Seroquel (Quetiapine Fumarate)

Seroquel Tablets (AstraZeneca)

DESCRIPTION

SEROQUEL (quetiapine fumarate) is an antipsychotic drug belonging to a new chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C 42 H 50 N 6 O 4 S 2 C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:

Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.

SEROQUEL is supplied for oral administration as 25 mg (peach), 100 mg (yellow) and 200 mg (white) tablets.

Inactive ingredients are povidone, dibasic dicalcium phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide.

The 25 mg tablets contain red ferric oxide and yellow ferric oxide and the 100 mg tablets contain only yellow ferric oxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

SEROQUEL is an antagonist at multiple neurotransmitter receptors in the brain; serotonin 5HT 1A and 5HT 2 (IC 50s =717 & 148nM respectively), dopamine D 1 and D 2 (IC 50s = 1268 & 329nM respectively), histamine H 1 (IC 50 =30nM), and adrenergic (alpha) 1 and (alpha) 2 receptors (IC 50s =94 & 271nM, respectively). SEROQUEL has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC 50s >5000 nM).

The mechanism of action of SEROQUEL, as with other antipsychotic drugs, is unknown. However, it has been proposed that this drug’ antipsychotic activity is mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5-HT 2 ) antagonism. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other effects of SEROQUEL.

SEROQUEL’S antagonism of histamine H 1 receptors may explain the somnolence observed with this drug.

SEROQUEL’S antagonism of adrenergic (alpha) 1 receptors may explain the orthostatic hypotension observed with this drug.

Pharmacokinetics

Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

Absorption: Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C max and AUC values increased by 25% and 15%, respectively.

Distribution: Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.

Metabolism and Elimination: Following a single oral dose of 14 C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose and was recovered in the urine and feces, respectively.

Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite.

Population Subgroups

Age: Oral clearance of quetiapine was reduced by 40% in elderly patients (>/= 65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary (See DOSAGE AND ADMINISTRATION ).

Gender: There is no gender effect on the pharmacokinetics of quetiapine.

Race: There is no race effect on the pharmacokinetics of quetiapine.

Smoking: Smoking has no effect on the oral clearance of quetiapine.

Renal Insufficiency: Patients with severe renal impairment (Clcr=10-30 mL/min/1.73 m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 80 mL/min/1.73 m 2 , n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.

Hepatic Insufficiency: Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In two of the 8 hepatically impaired patients, AUC and C max were 3-times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed. (See DOSAGE AND ADMINISTRATION ).

Drug-Drug Interactions: In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6, and 3A4.Quetiapine oral clearance is increased by the prototype cytochrome P450 3A4 inducer, phenytoin, and decreased by the prototype cytochrome P450 3A4 inhibitor, ketoconazole. Dose adjustment of quetiapine will be necessary if it is coadministered with phenytoin or ketoconazole. (See DRUG INTERACTIONS under PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Quetiapine oral clearance is not inhibited by the non-specific enzyme inhibitor, cimetidine.

Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium, or lorazepam. (See DRUG INTERACTIONS under PRECAUTIONS ).

Clinical Efficacy Data

The efficacy of SEROQUEL in the management of the manifestations of psychotic disorders was established in 3 short-term (6-week) controlled trials of psychotic inpatients who met DSM III-R criteria for schizophrenia. Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of SEROQUEL and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in psychosis. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS), a more recently developed but less well evaluated scale, was employed for assessing negative symptoms.

The results of the trials follow:

1. In a 6-week, placebo-controlled trial (n=361) involving 5 fixed doses of SEROQUEL (75, 150, 300, 600, and 750 mg/day on a tid schedule), the 4 highest doses of SEROQUEL were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score, with the maximum effect seen at 300 mg/day, and the effects of doses of 150 to 750 were generally indistinguishable. SEROQUEL, at a dose of 300 mg/day, was superior to placebo on the SANS.

2. In a 6-week, placebo-controlled trial (n=286) involving titration of SEROQUEL in high (up to 750 mg/day on a tid schedule) and low (up to 250 mg/day on a tid schedule) doses, only the high dose of SEROQUEL group (mean dose, 500 mg/day) was generally superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and the SANS.

3. In a 6-week dose and dose regimen comparison trial (n=618) involving two fixed doses of SEROQUEL (450 mg/day on both bid and tid schedules and 50 mg/day on a bid schedule), only the 450 mg/day (225 mg bid schedule) dose group was generally superior to the 50 mg/day (25 mg bid) SEROQUEL dose group on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and on the SANS.

Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 compared to those older than 40. The clinical significance of this finding is unknown.

INDICATIONS AND USAGE

SEROQUEL is indicated for the management of the manifestations of psychotic disorders.

The antipsychotic efficacy of SEROQUEL was established in short-term (6-week) controlled trials of schizophrenic inpatients .

The effectiveness of SEROQUEL in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use SEROQUEL for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications:

SEROQUEL is contraindicated in individuals with a known hypersensitivity to this medication or any of its ingredients.

Manufacturers’ Warnings In Clinical States:

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Two possible cases of NMS [2/2387 (0.1%)] have been reported in clinical trials with SEROQUEL. Clinical manifestations of NMS are hyperpyrexia, 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 creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude 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 (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for 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.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements 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 prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tradive dyskinesia 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 tardive dyskinesia, 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 should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) 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 tardive dyskinesia appear in a patient on SEROQUEL, drug discontinuation should be considered. However, some patients may require treatment with SEROQUEL despite the presence of the syndrome.

Precautions:

General

Orthostatic Hypotension: SEROQUEL may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha 1-adrenergic antagonist properties. Syncope was reported in 1% (22/2162) of the patients treated with SEROQUEL, compared with 0% (0/206) on placebo and about 0.5% (2/420) on active control drugs. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg bid (See DOSAGE AND ADMINISTRATION ). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

SEROQUEL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

Cataracts: The development of cataracts was observed in association with quetiapine treatment in chronic dog studies (see Animal Toxicology ). Lens changes have also been observed in patients during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to defect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6 month intervals during chronic treatment.

Seizures: During clinical trials, seizures occurred in 0.8% (18/2387) of patients treated with SEROQUEL compared 0.5% (1/206) on placebo and 1% (4/420) on active control drugs. As with other antipsychotics, SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’ dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Hypothyroidism: Clinical trials with SEROQUEL demonstrated a dose-related decrease in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first two to four weeks of treatment and maintained without adaptation or progression during more chronic therapy. Generally, these changes were of no clinical significance and TSH was unchanged in most patients, and levels of TBG were unchanged. In nearly all cases, cessation of SEROQUEL treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. About 0.4% (10/2386) of SEROQUEL patients did experience TSH increases. Six of the patients with TSH increases needed replacement thyroid treatment.

Cholesterol and Triglyceride Elevations: In a pool of 3- to 6-week placebo-controlled trials, SEROQUEL-treated patients had increases from baseline in cholesterol and triglyceride of 11% and 17%, respectively, compared to slight decreases for placebo patients. These changes were only weakly related to the increases in weight observed in SEROQUEL-treated patients.

Hyperprolactinemia: Although an elevation of prolactin levels was not demonstrated in clinical trials with SEROQUEL, increased prolactin levels were observed in rat studies with this compound and were associated with an increase in mammary gland neoplasia in rats (see Carcinogenesis ). Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor epidemiologic studies conducted to date have shown as association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

Transaminase Elevations: Asymptomatic, transient, and reversible elevations in serum transaminases (primarily ALT) 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 3- to 6-week placebo-controlled trials were approximately 6% for SEROQUEL compared to 1% for placebo. These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to prestudy levels with ongoing treatment with SEROQUEL.

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 altertness, 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: 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’ 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’ 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 and 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).

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe SEROQUEL.

Orthostatic Hypotension: Patients should be advised of the risk of orthostatic hypotension, especially during the 3-5 day period of initial dose titration, and also at times of reinitiating treatment or increases in dose.

Interference with Cognitive and Motor Performance: Since somnolence was a commonly reported adverse event associated with SEROQUEL treatment, patients should be advised of the risk of somnolence, especially during the 3-5 day period of initial dose titration. Patients should be cautioned about performing any activity requiring mental altertness, 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.

Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing: Patients should be advised not to breast feed if they are taking SEROQUEL.

Concomitant Medication: As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs.

Alcohol: Patients should be advised to avoid consuming alcoholic beverages while taking SEROQUEL.

Heat Exposure and Dehydration: Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

Laboratory Tests

No specific laboratory tests are recommended.

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 psychotic symptoms 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 noninducer (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 (one 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/kg) 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 adenocarcinomas 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 result 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).

