQUEL XR may be required to maintain control of psychotic symptoms in patients coadministered SEROQUEL XR and phenytoin and other hepatic enzyme inducers (e.g., barbiturates, rifampicin, etc.).

The dose of SEROQUEL XR may need to be reduced if phenytoin or carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g., sodium valproate).

Fluoxetine (60 mg daily), imipramine (75 mg b.i.d.), haloperidol (7.5 mg b.i.d.), and risperidone (3 mg b.i.d.) did not significantly alter the steady state pharmacokinetics of SEROQUEL.

Because of its potential for inducing hypotension, SEROQUEL XR may enhance the effects of certain antihypertensive agents.

SEROQUEL XR can be taken with or without food (see Action and Clinical Pharmacology, Pharmacokinetics).

Interactions with laboratory tests have not been established.

Interactions with herbal products have not been established.

Given the primary central nervous system effects of quetiapine, SEROQUEL XR (quetiapine fumarate extended-release) should be used with caution in combination with other centrally acting drugs.

As it exhibits in vitro dopamine antagonism, SEROQUEL XR may antagonize the effects of levodopa and dopamine agonists.

SEROQUEL did not affect the single dose pharmacokinetics of lorazepam.

In a clinical study examining the pharmacokinetics of SEROQUEL following coadministration with cimetidine, (a non-specific P450 enzyme inhibitor), no clinically significant interaction was observed.

Quetiapine is extensively metabolized by the liver (see Action and Clinical Pharmacology, Special Populations and Conditions). Therefore, SEROQUEL XR should be used with caution in patients with mild hepatic impairment, especially during the initial dosing period. Patients with mild hepatic impairment should be started on the lowest available dose (i.e., 50 mg/day) of SEROQUEL XR. The dose should be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerance in the individual patient. No pharmacokinetic data are available for quetiapine in patients with moderate to severe hepatic impairment. However, should clinical judgement deem treatment with SEROQUEL XR necessary, the drug should be used with great caution in patients with moderate or severe hepatic impairment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic and Action and Clinical Pharmacology, Special Populations and Conditions).

As with other antipsychotics, SEROQUEL XR should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of SEROQUEL XR may need to be slower, and the daily therapeutic target dose lower, than that used in younger patients. In clinical trials, 68 patients, 65 years of age or over, were treated with SEROQUEL XR (see Warnings and Precautions, Special Populations). Given the limited experience with SEROQUEL XR in the elderly, and the higher incidence of concomitant illness and concomitant medication in this population, SEROQUEL XR should be used with caution. The mean plasma clearance of SEROQUEL was reduced by 30% to 50% in elderly subjects when compared to younger patients. Elderly patients should be started on the lowest available dose (i.e., 50 mg/day) of SEROQUEL XR. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerance of the individual patient.

In elderly patients with MDD, initial dosing should begin at 50 mg on Days 1-3, the dose can be increased to 100 mg on Day 4, and 150 mg on Day 8.

As clinical experience is lacking, caution is advised (see Warnings and Precautions, Renal).

For more convenient dosing, patients who are currently being treated with divided doses of SEROQUEL (quetiapine, immediate release formulation) may be switched to SEROQUEL XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

SEROQUEL XR (quetiapine fumarate extended-release) tablets should be swallowed whole and not split, chewed or crushed.

SEROQUEL XR can be administered with or without food (see Action and Clinical Pharmacology, Pharmacokinetics).

SEROQUEL XR should be administered once daily, generally in the evening.

For many antidepressants a gradual taper is recommended prior to complete discontinuation of the drug (physicians should refer to the approved Product Monograph of the specific antidepressant). There are no systematically collected data to address switching patients from other antidepressants to SEROQUEL XR. Generally there should be no need for a wash-out period between stopping an antidepressant and starting SEROQUEL XR. The physician may elect to initiate SEROQUEL XR treatment while tapering the antidepressant, however patients may experience additive side effects during the overlap period.

SEROQUEL XR should be taken at the same time each day. If a previous days dose has been missed, administration should be resumed the next day at the normal administration time.

SEROQUEL XR is indicated for the symptomatic relief of major depressive disorder (MDD) when currently available approved antidepressant drugs have failed either due to lack of efficacy and/or lack of tolerability. While there is no evidence that the efficacy of SEROQUEL XR is superior to other antidepressants, it provides a treatment option for patients who have failed on previous antidepressant treatments.

Clinicians must take into account the safety concerns associated with antipsychotic drugs, a class of drugs to which SEROQUEL XR belongs. Safety concerns of this class include: weight gain; hyperlipidemia; hyperglycaemia; Tardive Dyskinesia; and Neuroleptic Malignant Syndrome (see Warnings and Precautions). SEROQUEL XR should only be prescribed in patients with MDD by clinicians who are aware of the importance and are experienced in the early detection and management of the above-mentioned safety issues associated with this class.

The usual target dose is 150 mg. Some patients may respond to doses as low as 50 mg/day and where clinically indicated dose may be increased to 300 mg/day after Day 4. In clinical trials, doses between 50-300 mg/day were shown to be efficacious, however, the incidence of certain adverse events increased with dose (see Adverse Reactions).

In MDD, the safety of doses above 300 mg/day has not been evaluated.

Some of the safety concerns associated with SEROQUEL XR and this class of agents (i.e., antipsychotics), may be dose-related (see Warnings and Precautions, Adverse Reactions). The SEROQUEL XR dose should thus be periodically reassessed to achieve and maintain the lowest effective dose. Furthermore, as the long-term safety of SEROQUEL XR in MDD has not been systematically evaluated, the physician who elects to use SEROQUEL XR in the treatment of MDD should use SEROQUEL XR for the shortest time that is clinically indicated. When long-term treatment is believed to be indicated, the physician must periodically re-evaluate the long-term usefulness of the drug for the individual patient keeping in mind the long-term risks.

