Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The information below is derived from a clinical trial database for SEROQUEL XR consisting of 951 patients exposed to SEROQUEL XR for the treatment of schizophrenia in placebo controlled trials. This experience corresponds to approximately 82.9 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses, and ECG results.

Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and tabulations that follow, standard MedDRA terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials There was no difference in the incidence and type of adverse reactions associated with discontinuation (6.4% for SEROQUEL XR vs. 7.5% for placebo) in a pool of controlled trials.

Adverse Reactions Occurring at an Incidence of 5% or More Among SEROQUEL XR Treated Patients in Short- Term, Placebo-Controlled Trials

Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in ≥ 5% patients treated with SEROQUEL XR (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 1. Treatment-Emergent Adverse Experience Incidence in 6-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia

In these studies, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were dry mouth (12%), somnolence (12%), dizziness (10%), and dyspepsia (5%).

Adverse Reactions that occurred in < 5% of patients and were considered drug-related (incidence greater than placebo and consistent with known pharmacology of drug class) in order of decreasing frequency: heart rate increased, hypotension, weight increased, tremor, akathisia, increased appetite, blurred vision, postural dizziness, pyrexia, dysarthria, dystonia, drooling, syncope, tardive dyskinesia, dysphagia, leukopenia, and rash.

Adverse Reactions that have historically been associated with the use of SEROQUEL and not listed elsewhere in the label

The following adverse reactions have also been reported with SEROQUEL: anaphylactic reaction, peripheral edema, rhinitis, eosinophilia, hypersensitivity, elevations in gamma- GT levels and restless legs syndrome.

Extrapyramidal Symptoms

Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat emergent EPS.

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 reactions potentially related to EPS was 8% for SEROQUEL XR and 8% for SEROQUEL (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was 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 extrapyramidal symptoms was consistent with that seen with the profile of SEROQUEL in schizophrenia patients.

Vital Signs and Laboratory Studies Vital Sign Changes

Quetiapine is associated with orthostatic hypotension [see WARNINGS and PRECAUTIONS].

Weight Gain

In schizophrenia trials with SEROQUEL XR, the proportions of patients meeting a weight gain criterion of ≥ 7% of body weight was 10% for SEROQUEL XR compared to 5% for placebo. In schizophrenia trials the proportions of patients meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significant greater incidence of weight gain for SEROQUEL (23%) compared to placebo (6%).

Laboratory Changes

An assessment of the premarketing experience for SEROQUEL suggested that it is associated with asymptomatic increases in ALT and increases in both total cholesterol and triglycerides [see WARNINGS and PRECAUTIONS]. In post- marketing clinical trials, elevations in total cholesterol (predominantly LDL cholesterol) have been observed.

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

Hyperglycemia

In 2 long-term placebo-controlled 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 ( ≥ 126 mg/dl) 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 patients treated with SEROQUEL and 1490 treated with placebo), the percent of patients who had a fasting blood glucose ≥ 126 mg/dl or a non fasting blood glucose ≥ 200 mg/dl 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 ≥ 200 mg/dl was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dl was 2.6%.

ECG Changes

0.8% 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. The incidence of adverse reactions of tachycardia was 3% for SEROQUEL XR compared to 1% for placebo. SEROQUEL use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. The slight tendency for tachycardia may be related to quetiapine's potential for inducing orthostatic changes [see WARNINGS and PRECAUTIONS].

Post Marketing Experience

The following adverse reactions where identified during post approval use of SEROQUEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction which were temporally related to SEROQUEL therapy include: anaphylactic reaction, restless legs, and leukopenia/neutropenia. If a patient develops a low white cell count consider discontinuation of therapy. Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count and history of drug induced leukopenia/neutropenia.

Other adverse reactions reported since market introduction, which were temporally related to SEROQUEL therapy, but not necessarily causally related, include the following: agranulocytosis, cardiomyopathy hyponatremia, myocarditis rhabdomyolysis, syndrome of inappropriate antidiuretic

hormone secretion (SIADH), and Stevens-Johnson syndrome (SJS).

The risks of using SEROQUEL XR in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of SEROQUEL XR, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.

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

SEROQUEL XR may antagonize the effects of levodopa and dopamine agonists.

The Effect of Other Drugs on Quetiapine

Phenytoin

Coadministration of quetiapine (250 mg three times/day) and phenytoin (100 mg three times /day) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of SEROQUEL XR may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (eg, carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (eg, valproate) [see DOSAGE AND ADMINISTRATION].

Divalproex

Coadministration of quetiapine (150 mg bid) and divalproex (500 mg bid) increased the mean maximum plasma concentration of quetiapine at steady-state by 17% without affecting the extent of absorption or mean oral clearance.

Thioridazine

Thioridazine (200 mg bid) increased the oral clearance of quetiapine (300 mg bid) by 65%.

Cimetidine

Administration of multiple daily doses of cimetidine (400 mg tid for 4 days) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg tid). Dosage adjustment for quetiapine is not required when it is given with cimetidine.

P450 3A Inhibitors

Coadministration of ketoconazole (200 mg once daily for 4 days), a potent inhibitor of cytochrome P450 3A, reduced oral clearance of quetiapine by 84%, resulting in a 335% increase in maximum plasma concentration of quetiapine. Caution (reduced dosage) is indicated when SEROQUEL XR is administered with ketoconazole and other inhibitors of cytochrome P450 3A (eg, itraconazole, fluconazole, erythromycin , protease inhibitors).

Fluoxetine, Imipramine, Haloperidol, and Risperidone

Coadministration of fluoxetine (60 mg once daily); imipramine (75 mg bid), haloperidol (7.5 mg bid), or risperidone (3 mg bid) with quetiapine (300 mg bid) did not alter the steady-state pharmacokinetics of quetiapine.

Effect of Quetiapine on Other Drugs

Lorazepam

The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg tid dosing.

Divalproex

The mean maximum concentration and extent of absorption of total and free valproic acid at steady-state were decreased by 10 to 12% when divalproex (500 mg bid) was administered with quetiapine (150 mg bid). The mean oral clearance of total valproic acid (administered as divalproex 500 mg bid) was increased by 11% in the presence of quetiapine (150 mg bid). The changes were not significant.

Lithium

Concomitant administration of quetiapine (250 mg tid) with lithium had no effect on any of the steady-state pharmacokinetic parameters of lithium.

Antipyrine

Administration of multiple daily doses up to 750 mg/day (on a tid schedule) of quetiapine to subjects with selected psychotic disorders had no clinically relevant effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. These results indicate that quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine.

Drug Abuse And Dependence

Controlled Substance

SEROQUEL XR is not a controlled substance.

Abuse

SEROQUEL XR has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of SEROQUEL XR, (eg, development of tolerance, increases in dose, drug-seeking behaviour).

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