Adverse Reactions:

The premarketing development program for SEROQUEL included over 2600 patients and/or normal subjects exposed to 1 or more doses of SEROQUEL. Of these 2600 subjects, approximately 2300 were patients who participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 865 patient-years. The conditions and duration of treatment with SEROQUEL varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

Adverse events 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 events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse events.

The stated frequencies of adverse events 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 of worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed in Short-Term, Controlled Trials

Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Overall, there was little difference in the incidence of discontinuation due to adverse events (4% of SEROQUEL vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence and hypotension were considered to be drug related (see PRECAUTIONS ):

Adverse Event SEROQUEL Placebo Somnolence 0.8% 0% Hypotension 0.4% 0%

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 cited figures, 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 population studied.

In these studies, the most commonly observed adverse events associated with the use of SEROQUEL (incidence of 5% or greater) and observed at a rate on SEROQUEL at least twice that of placebo were dizziness (10%), postural hypotension (7%), dry mouth (7%), and dyspepsia (6%).

Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse event occurrence on the basis of these demographic factors.

Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials

Dose-related Adverse Events: Spontaneously elicited adverse event data from a study comparing five fixed doses of SEROQUEL (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse events. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse events: dyspepsia, abdominal pain, and weight gain.

Extrapyramidal Symptoms: Data from one 6-week clinical trial comparing five fixed doses of SEROQUEL (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of treatment-emergent extrapyramidal symptoms (EPS) and dose-relatedness of EPS associated with SEROQUEL treatment. Three methods were used to measure EPS (1) Simpson-Angus total score (mean change from baseline) which evaluates parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapydramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to treat emergent EPS.

SEROQUEL Dose Groups Placebo 75 mg 150 mg 300 mg 600 mg 750 mg Parkinsonism -0.6 -1.0 -1.2 -1.6 -1.8 -1.8 EPS incidence 16% 6% 6% 4% 8% 6% Anticholinergic Medications 14% 11% 10% 8% 12% 11%

In three additional placebo-controlled clinical trials using variable doses of SEROQUEL, there were no differences between the SEROQUEL and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS, and the use of concomitant anticholinergic medications to treat EPS.

Vital Sign Changes: SEROQUEL is associated with orthostatic hypotension (see PRECAUTIONS ).

Weight Gain: 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 significantly 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 SGPT and increases in both total cholesterol and triglycerides (see PRECAUTIONS ).

An assessment of hematological parameters in short-term, placebo-controlled trials revealed no clinical important differences between SEROQUEL and placebo.

ECG Changes: Between group comparisons for pooled placebo-controlled trials revealed no statistically significant SEROQUEL/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- 6-week-placebo-controlled clinical trials revealing a 1% (4/399) incidence for SEROQUEL compared to 0.6% (1/156) incidence 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. This slight tendency to tachycardia may be related to SEROQUEL’s potential for inducing orthostatic changes (see PRECAUTIONS ).

Other Adverse Events Observed During the Premarketing Evaluation of SEROQUEL

Following is a list of COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with SEROQUEL at multiple doses >/= 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients. All reported events are included except those already listed in Table 1 or elsewhere in labeling, those events for which a drug cause was remote, and those event terms which were so general as to be uninformative. It is important to emphasize that, although the events reported occurred during treatment with SEROQUEL, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Nervous System: Frequent: hypertonia, dysarthria; Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased* urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia; Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased*, neuralgia, stuttering, subdural hematoma.

Body as a Whole: Frequent: flu syndrome; Infrequent: neck pain, pelvic pain*, suicide attempt, malaise, photosensitivity reaction, chills face edema, moniliasis; Rare: abdomen enlarged.

Digestive System: Frequent: anorexia; Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema; Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis.

Cardiovascular System: Frequent: palitation; Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accidenct, deep thrombophlebitis, T wave inversion; Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration.

Respiratory System: Frequent: pharyngitis, rhinitis, cough increased, dyspnea; Infrequent: pneumonia, epistaxis, asthma; Rare: hiccup, hyperventilation.

Metabolic and Nutritional System: Frequent: peripheral edema; Infrequent: weight loss, alkaline phosphatase increased, hyperlipemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia; Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication.

Skin and Appendages System: Frequent: sweating; Infrequent: pruritis, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer; Rare: exfoliative dermatitis, psoriasis, skin discoloration.

