WARNINGS AND PRECAUTIONS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. SEROQUEL XR (quetiapine fumarate) is not approved for the treatment of patients with dementia-related psychosis (see Boxed Warning ).
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine [ See Adverse Reactions, Hyperglycemia (6.2) ]. 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 reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, 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. 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.
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, including quetiapine. Rare cases of NMS have been reported with quetiapine. 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 creatine 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 (eg, 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.
Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its ά1-adrenergic antagonist properties. Syncope was reported in 0.3% (3/951) of the patients treated with SEROQUEL XR, compared with 0.3% (1/319) on placebo. Syncope was reported in 1% (23/2567) of the patients treated with SEROQUEL, compared with 0% (0/607) on placebo.
Quetiapine 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). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.
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 tardive 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, quetiapine 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 quetiapine, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.
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 quetiapine treatment, but a causal relationship to quetiapine 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 detect 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.
During clinical trials with SEROQUEL XR, seizures occurred in 0.1% (1/951) of patients treated with SEROQUEL XR compared to 0.9% (3/319) on placebo. During clinical trials with SEROQUEL, seizures occurred in 0.6% (18/2792) of patients treated with SEROQUEL compared to 0.2% (1/607) on placebo. As with other antipsychotics quetiapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, eg, Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
In SEROQUEL XR clinical trials, 0.5% (4/806) of patients on SEROQUEL XR vs. 0% (0/262) on placebo experienced decreased free thyroxine and 2.7% (21/786) on SEROQUEL XR vs. 1.2% (3/256) on placebo experienced increased TSH; however, no patients experienced a combination of clinically significant decreased free thyroxine and increased TSH. No patients had reactions of 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 and 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 quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. About 0.4% (12/2791) of SEROQUEL patients did experience TSH increases in monotherapy studies. Six of these patients with TSH increases needed replacement thyroid treatment.
Cholesterol and Triglyceride Elevations
In schizophrenia clinical trials, SEROQUEL XR treated patients had increases from baseline in mean cholesterol and triglycerides of 4% and 15%, respectively compared to decreases from baseline in mean cholesterol and triglycerides of 2% and 6% for placebo treated patients. In schizophrenia clinical trials, SEROQUEL treated patients had increases from baseline in mean cholesterol and triglyceride of 11% and 17%, respectively, compared to slight decreases for placebo patients.
An elevation of prolactin levels was not demonstrated in clinical trials with SEROQUEL XR as compared with placebo. Increased prolactin levels with quetiapine were observed in rat toxicity studies, and were associated with an increase in mammary gland neoplasia in rats. [ see Carcinogenesis, Mutagenesis, Impairment of Fertility ]. 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.
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 6-week placebo controlled schizophrenia trials were approximately 1% for SEROQUEL XR compared to 2% for placebo. In schizophrenia trials, 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 pre-study levels with ongoing treatment with SEROQUEL.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence and sedation were reported in 12% and 13% of patients on SEROQUEL XR respectively compared to 4% and 7% of placebo patients. In schizophrenia trials, somnolence was reported in 18% of patients on SEROQUEL compared to 11% of placebo patients. Since quetiapine 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 quetiapine therapy does not affect them adversely.
One case of priapism in a patient receiving quetiapine was reported prior to market introduction. While a causal relationship to use of quetiapine has not been established, other drugs with α-adrenergic blocking effects have been reported to induce priapism, and it is possible that quetiapine may share this capacity. Severe priapism may require surgical intervention.
Body Temperature Regulation
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 for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
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.
The possibility of a suicide attempt is inherent in schizophrenia; close supervision of high risk patients should accompany drug therapy. Prescriptions for SEROQUEL XR should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
In three, 6-week clinical studies in patients with schizophrenia (N=951) the incidence of treatment emergent suicidal ideation or suicide attempt, as measured by the Columbia Analysis of Suicidal Behavior, was low in Seroquel XR treated patients (0.6%) and similar to placebo (0.9%).
Use in Patients with Concomitant Illness
Clinical experience with SEROQUEL XR in patients with certain concomitant systemic illnesses [ see Pharmacokinetics ] is limited.
SEROQUEL XR 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 XR, caution should be observed in cardiac patients [see Warning and Precautions ]
Acute withdrawal symptoms, such as nausea, vomiting, and insomnia have very rarely been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine. Gradual withdrawal is advised.
USE IN SPECIFIC POPULATIONS
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/m2 basis or in rabbits at 25 to 100 mg/kg or 0.6 to 2.4 times the maximum human dose on a mg/m2 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/m2 basis) and in rabbits at 50 and 100 mg/kg (1.2 and 2.4 times the maximum human dose on a mg/m2 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/m2 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/m2 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/m2 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/m2 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 XR on labor and delivery in humans is unknown.
SEROQUEL XR was excreted in milk of treated animals during lactation. It is not known if SEROQUEL XR is excreted in human milk. It is recommended that women receiving SEROQUEL XR should not breast feed.
The safety and effectiveness of SEROQUEL XR in pediatric patients have not been established.
Sixty-eight patients in clinical studies with SEROQUEL XR were 65 years of age or over. In general, there was no indication of any different tolerability of SEROQUEL XR in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to SEROQUEL XR, 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 quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see Use in Special Populations (2.2) and Pharmacokinetics ].
Clinical experience with SEROQUEL XR in patients with renal impairment [see Clinical Pharmacology ] is limited.
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 Dosing and Administration (2.2) and Clinical Pharmacology ].