Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

SEROQUEL should be administered twice daily, with or without food.

Adults

For the treatment of schizophrenia: the total daily dose for the first 4 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 range 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.

For the treatment of manic episodes associated with bipolar disorder: as monotherapy or as adjunct therapy to mood stabilizers, 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). Further dosage adjustments up to 800 mg per day by Day 6 should be in increments of no greater than 200 mg per day.

The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg per day. The usual effective dose is in the range of 400 to 800 mg per day.

Renal and hepatic impairment

The oral clearance of quetiapine is reduced by approximately 25% in patients with renal or hepatic impairment. Quetiapine is extensively metabolised by the liver, and therefore should be used with caution in patients with known hepatic impairment.

Patients with renal or hepatic impairment should be started on SEROQUEL 25 mg/day. The dose should be increased daily, in increments of 25 to 50 mg, to an effective dose.

Child Dosage

The safety and efficacy of SEROQUEL have not been evaluated in children and adolescents.

Elderly Dosage

As with other antipsychotics, SEROQUEL should be used with caution in the elderly, especially during the initial dosing period. Elderly patients should be started on SEROQUEL 25 mg/day. The dose should be increased daily, in increments of 25 to 50 mg, to an effective dose, which is likely to be lower than that in younger patients.

Contra Indications

SEROQUEL is contra-indicated in patients who are hypersensitive to any component of this product.

Special Precautions

Cardiovascular disease

SEROQUEL should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension.

SEROQUEL may induce orthostatic hypotension, especially during the initial dose-titration period; this is more common in elderly patients than in younger patients.

QT Prolongation

In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. However, with overdose QT prolongation was observed. As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when quetiapine is prescribed with medicines known to increase QTc interval, and concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.

Seizures

In controlled clinical trials there was no difference in the incidence of seizures in patients treated with SEROQUEL or placebo. As with other antipsychotics, caution is recommended when treating patients with a history of seizures.

Tardive dyskinesia

As with other antipsychotics, there is a potential for SEROQUEL to cause tardive dyskinesia after long-term treatment. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of SEROQUEL should be considered.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including SEROQUEL (see Section 4.8). 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.

Severe neutropenia

Severe neutropenia (neutrophil count <0.5 X 10⁹/L) has been uncommonly reported in Seroquel clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with Seroquel. There is 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. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 10⁹/L).

Acute withdrawal reactions

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability have been described after abrupt cessation of Seroquel. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Gradual withdrawal over a period of at least one to two weeks is advisable.

Interactions

See also Section 4.5 Interactions with other medicinal products and other forms of interaction

Concomitant use of SEROQUEL with hepatic enzyme inducers such as 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.

During concomitant administration of drugs 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.  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.

Hyperglycaemia

Hyperglycaemia or exacerbation of pre-existing diabetes has been reported during treatment with quetiapine. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.

Elderly patients with dementia-related psychosis

Seroquel is not approved for the treatment of patients with dementia-related psychosis.

An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with risk factors for stroke.

Hepatic effects

If jaundice develops, Seroquel should be discontinued.

Lipids

Increases in triglycerides and cholesterol have been observed in clinical trials with quetiapine. Lipid increases should be managed as clinically appropriate.

Interactions

Drugs prolonging QT interval, CNS depressants, phenytoin, carbamazepine, barbiturates, rifampicin, thioridazine, ketoconazole, erythromycin.

Adverse Reactions

Given the primary central nervous system effects of quetiapine SEROQUEL should be used with caution in combination with other centrally acting drugs and alcohol.

The pharmacokinetics of lithium was not altered when co-administered with SEROQUEL

The pharmacokinetics of valproic acid and quetiapine were not altered to a clinically relevant extent when co-administered as valproate semisodium (also known as divalproex sodium (USAN)) and SEROQUEL (quetiapine fumarate). Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship.

The pharmacokinetics of quetiapine was not significantly altered following co-administration with the antipsychotics risperidone or haloperidol. However co-administration of SEROQUEL and thioridazine caused increases in the clearance of quetiapine.

Quetiapine did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, 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), co-administration 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. It should be noted that the recommended maximum daily dose of SEROQUEL is 750mg/day for the treatment of schizophrenia and 800mg/day for the treatment of manic episodes associated with bipolar disorder. Continued treatment at higher doses should only be considered as a result of careful consideration of the benefit risk assessment for an individual patient. Co-administration of SEROQUEL with another microsomal enzyme inducer, phenytoin, also caused increases in the clearance of quetiapine. Increased doses of SEROQUEL may be required to maintain control of psychotic symptoms in patients co-administered SEROQUEL and phenytoin and other hepatic enzyme inducers (e.g. barbiturates, rifampicin etc.). The dose of SEROQUEL may need to be reduced if phenytoin or carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g. sodium valproate).

CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. The pharmacokinetics of quetiapine was not altered following co-administration with cimetidine, a known P450 enzyme inhibitor. The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor). However, caution is recommended when SEROQUEL is co-administered with potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors).

Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QTc interval.

Manufacturer

Drug Availability

Updated