In short-term placebo-controlled clinical trials across all indications and ages, the incidence of suicide-related events (suicidal thoughts, self-harm and suicide) was 0.9% for both quetiapine (61/6270) and for placebo (27/3047).

In these trials of patients with schizophrenia the incidence of suicide-related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients 18-24 years of age, 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients ≥25 years of age.

In these trials of patients with bipolar mania the incidence of suicide-related events was 0% for both quetiapine (0/60) and placebo (0/58) in patients 18-24 years of age, 1.2% for both quetiapine (6/496) and placebo (6/503) in patients ≥25 years of age.

In these trials of patients with bipolar depression the incidence of suicide-related events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients 18-24 and 1.8% for both quetiapine (19/1616) and placebo (11/622) in patients ≥25 years of age. (See Warnings and Precautions.)

In these trials of patients with MDD the incidence of suicide related events was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo in patients 18-24 and 0.6% (11/1798) for quetiapine and 0.7% for placebo (7/1054) in patients ≥25 years of age.

In schizophrenia trials, 0.8% of SEROQUEL XR patients, and no placebo patients, had tachycardia (>120 bpm) at any time during the trials. In MDD monotherapy trials, 0.2% of SEROQUEL XR patients, and no placebo patients, had tachycardia (>120 bpm) at any time during the trials. SEROQUEL XR was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean decrease of 1 beat per minute for placebo. This is consistent with the rates of SEROQUEL.

This slight tendency to tachycardia may be related to the potential of SEROQUEL XR for inducing orthostatic changes (see Warnings and Precautions, Cardiovascular).

In acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms, the aggregated incidence of discontinuation symptoms after abrupt cessation was 12.1% for quetiapine and 6.7% for placebo. The aggregated incidence of the individual adverse events (e.g., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved 1 week after discontinuation. See Warnings and Precautions.

Somnolence may occur, usually during the first two weeks of treatment, which generally resolves with the continued administration of SEROQUEL XR.

In 6-week placebo-controlled schizophrenia clinical trials, for patients treated with SEROQUEL XR mean weight gain was 1.77 kg (n=951) compared to 2.19 kg (n=414) in patients treated with SEROQUEL (quetiapine, immediate release formulation). For patients treated with placebo the mean weight gain was 0.26 kg (n=319). In a 3-week placebo-controlled bipolar mania clinical trial, for patients treated with SEROQUEL XR mean weight gain was 1.3 kg (n=151) compared to 0.1 kg (n=160) in patients treated with placebo. In an 8-week placebo-controlled bipolar depression clinical trial, for patients treated with SEROQUEL XR mean weight gain was 1.3 kg (n=137) compared to −0.2 kg (n=140) in patients treated with placebo. In placebo-controlled MDD acute monotherapy clinical trials, for patients treated with SEROQUEL XR mean weight gain was 0.87 kg (n=1149) compared to 0.31 kg (n=648) in patients treated with placebo. In a longer-term randomized withdrawal MDD trial, patients who completed at least 158 days of SEROQUEL XR treatment (n=196), mean weight gain for patients in SEROQUEL XR 50, 150 and 300mg/day groups was 1.0 kg, 2.5 kg, and 3.0 kg respectively. In these same patients the percentage of patients experiencing a weight increase of ≥7% by 158 days in SEROQUEL XR 50, 150, and 300 mg/day groups was 13%, 24%, and 33% respectively. See Warnings and Precautions.

Based on the cumulative acute placebo-controlled clinical trial database, weight gain (based on ≥7% increase in body weight from baseline) was reported in 9.6% in quetiapine-treated patients and 3.8% in placebo-treated patients, which occurs predominantly during the early weeks of treatment in adults (see Warnings and Precautions).

As with other antipsychotics, common cases (≥1%-<10%) of peripheral edema have been reported in patients treated with quetiapine.

As with other antipsychotics, rare cases of neuroleptic malignant syndrome have been reported in patients treated with quetiapine (see Warnings and Precautions, Neurologic).

During acute therapy with SEROQUEL XR, the most commonly observed adverse events associated with the use of SEROQUEL XR (incidence of at least 5%, and an incidence at least 5% higher than that observed with placebo) were sedation, dry mouth, somnolence, constipation, dizziness, weight gain and dysarthria.

There have been common cases of increased appetite in patients administered quetiapine.

The most commonly observed adverse events associated with the use of SEROQUEL XR (incidence of at least 5%, and an incidence at least 5% higher than that observed with placebo) during acute monotherapy with SEROQUEL XR were dry mouth, sedation, somnolence dizziness and fatigue.

As with other antipsychotic agents, common cases of mild asthenia have been reported in patients treated with quetiapine.

During acute therapy with SEROQUEL XR, the most commonly observed adverse events associated with the use of SEROQUEL XR (incidence of at least 5%, and an incidence at least 5% higher than that observed with placebo) were dry mouth, somnolence, sedation, increased appetite, weight gain and dyspepsia.

During acute therapy with SEROQUEL XR, the most commonly observed adverse events associated with the use of SEROQUEL XR (incidence of at least 5%, and an incidence at least 5% higher than that observed with placebo) were sedation, dry mouth, somnolence, and dizziness.

There have been uncommon cases of dysphagia in patients administered quetiapine. In clinical trials, an increase in the rate of dysphagia with quetiapine versus placebo was only observed in bipolar depression.

