Clinical worsening and suicide risk associated with psychiatric disorders. The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. The risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviour (suicidality), whether or not they are taking antidepressant medications and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analysis of 24 short-term (4 to 16 weeks) placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (four trials) or other psychiatric disorders (four trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients taking a placebo. There was considerable variation in risk among the antidepressants but there was a tendency towards an increase for almost all antidepressants studied. This meta-analysis did not include trials involving quetiapine.
The risk of suicidality was most consistently observed in the major depressive disorder trials but there were signals of risk arising from the trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazepine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as emergence of suicidality, and to report such symptoms immediately to health care providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
The possibility of a suicide attempt is inherent in schizophrenia; 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.
Extrapyramidal symptoms. In placebo controlled clinical trials of adult patients with schizophrenia, bipolar mania and maintenance treatment of bipolar disorder, the incidence of EPS was no different from that of placebo across the recommended therapeutic dose range. In short-term, placebo controlled clinical trials of adult patients with bipolar depression, the incidence of EPS was higher in Seroquel treated patients than in placebo treated patients (see Adverse Reactions for rates of EPS observed in all indications).
Tardive dyskinesia. Seroquel should be prescribed in a manner that is most likely to minimise the occurrence of tardive dyskinesia.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic medicines administered to the patient increase. However, tardive dyskinesia can develop, although much less commonly after relatively brief treatment periods at low doses.
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of Seroquel should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see Adverse Reactions).
Neuroleptic malignant syndrome. Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including Seroquel. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability and increased creatine phosphokinase. In such an event, Seroquel should be discontinued and appropriate medical treatment given.
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 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.
Neutropenia. Severe neutropenia (< 0.5 x 109/L) has been uncommonly reported in Seroquel clinical trials. Most cases of severe neutropenia have occurred within the first two months of starting therapy with Seroquel. There was no apparent dose relationship. Possible risk factors for neutropenia include pre-existing low white cell count (WBC) and history of drug induced neutropenia. Quetiapine should be discontinued in patients with a neutrophil count < 1.0 x 109/L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 109/L) (see Adverse Reactions).
Hepatic enzyme inducers. Concomitant use of Seroquel with hepatic enzyme inducers, e.g. carbamazepine, may substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher doses of Seroquel may need to be considered if Seroquel is used concomitantly with a hepatic enzyme inducer.
CYP3A4 inhibitors. During concomitant administration of medicines which are potent CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics and protease inhibitors), plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials. As a consequence of this, lower doses of Seroquel should be used. Special consideration should be given in elderly and debilitated patients. The risk/ benefit ratio needs to be considered on an individual basis in all patients (see Interactions).
Hyperglycaemia and diabetes mellitus. Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Seroquel (see Adverse Reactions). 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 hyperglycaemia related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment emergent hyperglycaemia related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia related adverse events 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 (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Increased risk of mortality in elderly patients with dementia related psychosis. Elderly patients with dementia related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo. A meta-analysis of 17 placebo controlled trials with dementia related behavioural disorders showed a risk of death in the drug treated patients of approximately 1.6 to 1.7 times that seen in placebo treated patients. The clinical trials included in the meta-analysis were undertaken with Zyprexa (olanzapine), Abilify (aripiprazole), Risperdal (risperidone) and Seroquel (quetiapine). Over the course of these trials averaging about ten weeks in duration, the rate of death in drug treated patients was about 4.5% compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Seroquel is not approved for the treatment of elderly patients with dementia related psychosis or behavioural disorders.
Withdrawal. Acute withdrawal symptoms such as nausea, vomiting and insomnia have been described after abrupt cessation of antipsychotic medicines including Seroquel. Gradual withdrawal over a period of at least one to two weeks is advisable (see Adverse Reactions).
Dysphagia. Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Seroquel and other antipsychotic medicines should be used cautiously in patients at risk for aspiration pneumonia (e.g. elderly patients).
Lipids. Increases in triglycerides and cholesterol have been observed in clinical trials with quetiapine (see Adverse Reactions). Monitoring is recommended at baseline and periodically during treatment for all patients. Lipid increases should be managed as clinically appropriate. Lactose. Seroquel tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose/ galactose malabsorption should not take this medicine.