Urogenital System: Infrequent: dysmenorrhea*, vaginitis*, urinary incontinence, metorrhagia*, impotence*, dysuria, vaginal moniliasis*, abnormal ejaculation*, cystitis, urinary frequency, amenorrhea*, female lactation*, leukorrhea*, vaginal hemorrhage*, vulvovaginitis* orchitis*; Rare: gynecomastia*, nocturia, polyuria, acute kidney failure.

Special Senses: Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain; Rare: abnormality of accommodation, deafness, glaucoma.

Musculoskeletal System: Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain.

Hemic and Lymphatic System: Frequent: leukopenia; Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis; Rare: hemolysis, thrombocytopenia.

Endorcine System: Infrequent: hypothyroidism, diabetes mellitus; Rare: hyperthyroidism.

*adjusted for gender

Post Marketing Experience: Adverse events reported since market introduction which were temporally related to SEROQUEL therapy include the following: rarely 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.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class: SEROQUEL is not a controlled substance.

Physical and Psychologic dependence: SEROQUEL 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, e.g., development of tolerance, increases in dose, drug-seeking behavior.

OVERDOSAGE

Human experience: Experience with SEROQUEL® (quetiapine fumarate) in acute overdosage was limited in the clinical trial database (6 reports) with estimated doses ranging from 1200 mg to 9600 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug’ known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block.

Management of Overdosage: In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of SEROQUEL. Similarly it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.

There is no specific antidote to SEROQUEL. Therefore appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Dosage And Administration:

Usual Dose: SEROQUEL should generally be administered with an initial dose of 25 mg bid, with increases in increments of 25-50 mg bid or tid on the second and third day, as tolerated, to a target dose range of 300 to 400 mg daily by the fourth day, given bid or tid. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady state for SEROQUEL would not be achieved for approximately 1-2 days in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 25-50 mg bid are recommended. Most efficacy data with SEROQUEL were obtained using tid regimens, but in one controlled trial 225 mg bid was also effective.

Antipsychotic efficacy was demonstrated in a dose range of 150 to 750 mg/day in the clinical trials supporting the effectiveness of SEROQUEL. In a dose response study, doses above 300 mg/day were not demonstrated to be more efficacious than the 300 mg/day dose. In other studies, however, doses in the range of 400-500 mg/day appeared to be needed. The safety of doses above 800 mg/day has not been evaluated in clinical trials.

Dosing in Special Populations

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 had a predisposition to hypotensive reactions (see CLINICAL PHARMACOLOGY ). When indicated, dose escalation should be performed with caution in these patients.

The elimination of quetiapine was enhanced in the presence of phenytoin. Higher maintenance doses of quetiapine may be required when it is coadministered with phenytoin and other enzyme inducers such as carbamazepine and phenobarbital. (See Drug Interactions under PRECAUTIONS )

Maintenance Treatment: While there is no body of evidence available to answer the question of how long the patient treated with SEROQUEL should remain on it, the effectiveness of maintenance treatment is well established for many other antipsychotic drugs. It is recommended that responding patients be continued on SEROQUEL, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Reinitiation of Treatment in Patients Previously Discontinued: Although there are no data to specifically address reinitiation of treatment, it is recommended that when restarting patients who have had an interval of less than one week off SEROQUEL, titration of SEROQUEL is not required, and the maintenance dose may be reinitiated. When restarting therapy of patients who have been off SEROQUEL for more than one week, the initial titration schedule should be followed.

Switching from Other Antipsychotics: There are no systematically collected data to specifically address switching from other antipsychotics to SEROQUEL.

HOW SUPPLIED

25 mg Tablets (NDC 0310-0275) peach, round, biconvex, film coated tablets, identified with ‘SEROQUEL’ and ’25’ on one side and plain on the other side, are supplied in bottles of 100 tablets and hospital unit dose packages of 100 tablets.

100 mg Tablets (NDC 0310-0271) yellow, round, biconvex film coated tablets, identified with ‘SEROQUEL’ and ‘100’ on one side and plain on the other side, are supplied in bottles of 100 tablets and hospital unit dose packages of 100 tablets.

200 mg Tablets (NDC 0310-0272) white, round, biconvex, film coated tablets, identified with ‘SEROQUEL’ and ‘200’ on one side and plain on the other side, are supplied in bottles of 100 tablets and hospital unit dose packages of 100 tablets.

Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F).

Seroquel Tablets (AstraZeneca)

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