During post-marketing experience, leucopenia and/or neutropenia have been reported during SEROQUEL treatment. Resolution of leucopenia and/or neutropenia has followed cessation of therapy with SEROQUEL. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count and history of drug-induced leucopenia and/or neutropenia. (See Warnings and Precautions, Hematologic.)

As with some other antipsychotics, hyperglycaemia and diabetes mellitus (including exacerbation of pre-existing diabetes, diabetic ketoacidosis, and diabetic coma including some fatal cases) in the aggregate have been reported rarely (≥0.01%-<0.1%) during the use of SEROQUEL, sometimes in patients with no reported history of hyperglycaemia. (See Warnings and Precautions, Endocrine and Metabolism.)

Anaphylactic reactions have been reported very rarely in post-marketing reports, including a case with a fatal outcome, possibly related to SEROQUEL treatment. The reporting rate of anaphylaxis associated with SEROQUEL use, which is generally accepted to be an underestimate due to underreporting, does not exceed the background incidence rate estimates. Estimates of the background incidence rate (all cause) of severe life-threatening anaphylaxis in the general population range between 80 and 210 cases per million person-years, and the incidence rate of drug-induced anaphylaxis is reported to be 16 cases per million person-years. In addition, the all cause fatal anaphylaxis rate is reported to be one per million person-years while the drug-induced fatal anaphylaxis is estimated to be 0.3 cases per million person-years. If a patient develops anaphylaxis after treatment with SEROQUEL XR, the drug should be discontinued and an alternative treatment started.

Based on post-marketing reports, galactorrhea has been reported rarely.

As with other antipsychotics, common cases of leucopenia and/or neutropenia have been observed in patients administered quetiapine. Uncommon cases of eosinophilia and thrombocytopenia (platelet count decreased, ≤100×10⁹/L on at least one occasion) have been observed.

Based on clinical trial adverse event reports not associated with neuroleptic malignant syndrome, rare cases of elevations in blood creatine phosphokinase have been reported in patients administered quetiapine.

Common cases of elevations in serum prolactin levels have been observed (>20 µg/L in males and >30 µg/L in females) (see Warnings and Precautions, Endocrine and Metabolism, Hyperprolactinemia).

In three-arm, SEROQUEL XR placebo-controlled monotherapy clinical trials, among patients with a baseline neutrophil count ≥1.5×10⁹/L, the incidence of at least one occurrence of neutrophil count <1.5×10⁹/L was 1.5% in patients treated with SEROQUEL XR and 1.5% for SEROQUEL, compared to 0.8% in placebo-treated patients.

In all placebo-controlled monotherapy clinical trials among patients with a baseline neutrophil count ≥1.5×10⁹/L, the incidence of at least one occurrence of neutrophil count <1.5×10⁹/L was 1.72% in patients treated with SEROQUEL, compared to 0.73% in placebo-treated patients. In clinical trials conducted prior to a protocol amendment for discontinuation of patients with treatment-emergent neutrophil count <1.0×10⁹/L, among patients with a baseline neutrophil count ≥1.5×10⁹/L, the incidence of at least one occurrence of neutrophil count <0.5×10⁹/L was 0.21% in patients treated with SEROQUEL and 0% in placebo-treated patients and the incidence ≥0.5-<1.0×10⁹/L was 0.75% in patients treated with SEROQUEL and 0.11% in placebo-treated patients. (See Warnings and Precautions, Hematologic.)

Common cases of asymptomatic elevations in serum transaminases [AST, ALT] or uncommon cases of γ-GT levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

SEROQUEL treatment was associated with small dose-related decreases in thyroid hormone levels, particularly total T₄ and free T₄. The reduction in total and free T₄ was maximal within the first 2 to 4 weeks of quetiapine treatment, with no further reduction during long-term treatment. There was no evidence of clinically significant changes in TSH concentration over time. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T₄, irrespective of the duration of treatment. Smaller decreases in total T₃ and reverse T₃ were seen only at higher doses. Levels of TBG were unchanged and in general reciprocal increases in TSH were not observed and there was no indication that SEROQUEL causes clinically relevant hypothyroidism (see Warnings and Precautions, Endocrine and Metabolism).

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The figures cited, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the populations studied.

There have been uncommon cases of restless legs syndrome in patients administered quetiapine.

There have been common reports of rhinitis in patients administered quetiapine.

There have been rare reports (≥0.01%-<0.1%) of priapism in patients administered quetiapine.

In three-arm, placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of SEROQUEL XR, the incidence of any adverse events potentially related to EPS was 7.5% for SEROQUEL XR, 7.7% for SEROQUEL, and 4.7% in the placebo group and without evidence of dose response. In these studies, the incidence rates of the individual adverse events (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) were generally low and did not exceed 3% for any treatment group.

At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups.

The incidence of EPS was consistent with that seen with the profile of SEROQUEL in schizophrenia patients. The incidence of EPS did not increase with the dose of SEROQUEL XR.

In short-term placebo-controlled clinical trials in schizophrenia and bipolar mania, the aggregated incidence of EPS-related adverse events was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). In short-term placebo-controlled clinical trials in bipolar depression, the aggregated incidence of EPS-related adverse events was 8.9% for quetiapine compared to 3.8% for placebo. The incidence of individual EPS-related adverse events (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity), however was generally low and did not exceed 4% for any individual adverse event. In short-term, placebo-controlled monotherapy clinical trials in MDD the aggregated incidence of EPS was 5.4% for SEROQUEL XR and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with MDD, the aggregated incidence of EPS was 9.0% for SEROQUEL XR and 2.3% for placebo. In long-term studies of schizophrenia, bipolar disorder and MDD the aggregated exposure adjusted incidence of treatment-emergent EPS was similar between quetiapine and placebo.