Carcinogenesis, mutagenesis, impairment of fertility. Carcinogenicity. In the rat study (20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia. The incidence of carcinoma of the adrenal cortex was increased in male rats at the highest dose.
In the male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent specific mechanisms resulting from enhanced hepatic thyroxine clearance.
Genotoxicity. Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen. Quetiapine showed no evidence of genotoxicity in a series of assays for gene mutation (bacteria and Chinese hamster ovary cells) and chromosomal damage (human lymphocytes and the in vivo micronucleus test).
Use in pregnancy. (Category B3)
The safety and efficacy of quetiapine during human pregnancy have not been established. Therefore, Seroquel should only be used during pregnancy if the benefits justify the potential risks.
Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of dioestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
Teratogenic effects were not observed following administration of quetiapine at oral doses up to 200 mg/kg in rats (less than the exposure to quetiapine at the maximum recommended clinical dose based on area under the curve (AUC)) and 100 mg/kg in rabbits (approximately twice the maximum clinical exposure based on body surface area (BSA)).
Use in lactation. The degree to which quetiapine is excreted into human milk is unknown, however in a study in lactating rats the concentration of quetiapine and/or its metabolites was higher in milk than in plasma. Women who are breastfeeding should, therefore, be advised to avoid breastfeeding while taking Seroquel.
Use in children. Use in children and adolescents (10 to 17 years of age). Paediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For paediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for paediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the potential benefits and risks associated with medication treatment. Medication treatment for both paediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.
Efficacy and safety of Seroquel have been demonstrated for adolescents aged from 13 years with schizophrenia and for children/ adolescents aged from 10 years with bipolar I disorder experiencing acute mania in two clinical trials of three and six weeks duration, respectively. Safety data was provided for up to 26 weeks in a third open label safety and tolerability trial (see Clinical trials, Children and adolescents). The safety and efficacy of Seroquel in children and adolescents have not been assessed beyond these time periods.
Although not all adverse reactions that have been identified in adult patients have been observed in clinical trials with Seroquel in children and adolescent patients, the same precautions that appear above for adults should be considered for children and adolescents. As seen in adults, increases in TSH, serum cholesterol, triglycerides and weight have been observed (see Precautions, Effects on laboratory tests, and Adverse Reactions).
The following events were reported more frequently in the short-term studies in children and adolescents than in studies in adults: EPS and increases in appetite and serum prolactin. Increased blood pressure has not been identified in the adult population but was seen in children and adolescents. Blood pressure should be monitored at the beginning of, and periodically during treatment in children and adolescents (see Adverse Reactions).
Long-term safety data including growth, maturation and behavioural development, beyond 26 weeks of treatment with Seroquel, are not available for children and adolescents (10 to 17 years of age).
Effect on ability to drive or operate machinery. Somnolence has been very commonly reported in patients treated with quetiapine. Given its primary central nervous system effects, quetiapine has the potential to impair judgment, thinking or motor skills. Patients likely to drive or operate other machines should, therefore, be cautioned appropriately.
Interactions with other medicines Antipsychotic and other centrally acting medicines. Given the primary central nervous system effects of quetiapine, Seroquel should be used with caution in combination with other centrally acting medicines and alcohol.
Thioridazine. Thioridazine (200 mg twice a day) increased the oral clearance of quetiapine (300 mg twice a day) by 65%.
Lorazepam. The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg three times a day dosing. Dosage adjustment is not required.
Levodopa and dopamine agonists. As it exhibits in vitro dopamine antagonism, Seroquel may antagonise the effects of levodopa and dopamine agonists.
Carbamazepine and phenytoin. See Hepatic enzyme inducers below.
Potential interactions that have been excluded. Antipsychotics. The pharmacokinetics of quetiapine were not significantly altered following coadministration with the antipsychotics risperidone (3 mg twice a day) or haloperidol (7.5 mg twice a day). The pharmacokinetics of lithium were not altered when coadministered with quetiapine (250 mg three times a day). The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when coadministered.
Imipramine and fluoxetine. See CYP inhibitors below.
CYP inhibitors. CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine (see Actions, Pharmacokinetics). CYP2D6 and CYP2C9 are also involved.
CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics and protease inhibitors). During concomitant administration of medicines which are potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors) plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials (see Ketoconazole below). As a consequence of this, lower doses of Seroquel should be used. Special consideration should be given in elderly or debilitated patients. The risk/ benefit ratio needs to be considered on an individual basis.
