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Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with SEROQUEL especially during the 3-5 day period of initial dose-titration. In the 3-to 6-week placebo-controlled trials, somnolence was reported in 18% of patients on SEROQUEL compared to 11% of placebo patients. Since SEROQUEL has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are
reasonably certain that SEROQUEL therapy does not affect them adversely. Priapism Text Continues Below
One case of priapism in a patient receiving SEROQUEL has been reported prior to market introduction. While a causal relationship to use of SEROQUEL has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that SEROQUEL may share this capacity. Severe priapism may require surgical intervention. Body Temperature Regulation Although not reported with SEROQUEL, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing SEROQUEL for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e. g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. Dysphagia 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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Suicide The possibility of a suicide attempt is inherent in schizophrenia and close supervision of high risk patients should accompany drug therapy. Prescriptions for SEROQUEL should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Use in Patients with Concomitant Illness Clinical experience with SEROQUEL in patients with certain concomitant systemic illnesses (see Renal Impairment and Hepatic Impairment under CLINICAL PHARMACOLOGY, Special Populations) is limited. SEROQUEL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with SEROQUEL, caution should be observed in cardiac patients (see Orthostatic Hypotension). Drug Interactions The risks of using SEROQUEL in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of SEROQUEL, caution should be used when it is taken in combination with other centrally acting drugs. SEROQUEL potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be avoided while taking SEROQUEL. Because of its potential for inducing hypotension, SEROQUEL may enhance the effects of certain antihypertensive agents. SEROQUEL may antagonize the effects of levodopa and dopamine agonists. The Effect of Other Drugs on SEROQUEL Phenytoin: Coadministration of quetiapine (250 mg tid) and
phenytoin (100 mg tid) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of SEROQUEL may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e. g., carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e. g., valproate) (see DOSAGE AND ADMINISTRATION). 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 is indicated when SEROQUEL is administered with ketoconazole and other inhibitors of cytochrome P450 3A (e. g., itraconazole, fluconazole, and erythromycin).
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.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/ kg and to rats by gavage at doses of 25, 75, and 250 mg/ kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (800 mg/ day) on a mg/ m 2 basis (mice) or 0.3, 0.9, and 3.0 times the maximum human dose on a mg/ m 2 basis (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses of 250 and 750 mg/ kg or 1.5 and 4.5 times the maximum human dose on a mg/ m 2 basis and in male rats at a dose of 250 mg/ kg or 3.0 times the maximum human dose on a mg/ m 2 basis. Mammary gland denocarcinomas were statistically significantly increased in female rats at all doses tested (25, 75, and 250 mg/ kg or 0.3, 0. 9, and 3.0 times the maximum recommended human dose on a mg/ m 2 basis). Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-yr toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32-and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown (see Hyperprolactinemia in PRECAUTIONS, General). Mutagenesis The mutagenic potential of quetiapine was tested in six in vitro bacterial gene mutation assays and in an in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. However, sufficiently high concentrations of quetiapine may not have been used for all tester strains. Quetiapine did produce a reproducible increase in mutations in one Salmonella typhimurium tester strain in the presence of metabolic activation. No evidence of clastogenic potential was obtained in an in vitro chromosomal
aberration assay in cultured human lymphocytes or in the in vivo micronucleus assay in rats. Impairment of Fertility Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/ kg or 0.6 and 1.8 times the maximum human dose on a mg/ m 2 basis. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 150 mg/ kg even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/ kg, or 0.3 times the maximum human dose on a mg/ m 2 basis. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose of 50 mg/ kg, or 0.6 times the maximum human dose on a mg/ m 2 basis. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/ kg, or 0.1 and 0.6 times the maximum human dose on a mg/ m 2 basis. The no-effect dose in female rats was 1 mg/ kg, or 0.01 times the maximum human dose on a mg/ m 2 basis. Pregnancy Pregnancy Category C
The teratogenic potential of quetiapine was studied in Wistar rats and Dutch Belted rabbits dosed during the period of organogenesis. No evidence of a teratogenic effect was detected in rats at doses of 25 to 200 mg/ kg or 0.3 to 2.4 times the maximum human dose on a mg/ m 2 basis or in rabbits at 25 to 100 mg/ kg or 0.6 to 2.4 times the maximum human dose on a mg/ m 2 basis. There was, however, evidence of embryo/ fetal toxicity. Delays in skeletal ossification were detected in rat fetuses at doses of 50 and 200 mg/ kg (0.6 and 2.4 times the maximum human dose on a mg/ m 2 basis) and in rabbits at 50 and 100 mg/ kg (1.2 and 2.4 times the maximum human dose on a mg/ m 2 basis). Fetal body weight was reduced in rat fetuses at 200 mg/ kg and rabbit fetuses at 100 mg/ kg (2.4 times the maximum human dose on a mg/ m 2 basis for both species). There was an increased incidence of a minor soft tissue anomaly (carpal/ tarsal flexure) in rabbit fetuses at a dose of 100 mg/ kg (2.4 times the maximum human dose on a mg/ m 2 basis). Evidence of maternal toxicity (i. e., decreases in body weight gain and/ or death) was observed at the high dose in the rat study and at all doses in the rabbit study. In a peri/ postnatal reproductive study in rats, no drug-related effects were observed at doses of 1, 10, and 20 mg/ kg or 0.01, 0.12, and 0.24 times the maximum human dose on a mg/ m 2 basis. However, in a preliminary peri/ postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 150 mg/ kg, or 3.0 times the maximum human dose on a mg/ m 2 basis. There are no adequate and well-controlled studies in pregnant women and quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of SEROQUEL on labor and delivery in humans is unknown. Nursing Mothers SEROQUEL was excreted in milk of treated animals during lactation. It is not known if SEROQUEL is excreted in human milk. It is recommended that women receiving SEROQUEL should not breast feed. Pediatric Use The safety and effectiveness of SEROQUEL in pediatric patients have not been established. Geriatric Use Of the approximately 2400 patients in clinical studies with SEROQUEL, 8% (190) were 65 years of age or over. In general, there was no indication of any different tolerability of SEROQUEL in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to SEROQUEL, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of SEROQUEL was reduced by 30% to 50% in elderly patients when compared to younger patients (see Pharmacokinetics under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Page: << Prev | 1 | 2 | 3 | 4 | 5
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