Adverse Events Reported for at Least 1% of SEROQUEL XR-Treated Subjects (Doses ranging from 50 to 300 mg/day) and for a Higher Percentage of SEROQUEL XR-Treated Subjects Than Subjects Who Received Placebo in a Short-Term, Placebo-Controlled Elderly MDD Monotherapy Phase III Trial

As with other antipsychotics with α1 adrenergic blocking activity, SEROQUEL XR may induce postural hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose titration period (see Warnings and Precautions, Cardiovascular). In placebo-controlled clinical trials in schizophrenia, postural hypotension was reported with an incidence of 8% in SEROQUEL (quetiapine, immediate release formulation)-treated patients compared to 2% in placebo-treated patients. SEROQUEL was associated with a mean baseline to endpoint increase in heart rate of 3.9 beats per minute, compared to 1.6 beats per minute among placebo-treated patients.

Uncommon cases of hypersensitivity including angioedema have been reported.

Blood glucose increases to hyperglycaemic levels (fasting blood glucose ≥7.0 mmol/L or a non fasting blood glucose ≥11.1 mmol/L on at least one occasion) have been observed commonly (≥1%-<10%) with quetiapine in clinical trials.

In two long-term bipolar maintenance placebo-controlled adjunct clinical trials, mean exposure 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the exposure-adjusted rate of any increased blood glucose level (≥7.0 mmol/L) for patients more than 8 hours since a meal was 18.0 per 100 patient years for SEROQUEL (10.7% of patients) and 9.5 for placebo per 100 patient-years (4.6% of patients).

In short-term (12 weeks duration or less) placebo-controlled clinical trials (3342 treated with quetiapine and 1490 treated with placebo), the percent of patients who had a fasting blood glucose ≥7.0 mmol/L or a non fasting blood glucose ≥11.1 mmol/L was 3.5% for quetiapine and 2.1% for placebo.

In a 24-week trial (active-controlled, 115 patients treated with SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥11.1 mmol/L was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥7.0 mmol/L was 2.6%. (See Warnings and Precautions, Endocrine and Metabolism.)

There have been common cases of abnormal dreams and nightmares in patients administered quetiapine.

Very common (≥10%) cases of elevations in serum triglyceride levels (≥2.258 mmol/L on at least one occasion) and elevations in total cholesterol (predominantly LDL cholesterol) (≥6.2064 mmol/L on at least one occasion) have been observed during treatment with quetiapine in clinical trials (see Warnings and Precautions, Cardiovascular). Lipid increases should be managed as clinically appropriate.

In one 24-week clinical trial, where LDL cholesterol was directly measured as opposed to calculated, there was a slight mean increase in total cholesterol in patients administered SEROQUEL, which was driven by increases in LDL cholesterol. The mean LDL level increased at Week 24 by 10% in patients administered SEROQUEL, which was statistically significant. The total cholesterol/HDL ratio did not change significantly during therapy with SEROQUEL. Furthermore, triglycerides did not increase significantly nor did HDL cholesterol decrease during therapy. (See Warnings and Precautions, Cardiovascular.)

There have been uncommon reports (≥0.1%-<1%) of seizures in patients administered quetiapine, although the frequency was no greater than that observed in patients administered placebo in controlled clinical trials (see Warnings and Precautions, Neurologic).

There have been common cases of irritability in patients administered quetiapine.

There have been uncommon cases of dysarthria in patients administered quetiapine.

The safety and efficacy of SEROQUEL XR in children under the age of 18 years have not been established.

SEROQUEL XR is not indicated in elderly patients with dementia. See Warnings and Precautions, Boxed Serious Warnings and Precautions and Special Populations.

SEROQUEL XR is indicated for the symptomatic relief of major depressive disorder (MDD) when currently available approved antidepressant drugs have failed either due to lack of efficacy and/or lack of tolerability. While there is no evidence that the efficacy of SEROQUEL XR is superior to other antidepressants, it provides a treatment option for patients who have failed on previous antidepressant treatments.

Clinicians must take into account the safety concerns associated with antipsychotic drugs, a class of drugs to which SEROQUEL XR belongs. Safety concerns of this class include: weight gain; hyperlipidemia; hyperglycaemia; Tardive Dyskinesia; and Neuroleptic Malignant Syndrome (see Warnings and Precautions). SEROQUEL XR should only be prescribed in patients with MDD by clinicians who are aware of the importance and are experienced in the early detection and management of the above-mentioned safety issues associated with this class.

Long-term safety of SEROQUEL XR in MDD has not been systematically evaluated. Thus, the physician who elects to use SEROQUEL XR in the treatment of MDD should use SEROQUEL XR for the shortest time that is clinically indicated. When lengthier treatment is indicated, the physician must periodically re-evaluate the long-term usefulness of the drug for the individual patient keeping in mind the long-term risks.

SEROQUEL XR (quetiapine fumarate extended-release) is indicated for the management of the manifestations of schizophrenia.

SEROQUEL XR is indicated as monotherapy for the:

• Acute management of manic episodes associated with bipolar disorder.

  
  

• Acute management of depressive episodes associated with bipolar I and bipolar II disorder.

In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects e.g., drowsiness and sedation, tachycardia and hypotension.

In post-marketing experience, there have been cases of coma and death in patients taking a SEROQUEL (quetiapine, immediate-release formulation) overdose. The lowest reported dose associated with coma has been in a patient who took 5000 mg and had a full recovery within 3 days. The lowest reported dose associated with a death was in a patient who took 6000 mg.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose (see Warnings and Precautions, Cardiovascular, Hypotension and Syncope).