It is also not recommended to take Seroquel together with grapefruit juice.
Ketoconazole. In a multiple dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, coadministration of ketoconazole (200 mg once daily for four days) resulted in an increase in mean Cmax and AUC of quetiapine of 335 and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours, but the mean Tmax was unchanged.
Potential interactions that have been excluded. Cimetidine. The pharmacokinetics of quetiapine (150 mg three times a day) were not significantly altered (20% decrease in clearance) following coadministration with cimetidine (400 mg three times a day for four days), a known P450 enzyme inhibitor. Dosage adjustment for quetiapine is not required when it is given with cimetidine.
Imipramine and fluoxetine. The pharmacokinetics of quetiapine were not significantly altered following coadministration with the antidepressants imipramine (75 mg twice a day; a known CYP2D6 inhibitor) or fluoxetine (60 mg once daily; a known CYP3A4 and CYP2D6 inhibitor).
Hepatic enzyme inducers (e.g. carbamazepine and phenytoin). Quetiapine (administration of multiple daily doses up to 750 mg/day, on a three times a day dosing schedule) did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, concomitant use of quetiapine with hepatic enzyme inducers such as carbamazepine or phenytoin may substantially decrease systemic exposure to quetiapine (see Carbamazepine and phenytoin below). Depending on clinical response, increased doses of Seroquel may be required to maintain control of psychotic symptoms in patients coadministered Seroquel and hepatic enzyme inducers (e.g. carbamazepine, phenytoin, barbiturates, rifampicin, glucocorticoids). The safety of doses above 800 mg/day has not been established in the clinical trials. Continued treatment at higher doses should only be considered as a result of careful consideration of the benefit/ risk assessment for an individual patient.
The dose of Seroquel may need to be reduced if phenytoin, carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a noninducer (e.g. sodium valproate).
Carbamazepine and phenytoin. In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), coadministration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, and hence, in each patient, consideration for a higher dose of Seroquel, depending on clinical response, should be considered.
Coadministration of quetiapine (250 mg three times a day) and phenytoin (100 mg three times a day; another microsomal enzyme inducer) also caused increases in clearance of quetiapine by fivefold.
Cardiovascular medicines. Caution should be used when Seroquel is used concomitantly with medicines known to cause electrolyte imbalance or to increase QTc interval.
Because of its potential for inducing hypotension, Seroquel may enhance the effects of certain antihypertensive medicines.
Medications to manage attention deficit hyperactivity disorder (ADHD). The data regarding safety and efficacy of Seroquel for the treatment of bipolar mania in children and adolescents receiving psychostimulants for comorbid ADHD are limited. Therefore, concomitant use of ADHD medication and Seroquel is not recommended. If concomitant therapy is considered necessary, patients should be carefully monitored for the effect of the combination of treatments on the signs and symptoms of both ADHD and acute mania. Effects on blood pressure may be cumulative and blood pressure should be carefully monitored.
Effect on laboratory tests. Leucopenia and/or neutropenia. As with other antipsychotics, transient leucopenia and/or neutropenia have been observed in patients administered Seroquel. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leucopenia and/or neutropenia. Occasionally, eosinophilia has been observed (see Adverse Reactions).
Serum transaminase. Asymptomatic elevations in serum transaminase (ALT, AST) or γ-glutamyl transferase levels have been observed in some patients administered Seroquel. These elevations were usually reversible on continued Seroquel treatment (see Adverse Reactions).
Triglycerides and cholesterol. Small elevations in nonfasting serum triglyceride levels and total cholesterol (predominantly low density lipoprotein (LDL) cholesterol) have been observed during treatment with Seroquel (see Adverse Reactions).
Thyroid hormone levels. Seroquel treatment was associated with small dose related decreases in thyroid hormone levels, particularly total T4 and free T4. The reduction in total and free T4 was maximal within the first two to four weeks of quetiapine treatment, with no further reduction during long-term treatment. 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 0.7% (26/3,489) of Seroquel adult patients experienced TSH increases in monotherapy studies. Six of the patients with TSH increases needed replacement thyroid treatment. In the adult mania adjunct studies, 12% (24/196) of the Seroquel treated patients compared to 7% (15/203) placebo treated patients had elevated TSH levels.