One death has been reported in a clinical trial following an overdose of 13 600 mg of quetiapine alone, however, survival has also been reported in acute overdoses of up to 30 000 mg of quetiapine. Most patients who overdosed reported no adverse events or recovered fully from the reported events.

There is no specific antidote to quetiapine. In cases of severe intoxication, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

Close medical supervision and monitoring should be continued until the patient recovers.

Each pale yellow, capsule-shaped, biconvex, film-coated, extended-release tablet, intagliated with “XR 300” on one side and plain on the other, contains: quetiapine fumarate equivalent to quetiapine free base 300 mg. Nonmedicinal ingredients: tablet core: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate; coating: hydroxypropyl methylcellulose, polyethylene glycol 400, titanium dioxide and yellow ferric oxide. HDPE bottles of 60.

Each yellow, capsule-shaped, biconvex, film-coated, extended-release tablet, intagliated with “XR 200” on one side and plain on the other, contains: quetiapine fumarate equivalent to quetiapine free base 200 mg. Nonmedicinal ingredients: tablet core: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate; coating: hydroxypropyl methylcellulose, polyethylene glycol 400, titanium dioxide and yellow ferric oxide. HDPE bottles of 60.

Each peach coloured, capsule-shaped, biconvex, film-coated, extended-release tablet, intagliated with “XR 50” on one side and plain on the other, contains: quetiapine fumarate equivalent to quetiapine free base 50 mg. Nonmedicinal ingredients: tablet core: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate; coating: hydroxypropyl methylcellulose, polyethylene glycol 400, red ferric oxide, titanium dioxide and yellow ferric oxide. High-density polyethylene (HDPE) bottles of 60.

Each white, capsule-shaped, biconvex, film-coated, extended-release tablet, intagliated with “XR 400” on one side and plain on the other, contains: quetiapine fumarate equivalent to quetiapine free base 400 mg. Nonmedicinal ingredients: tablet core: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate; coating: hydroxypropyl methylcellulose, polyethylene glycol 400 and titanium dioxide. HDPE bottles of 60.

Each white, capsule-shaped, biconvex, film-coated, extended-release tablet, intagliated with ‘XR 150’ on one side and plain on the other, contains: quetiapine fumarate equivalent to quetiapine free base 150 mg. Nonmedicinal ingredients: tablet core: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate; coating: hydroxypropyl methylcellulose, polyethylene glycol 400 and titanium dioxide. HDPE bottles of 60.

There is little experience with SEROQUEL XR in patients with renal impairment, except in a low (subclinical) single dose study with SEROQUEL (see Action and Clinical Pharmacology, Special Populations and Conditions). SEROQUEL XR should thus be used with caution in patients with known renal impairment, especially during the initial dosing period (see Dosage and Administration).

Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) associated with SEROQUEL XR have been reported. The proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of placebo-controlled trials were approximately 1% for both SEROQUEL XR and placebo.

During premarketing clinical trials, therapy with SEROQUEL was associated with elevation of hepatic transaminases, primarily ALT. Within a clinical trial database of 1892 SEROQUEL-treated schizophrenia patients, with baseline ALT levels <60 IU/L, 5.3% (101/1892) had treatment-emergent ALT elevations to >120 IU/L, 1.5% (29/1892) had elevations to >200 IU/L, and 0.2% (3/1892) had elevations to >400 IU/L. No patients had values in excess of 800 IU/L. None of the SEROQUEL-treated patients who had elevated transaminase values manifested clinical symptomatology associated with liver impairment. The majority of transaminase elevations were seen during the first two months of treatment. Most elevations were transient (80%) while patients continued on SEROQUEL therapy. Of the 101 SEROQUEL-treated patients whose enzyme levels increased to >120 IU/L, 40 discontinued treatment while their ALT values were still raised. In 114 SEROQUEL-treated patients whose baseline ALT was >90 IU/L, only 1 experienced an elevation to >400 IU/L.

Precautions should be exercised when using SEROQUEL XR in patients with pre-existing hepatic disorders, in patients who are being treated with potentially hepatotoxic drugs, or if treatment-emergent signs or symptoms of hepatic impairment appear.

For patients who have known or suspected abnormal hepatic function prior to starting SEROQUEL XR, standard clinical assessment, including measurement of transaminase levels is recommended. Periodic clinical reassessment with transaminase levels is recommended for such patients, as well as for patients who develop any signs and symptoms suggestive of a new onset liver disorder during SEROQUEL XR therapy.

As with other drugs that have high α₁ adrenergic receptor blocking activity, SEROQUEL XR may induce orthostatic hypotension, dizziness and sometimes syncope, especially during the initial dose titration period. These events may lead to falls.

In placebo-controlled SEROQUEL XR trials, there was little difference in the adverse reaction reporting rate of syncope in patients treated with SEROQUEL XR (0.5%, 11/2388) compared to patients on placebo (0.3%, 4/1267).

Syncope was reported in 1% (35/4083) of patients treated with SEROQUEL (quetiapine, immediate release formulation), compared with 0.3% (3/1006) on placebo and 0.4% (2/527) on active control drugs.

SEROQUEL XR should be used with caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or other conditions predisposing to hypotension (e.g., dehydration, hypovolemia and treatment with antihypertensive medications) (see Overdosage).

During clinical trials with quetiapine, elevation in prolactin levels occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo (see Adverse Reactions).

Increased prolactin levels with quetiapine were observed in rat studies. As is common with compounds which stimulate prolactin release, the administration of quetiapine resulted in an increase in the incidence of mammary neoplasms in rats. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear. To date, neither clinical nor epidemiological studies have shown an association between chronic administration of drugs that stimulate prolactin release, and mammary tumourigenesis. Tissue culture experiments, however, indicate that approximately one third of human breast cancers are prolactin dependent in vitro; a factor of potential importance if prescription of these drugs is contemplated in a patient with previously detected breast cancer.

Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea, and menorrhagia.

In the multiple fixed-dose schizophrenia clinical trial there were no differences in prolactin levels at study completion for SEROQUEL, across the recommended dose range, and placebo.

Acute discontinuation symptoms, such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability have been described after abrupt cessation of antipsychotic drugs, including SEROQUEL XR. Gradual withdrawal over a period of at least one to two weeks is advisable. Symptoms usually resolved after 1 week post-discontinuation. See Adverse Reactions.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with SEROQUEL XR. The safety and efficacy of SEROQUEL XR during human pregnancy have not been established. Therefore, SEROQUEL XR should only be used during pregnancy if the expected benefits justify the potential risks.

In 6-week placebo-controlled schizophrenia clinical trials, for patients treated with SEROQUEL XR mean weight gain was 1.77 kg (n=951) compared to 2.19 kg (n=414) in patients treated with SEROQUEL. For patients treated with placebo the mean weight gain was 0.26 kg (n=319). In a 3-week placebo-controlled bipolar mania clinical trial, for patients treated with SEROQUEL XR mean weight gain was 1.3 kg (n=151) compared to 0.1 kg (n=160) in patients treated with placebo. In an 8-week placebo-controlled bipolar depression clinical trial, for patients treated with SEROQUEL XR mean weight gain was 1.3 kg (n=137) compared to −0.2 kg (n=140) in patients treated with placebo. In 6-week placebo-controlled MDD acute monotherapy clinical trials, for patients treated with SEROQUEL XR mean weight gain was 0.87 kg (n=1149) compared to 0.31 kg (n=648) in patients treated with placebo. In a longer-term randomized withdrawal MDD trial, patients who completed at least 158 days of SEROQUEL XR treatment (n=196), mean weight gain for patients in SEROQUEL XR 50, 150 and 300 mg/day groups was 1.0 kg, 2.5 kg, and 3.0 kg respectively. In these same patients the percentage of patients experiencing a weight increase of ≥7% by 158 days in SEROQUEL XR 50, 150, and 300 mg/day groups was 13%, 24%, and 33% respectively.

Based on the cumulative acute placebo-controlled clinical trial database, weight gain (based on ≥7% increase in body weight from baseline) was reported in 9.6% in quetiapine-treated patients and 3.8% in placebo-treated patients, which occurs predominantly during the early weeks of treatment in adults (see Adverse Reactions).

Consistent with its dopamine antagonist effects, SEROQUEL XR may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage of other drugs, or may mask symptoms of disease such as brain tumour or intestinal obstruction.

Depressive episodes are associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission of depression occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. In addition to depressive episodes associated with bipolar disorder and MDD, depression may be co-morbid with schizophrenia.

Schizophrenia as well as manic episodes associated bipolar disorder, can also be associated with an increased risk of suicide-related events, and thus close supervision and appropriate clinical management of high risk patients should accompany drug therapy.

Patients with a history of suicide-related events are also known to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

In a bipolar mania clinical trial with SEROQUEL XR, the incidence of treatment-emergent suicidal ideation or suicidal behaviour, as measured by the Columbia Analysis of Suicidal Behaviour, was 1.3% for SEROQUEL XR-treated patients and 3.8% for placebo-treated patients.

In a bipolar depression clinical trial with SEROQUEL XR, the incidence of treatment-emergent suicidal ideation or suicidal behaviour, as measured by the Columbia Analysis of Suicidal Behaviour, was 0.7% for SEROQUEL XR-treated patients and 1.4% for placebo-treated patients.

In MDD acute clinical trials, the incidence of treatment emergent suicidal ideation or suicide attempt was 0.7% in SEROQUEL XR treated patients and 0.7% in placebo-treated patients. In a longer-term randomized withdrawal study in patients with MDD, the incidence during randomized treatment was 0.3% for SEROQUEL XR and 0.5% for placebo.

Somnolence was a very commonly reported adverse event in patients treated with SEROQUEL XR, especially during the initial dose titration period. Since SEROQUEL XR may cause sedation and impair motor skill, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are reasonably certain that therapy with SEROQUEL XR does not affect them adversely. Somnolence may lead to falls.

The safety and efficacy of SEROQUEL XR in children under the age of 18 years have not been established.

As with some other antipsychotics, hyperglycaemia and diabetes mellitus (including exacerbation of pre-existing diabetes, diabetic ketoacidosis, and diabetic coma including some fatal cases) in the aggregate have been reported rarely (≥0.01%-<0.1%) during the use of quetiapine in post-marketing experience, sometimes in patients with no reported history of hyperglycaemia (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Blood glucose increases to hyperglycaemic levels (fasting blood glucose ≥7.0 mmol/L or a non fasting blood glucose ≥11.1 mmol/L on at least one occasion) have been observed commonly (≥1%-<10%) with quetiapine in clinical trials. Occasional reports of diabetes have also been observed in clinical trials with quetiapine (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings).

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Severe neutropenia (<0.5×10⁹/L) has been uncommonly reported in quetiapine clinical trials. There was no apparent dose relationship. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count (WBC) and history of drug induced leucopenia and/or neutropenia. SEROQUEL XR should be discontinued in patients with a neutrophil count <1.0×10⁹/L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5×10⁹/L). (See Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings and Post-Market Adverse Drug Reactions.)