In acute placebo controlled studies in children and adolescent patients with schizophrenia or bipolar mania the incidence of shifts to potentially clinically important thyroid function values at any time for Seroquel and placebo treated patients for elevated TSH was 2.9 versus 0.7%, respectively, and for decreased total thyroxine was 2.8 versus 0% respectively. Of the Seroquel treated patients with elevated TSH levels, one had a simultaneous low free T4 level at the end of treatment.
Methadone and tricyclic antidepressant enzyme immunoassays. There have been reports of false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.
Adverse effects Clinical study experience. Schizophrenia (adults). The treatment emergent adverse events that occurred during acute therapy (up to six weeks) of schizophrenia in at least 1% (rounded to the nearest percent) of patients treated with Seroquel in placebo controlled phase II/III trials where the incidence in patients treated with quetiapine was greater than the incidence in placebo treated patients are listed in Table 6 regardless of causality.
Bipolar I disorder, acute mania (adults). Adverse events that occurred during the treatment of acute mania in 5% or more of patients treated with Seroquel in either the monotherapy or adjunct therapy, placebo controlled trials and observed at a rate of at least twice that of placebo are listed in Table 7 regardless of causality.
Bipolar I disorder, maintenance (adults). The safety results of two clinical trials show that Seroquel is generally safe and well tolerated when used in combination with lithium or valproate in long-term treatment. Adverse events occurring at an incidence of 5% or more in any randomised treatment group from placebo controlled clinical trials in patients with bipolar I disorder treated with Seroquel in combination with lithium or valproate as maintenance therapy is summarised by randomised treatment and by assigned mood stabiliser for the combined studies in Table 8 regardless of causality.
Adverse events occurring at an incidence of 5% or more in any randomised treatment group from placebo controlled clinical trials in patients with bipolar I disorder treated with Seroquel as monotherapy maintenance therapy is summarised by randomised treatment in Table 9 regardless of causality.
Bipolar depression (adults). The safety results of four placebo controlled clinical trials show that Seroquel is generally safe and well tolerated when used for treatment of bipolar depression. All four studies contained an eight week acute phase with two of these studies containing a continuation phase of an additional 52 weeks. Adverse events occurring at an incidence of 5% or more in any treatment group in the acute phase for the combined studies are summarised in Table 10 regardless of causality.
Adverse events occurring at an incidence of 5% or more in any treatment group in the continuation phase for the combined studies are summarised in Table 11 regardless of causality.
Other findings observed during clinical studies. Somnolence. Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of Seroquel. Somnolence may lead to falls.
Weight gain (adults). In schizophrenia trials the proportions of patients meeting a weight gain criterion of ≥ 7% of bodyweight from baseline were compared in a pool of four three to six week placebo controlled clinical trials, revealing a statistically significantly greater incidence of weight gain for Seroquel (23%) compared to placebo (6%). In mania monotherapy trials the proportions of patients meeting the same weight gain criterion were 21% compared to 7% for placebo and in mania adjunct therapy trials the proportion of patients meeting the same weight criterion were 13% compared to 4% for placebo. In bipolar depression trials, the proportions of patients meeting the same weight gain criterion were 8% compared to 2% for placebo.
Withdrawal (discontinuation symptoms). In acute placebo controlled monotherapy clinical trials in adults which evaluated discontinuation symptoms, the aggregated incidence of discontinuation symptoms after abrupt cessation was 16.0% for quetiapine and 7.3% for placebo. The aggregated incidence of individual adverse events (eg, insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability) did not exceed 6.7% in any treatment group and usually resolved after one week postdiscontinuation (see Precautions).
Leucopenia/ neutropenia. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leucopenia and/or neutropenia. Neutrophil count decreases have commonly been observed. In placebo controlled monotherapy clinical trials in adults, 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 1.72% in patients treated with quetiapine, compared to 0.73% in placebo treated patients. In clinical trials conducted prior to a protocol amendment for discontinuation of patients with treatment emergent neutrophil count < 1.0 x 109/L, among patients with a baseline neutrophil count ≥ 1.5 x 109/L, the incidence of at least one occurrence of neutrophil count < 0.5 x 109/L (severe neutropenia) was 0.21% (uncommon) in patients treated with quetiapine and 0% in placebo treated patients and the incidence ≥ 0.5 to < 1.0 x 109/L (moderate neutropenia) was 0.75% (uncommon) in patients treated with quetiapine and 0.11% in placebo treated patients (see Precautions).