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. SEROQUEL XR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Neuroleptic Malignant Syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including SEROQUEL XR.

The clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system pathology.

The management of NMS should include immediate discontinuation of antipsychotic drugs, including SEROQUEL XR, and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

Decreased clearance of SEROQUEL was observed in patients with mild hepatic impairment (see Action and Clinical Pharmacology, Special Populations and Conditions). No pharmacokinetic data are available for quetiapine in patients with moderate or severe hepatic impairment. However, should clinical judgement deem treatment with SEROQUEL XR necessary, the drug should be used with great caution in patients with moderate or severe hepatic impairment (see Action and Clinical Pharmacology, Special Populations and Conditions and Dosage and Administration).

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing SEROQUEL XR (quetiapine fumarate extended-release) for patients who will be experiencing conditions which may contribute to an elevation of core temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.

Elderly patients with dementia treated with atypical antipsychotic drugs showed increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. In two placebo-controlled trials with oral SEROQUEL in this population, the incidence of mortality was 5.5% for SEROQUEL-treated patients compared to 3.2% for placebo-treated patients. SEROQUEL XR is not indicated in elderly patients with dementia.

The number of patients 65 years of age or over exposed to SEROQUEL XR during clinical trials was limited (n=68). When compared to younger patients the mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly subjects. In addition, as this population has more frequent hepatic, renal, central nervous system, and cardiovascular dysfunctions, and more frequent use of concomitant medication, caution should be exercised with the use of SEROQUEL XR in the elderly patient (see Dosage and Administration).

In a clinical trial that evaluated non-demented elderly patients (aged 66 to 89 years) with MDD, the tolerability of SEROQUEL XR once daily was comparable to that seen in adults (aged 18-65 years) other than the incidence of extrapyramidal symptoms. See Warnings and Precautions, Neurologic, Tardive Dyskinesia (TD) and Extrapyramidal Symptoms (EPS); Adverse Reactions.

The development of cataracts was observed in association with quetiapine treatment in chronic dog studies at 4 times the recommended human dose. Lens changes have also been observed in patients during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established. The possibility of lenticular changes during long-term use of SEROQUEL XR in man, thus can not be excluded at this time. Eye examinations (e.g., slit lamp exam) prior to or shortly after initiation of treatment with SEROQUEL XR and at 6 month intervals thereafter, are recommended. If clinically significant lens changes associated with SEROQUEL XR use are observed, discontinuation of SEROQUEL XR should be considered.

Very common (≥10%) cases of elevations in serum triglyceride levels (≥2.258 mmol/L on at least one occasion) and elevations in total cholesterol (predominantly LDL cholesterol) (≥6.2064 mmol/L on at least one occasion) have been observed during treatment with quetiapine in clinical trials (see Adverse Reactions). Lipid increases should be managed as clinically appropriate.

In schizophrenia clinical trials, SEROQUEL XR-treated patients had increases from baseline in mean cholesterol and triglycerides of 4% and 14%, respectively, compared to decreases from baseline in mean cholesterol and triglycerides of 2% and 6% for placebo-treated patients. In a 3-week bipolar mania clinical trial, SEROQUEL XR-treated patients had increases from baseline in mean cholesterol and triglycerides of 2% and 20%, respectively, compared to decreases in mean cholesterol and triglycerides of 2% and 5% for placebo-treated patients. In a bipolar depression clinical trial, SEROQUEL XR-treated patients had decreases from baseline in mean cholesterol and increases from baseline in mean triglycerides of 2% and 11%, respectively, compared to decreases in mean cholesterol and triglycerides of 3% and 2% for placebo-treated patients. In 6-week MDD monotherapy clinical trials, SEROQUEL XR treated patients had increases from baseline in mean triglycerides of 8%, compared to a mean decrease of 1% for placebo-treated patients. In the same trials, both SEROQUEL XR- and placebo-treated patients had decreases from baseline in mean cholesterol of 1% and 3%, respectively. In a longer-term randomized withdrawal MDD trial, patients who completed at least 158 days of SEROQUEL XR treatment (n=196), showed mean increases from baseline in triglycerides of approximately 5% and mean decreases from baseline in cholesterol of approximately 4%.

In controlled clinical trials with SEROQUEL XR, there was no difference in the incidence of seizures in patients treated with SEROQUEL XR (0.04%, 1/2388) or placebo (0.2%, 3/1267). Nevertheless, as with other antipsychotics, caution is recommended when treating patients with a history of seizures or with conditions associated with a lowered seizure threshold (see Adverse Reactions).

Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon estimates to predict which patients are likely to develop the syndrome.

In short-term placebo-controlled clinical trials in schizophrenia and bipolar mania, the aggregated incidence of EPS-related adverse events was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). In short-term placebo-controlled clinical trials in bipolar depression, the aggregated incidence of EPS-related adverse events was 8.9% for quetiapine compared to 3.8% for placebo. The incidence of individual EPS-related adverse events (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity), however was generally low and did not exceed 4% for any individual adverse event. In short-term, placebo-controlled monotherapy clinical trials in MDD the aggregated incidence of EPS was 5.4% for SEROQUEL XR and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with MDD, the aggregated incidence of EPS was 9.0% for SEROQUEL XR and 2.3% for placebo. In long-term studies of schizophrenia, bipolar disorder, and MDD the aggregated exposure adjusted incidence of treatment-emergent EPS was similar between quetiapine and placebo.

The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, SEROQUEL XR should be prescribed in a manner that is most likely to minimize the occurrence of TD. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that is known to respond to antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of TD appear in a patient on SEROQUEL XR, drug discontinuation should be considered. However, some patients may require treatment with SEROQUEL XR despite the presence of the syndrome.

In SEROQUEL XR clinical trials, 0.2% (4/1755) of patients on SEROQUEL XR compared to 0% (0/796) on placebo experienced decreased free thyroxine and 2.7% (46/1716) on SEROQUEL XR compared to 1.4% (11/785) on placebo experienced increased TSH; however, no patients experienced a combination of clinically significant decreased free thyroxine and increased TSH. In schizophrenia trials, no patients had events of hypothyroidism.

In clinical trials, on average SEROQUEL was associated with about a 20% mean reduction in thyroxine levels (both total and free). Forty-two percent of SEROQUEL-treated patients showed at least a 30% reduction in total T₄ and 7% showed at least a 50% reduction. Maximum reduction of thyroxine levels generally occurred during the first two to four weeks of treatment with SEROQUEL. These reductions were maintained without adaptation or progression during longer term treatment. Decreases in T₄ were not associated with systematic changes in TSH or clinical signs or symptoms of hypothyroidism. Approximately 0.4% (12/2595) of patients treated with SEROQUEL experienced persistent increases in TSH, and 0.25% of patients were treated with thyroid replacement.

The degree to which quetiapine is excreted into human milk is unknown. Women who are breast-feeding should therefore be advised to avoid breast-feeding while taking SEROQUEL XR.

In 8 cirrhotic subjects with mild hepatic impairment, administration of a single 25 mg (sub-clinical) oral dose of SEROQUEL resulted in a 40% increase in both AUC and C_max. Clearance of the drug decreased by 25% whereas t_½ was elevated by nearly 45%. Therefore, SEROQUEL XR should be used with caution in patients with mild hepatic impairment, especially during the initial dosing period. No pharmacokinetic data are available for quetiapine in patients with moderate or severe hepatic impairment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic and Dosage and Administration).

Quetiapine has a mean apparent volume of distribution of 10±4 L/kg, and is approximately 83% bound to plasma proteins.

The pharmacokinetics of quetiapine and norquetiapine are linear within the clinical dose range. The kinetics of quetiapine are similar in men and women, and smokers and non-smokers.

SEROQUEL XR (quetiapine fumarate extended-release), a dibenzothiazepine derivative, is a psychotropic agent. Quetiapine and the active plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. It is the direct and indirect effects of quetiapine and norquetiapine that contribute to the pharmacological activity of SEROQUEL XR.

Quetiapine is well absorbed following oral administration. SEROQUEL XR achieves peak plasma concentrations at approximately 6 hours after administration (T_max). SEROQUEL XR displays dose-proportional pharmacokinetics for doses of up to 800 mg administered once daily. The maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) for SEROQUEL XR administered once daily are comparable to those achieved for the same total daily dose of SEROQUEL (quetiapine, immediate-release formulation) administered twice daily. The mean plasma concentrations for each dose of SEROQUEL XR versus 300 mg of SEROQUEL (quetiapine fumarate immediate-release) over a 24-hour dosing interval under fasting conditions are shown in Figure 1. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.

Quetiapine exhibits affinity for brain serotonin 5HT₂ and 5HT_1A receptors (in vitro, Ki=288 and 557 nM, respectively), and dopamine D₁ and D₂ receptors (in vitro, Ki=558 and 531 nM, respectively). It is this combination of receptor antagonism with a higher selectivity for 5HT₂ relative to D₂ receptors, which is believed to contribute to the clinical psychotropic properties and low extrapyramidal symptoms (EPS) liability of quetiapine. Quetiapine also has high affinity for histamine H₁ receptors (in vitro, Ki=10 nM) and adrenergic α₁ receptors (in vitro, Ki=13 nM), with a lower affinity for adrenergic α₂ receptors (in vitro, Ki=782 nM), but no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors.

At single low (sub-clinical) doses, the mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²). However, the individual clearance values remained within the range observed for healthy subjects (see Warnings and Precautions, Renal and Dosage and Administration).

In a study (n=10) examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the SEROQUEL XR C_max and AUC of 44% to 52% and 20% to 22%, respectively, for the 50-mg and 300-mg tablets. In comparison, a light meal had no significant effect on the C_max or AUC of quetiapine. This increase in exposure is not clinically significant, and therefore SEROQUEL XR can be taken with or without food.

Norquetiapine, similar to quetiapine, exhibits affinity for brain serotonin 5HT₂ and dopamine D₁ and D₂ receptors. Norquetiapine also has high affinity at histaminergic and adrenergic α1 receptors, with a lower affinity at adrenergic α2 and serotonin 5HT_1A receptors. Additionally norquetiapine has high affinity for the norepinephrine transporter (NET).

Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M₁ receptors whereas norquetiapine has high affinity.

The elimination half-life of quetiapine is approximately 6-7 hours upon multiple dosing within the proposed clinical dosage range. Quetiapine is extensively metabolized by the liver, with the parent compound accounting for less than 5% of the dose in the urine and faeces, one week following the administration of radiolabelled quetiapine. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed in these patients. The elimination half-life of norquetiapine is approximately 12 hours. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.

Major routes of metabolism of quetiapine involve oxidation of the alkyl side chain, hydroxylation of the dibenzothiazepine ring, sulphoxidation, and phase 2 conjugation. The principal human plasma metabolites are the sulfoxide, and the parent acid metabolite, neither of which are pharmacologically active.

In vitro investigations established that CYP 3A4 is the primary enzyme responsible for cytochrome P450-mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.

Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans.

The mean clearance of quetiapine in the elderly is approximately 30 to 50% of that seen in adults aged 18-65 years (see Warnings and Precautions, Special Populations and Dosage and Administration).