Cholesterol and triglyceride elevations (adults). In schizophrenia trials, the proportions of patients with elevations to levels of cholesterol ≥ 6.2064 mmol/L and triglycerides ≥ 2.258 mmol/L were 16 and 23% for Seroquel treated patients, respectively, compared to 7 and 16% for placebo treated patients, respectively. In bipolar depression trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 9 and 14% for Seroquel treated patients, respectively, compared to 6 and 9% for placebo treated patients, respectively.
Increases in blood glucose levels. In placebo controlled clinical trials in adults, the percentage of patients who had a shift to a high blood glucose level (fasting blood glucose ≥ 7 mmol/L or a nonfasting blood glucose ≥ 11.1 mmol/L on at least one occasion) was 5.1% in patients treated with quetiapine and 4.2% in placebo treated patients (see Precautions).
Decreases in haemoglobin levels. Decreased haemoglobin to 8.07 mmol/L males, 7.45 mmol/L females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. In short-term placebo controlled trials, decreased haemoglobin to 8.07 mmol/L males, 7.45 mmol/L females on at least one occasion in 8.3% of quetiapine patients compared to 6.2% of placebo patients.
Extrapyramidal symptoms (adults). The following clinical trials included treatment with Seroquel and Seroquel XR. In short-term placebo controlled clinical trials in schizophrenia and bipolar mania the aggregate incidence of EPS was similar to placebo (schizophrenia: quetiapine 7.8%, placebo 8.0%; bipolar mania: quetiapine 11.2%, placebo 11.4%). In short-term, placebo controlled clinical trials in bipolar depression the aggregate incidence of EPS from the combined data was 8.9% for quetiapine compared to 3.8% for placebo though the incidence of the individual adverse events (e.g. akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. In long-term studies of schizophrenia and bipolar disorder the aggregated exposure adjusted incidence of treatment emergent extrapyramidal symptoms was similar between quetiapine and placebo. (See Precautions, Extrapyramidal symptoms.)
Irritability. In acute placebo controlled clinical trials in patients ≥ 18 years of age, the incidence of irritability was 2.3% for quetiapine and 1.7% for placebo.
Dysphagia. An increase in the rate of dysphagia with quetiapine vs placebo was only observed in the adult clinical trials in bipolar depression.
Other adverse drug reactions. In addition to the above, the following adverse drug reactions have also been observed in adult clinical trials (placebo controlled trials, active arm controlled trials and open label uncontrolled trials) with quetiapine.
Common (≥ 1% to < 10%). Eye disorders: vision blurred.
General disorders and administration site conditions: peripheral oedema; irritability.
Investigations: elevations in serum prolactin (prolactin levels (patients ≥ 18 years of age): > 20 microgram/L males; > 30 microgram/L females at any time).
Metabolism and nutritional disorders: increased appetite.
Nervous system disorders: syncope (see Precautions); dysarthria.
Psychiatric disorders: abnormal dreams and nightmares.
Uncommon (≥ 0.1% to < 1%). Blood and lymphatic system disorders: eosinophilia.
Gastrointestinal disorders: dysphagia.
Investigations: platelet count decreased (platelets ≤ 100 x 109/L on at least one occasion).
Immune system disorders: hypersensitivity.
Nervous system disorders: seizure (see Precautions); restless legs syndrome; tardive dyskinesia (see Precautions).
Rare (≥ 0.01% to < 0.1%). General disorders and administration site conditions: neuroleptic malignant syndrome (see Precautions).
Investigations: elevations in blood creatine phosphokinase (not associated with neuroleptic malignant syndrome).
Reproductive system and breast disorders: priapism.
Children and adolescents (schizophrenia and acute mania). The incidence of common (≥ 5%) adverse events that occurred in children and adolescents (10 to 17 years) in two short-term treatment placebo controlled trials in schizophrenia and bipolar mania is listed below in Table 12 regardless of causality.
The adverse events ≥ 5% reported in a 26 week, open label clinical trial with Seroquel in children and adolescents with schizophrenia and bipolar mania were: somnolence (22.9%), headache (18.7%), sedation (14.2%), weight increased (13.4%), vomiting (10.8%), nausea (9.5%), dizziness (8.7%), fatigue (8.2%), insomnia (8.2%), increased appetite (7.1%), upper respiratory tract infection (6.8%), agitation (5.3%), irritability (5.0%), tachycardia (5.0%).
Comparison to adult adverse drug reactions. The same adverse drug reactions described for adults should be considered for children and adolescents. The following list summarises adverse drug reactions that occur in a higher frequency category in children and adolescent patients (10 to 17 years of age) than in the adult population, or adverse drug reactions that have not been identified in the adult population.
Very common (≥ 10%). Metabolism and nutrition disorders: increased appetite.
Investigations: elevations in serum prolactin (prolactin levels (patients < 18 years of age): > 20 microgram/L males; > 26 microgram/L females at any time. Less than 1% of patients had an increase to a prolactin level > 100 microgram/L);
increases in blood pressure: (based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases > 20 mmHg for systolic or > 10 mmHg for diastolic blood pressure at any time in two acute (three to six weeks) placebo controlled trials in children and adolescents).
Nervous system disorders: extrapyramidal symptoms (see text below).
Weight gain (children and adolescents). In one six week, placebo controlled trial in adolescent patients (13 to 17 years of age) with schizophrenia, the mean increase in bodyweight was 2.0 kg in the Seroquel group and -0.4 kg in the placebo group. 21% of Seroquel treated patients and 7% of placebo treated patients gained ≥ 7% of their bodyweight.
In one three week, placebo controlled trial in children and adolescent patients (10 to 17 years of age) with bipolar mania, the mean increase in bodyweight was 1.7 kg in the Seroquel group and 0.4 kg in the placebo group. 12% of Seroquel treated patients and 0% of placebo treated patients gained ≥ 7% of their bodyweight.
In the open label study that enrolled patients from the above two trials, 63% of patients (241/380) completed 26 weeks of therapy with Seroquel. After 26 weeks of treatment, the mean increases in bodyweight and BMI were 4.4 kg and 1.1 kg/m2, respectively. 45% of the patients gained ≥ 7% of their bodyweight, (not adjusted for normal growth). 18.3% of the patients had a clinically significant change in BMI (adjusted for growth).
Extrapyramidal symptoms (EPS) (children and adolescents). In a short-term placebo controlled monotherapy trial in adolescent patients (13 to 17 years of age) with schizophrenia, the aggregated incidence of EPS was 12.9% for Seroquel and 5.3% for placebo, though the incidence of the individual adverse events (e.g. akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) was generally low and did not exceed 4.1% in any treatment group. In a short-term placebo controlled monotherapy trial in children and adolescent patients (10 to 17 years of age) with bipolar mania, the aggregated incidence of EPS was 3.6% for Seroquel and 1.1% for placebo.
Suicide/ suicidal thoughts or clinical worsening (all ages). In short-term placebo controlled clinical trials across all indications and ages, the incidence of suicide related events was 0.9% for both quetiapine (61/6270) and placebo (27/3047).
In these trials of patients with schizophrenia the incidence of suicide related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients 18 to 24 years of age, 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients ≥ 25 years of age, and 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients < 18 years of age.
In these trials of patients with bipolar mania the incidence of suicide related events was 0% for both quetiapine (0/60) and placebo (0/58) in patients 18 to 24 years of age, 1.2% for both quetiapine (6/496) and placebo (6/503) in patients ≥ 25 years of age, and 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients < 18 years of age.
In these trials of patients with bipolar depression the incidence of suicide related events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients 18 to 24 and 1.8% for both quetiapine (19/1616) and placebo (11/622) in patients ≥ 25 years of age. There have been no trials conducted in patients < 18 years of age with bipolar depression (see Precautions).
Postmarketing experience. Very rare postmarketing cases of anaphylactic reaction and rare postmarketing cases of galactorrhoea have been received.
Very rare cases of cataract and urinary retention have been reported in the postmarketing data, but no causal link between these reports and quetiapine has been established.
Very rare cases of exacerbation of pre-existing diabetes have been reported.
Dosage and administration 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 response should be sought. The need for continued treatment should be reassessed periodically.
Seroquel can be administered with or without food.
Adults. Bipolar disorder. Maintenance treatment. Seroquel should be administered twice daily.
Patients who have responded to Seroquel for acute treatment of bipolar disorder should continue therapy at the same dose. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest possible dose needed to maintain remission.
For prevention of relapse/ recurrence of manic, depressive and mixed episodes in bipolar disorder, the usual effective dose is within the range of 300 to 800 mg/day (see Actions, Clinical Trials).
The dose of Seroquel can be readjusted depending on the clinical response and tolerability of the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.
Bipolar depression. When treating depressive episodes in bipolar disorder, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist.
Seroquel should be administered once daily at bedtime.
Seroquel should be titrated as follows: 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). The dose may be adjusted up to 600 mg/day in increments of 100 mg/day depending on the clinical response and tolerability of the individual patient.
Acute mania. Seroquel should be administered twice daily. The total daily dose for the first four days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4), alone or in combination with a mood stabiliser. Further dosage adjustments, up to 800 mg/day by day 6 should be in increments of no greater than 200 mg/day.
The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg/day. The usual effective dose is in the range of 400 to 800 mg/day.
Schizophrenia. Seroquel should be administered twice daily. The total daily dose for the first four days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4).
From day 4 onwards, the dose should be titrated to the usual effective dose of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.
Elderly. As with other antipsychotics, Seroquel should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of quetiapine was reduced by 30 to 50% in elderly subjects when compared with younger patients.
Children and adolescents. The safety and efficacy of Seroquel have been evaluated in children and adolescents 10 to 17 years of age with bipolar mania (as monotherapy), and 13 to 17 years of age with schizophrenia. Seroquel should be administered twice daily. However, Seroquel may be administered three times daily based on response and tolerability.
Acute mania: monotherapy (10 to 17 years of age). The total daily dose for the first five days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), 300 mg (day 4) and 400 mg (day 5). After day 5, the dose should be adjusted within the effective dose range of 400 to 600 mg/day depending upon the clinical response and tolerability of the patient. Patients should be administered the lowest effective dose. Dosage adjustments should be in increments of no greater than 100 mg/day.
Schizophrenia (13 to 17 years of age). The total daily dose for the first five days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), 300 mg (day 4) and 400 mg (day 5). After day 5, the dose should be adjusted within the effective dose range of 400 to 800 mg/day depending upon the clinical response and tolerability of the patient. Patients should be administered the lowest effective dose. Dosage adjustments should be in increments of no greater than 100 mg/day.
Renal impairment. Dosage adjustment is not necessary.
Hepatic impairment. Quetiapine is extensively metabolised by the liver. Therefore, Seroquel should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased in increments of 25 to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.
Overdosage In clinical trials, experience with Seroquel in overdosage is limited. Estimated doses of quetiapine up to 30 g have been taken, without fatal consequences and with patients recovering without sequelae, however, death has been reported in a clinical trial following an overdose of quetiapine 13.6 g alone. In postmarketing experience, there have been very rare reports of overdose of Seroquel alone resulting in death or coma.
In postmarketing experience there were cases reported of QT prolongation with overdose.
Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose (see Precautions, Concomitant cardiovascular illness).
Symptoms. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e. drowsiness and sedation, tachycardia and hypotension.
Treatment. There is no specific antidote to quetiapine. In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. While the prevention of absorption in overdose has not been investigated, administration of activated charcoal together with a laxative should be considered.
Close medical supervision and monitoring should be continued until the patient recovers.
Contact the Poisons Information Centre on 131 126 for advice on management.
Presentation Tablets (film coated), 25 mg (free base) (peach, round, biconvex, marked SEROQUEL 25, plain on reverse): 20's*, 60's; 100 mg (free base) (yellow, round, biconvex, marked SEROQUEL 100, plain on reverse): 20's*, 90's; 150 mg* (free base) (pale yellow, round, biconvex, marked SEROQUEL 150, plain on reverse): 60's; 200 mg (free base) (white, round, biconvex, marked SEROQUEL 200, plain on reverse): 20's*, 60's; 300 mg (free base) (white, capsoid, marked SEROQUEL, 300 on reverse): 20's*, 60's, 100's* (PVC/ aluminium foil blister pack).
4 Day starter pack: 25 mg x 6, 100 mg x 3 and 200 mg x 1.*
*Not currently marketed in Australia.
Storage Store below 30°C.
Poison Schedule S4.
Source Reference Date of TGA approved information: 03/03/2010
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