Medsafe Logo


INFORMATION FOR HEALTH PROFESSIONALS

Home  |  Consumers  |  Health Professionals  |  Regulatory  |  Other  |  Hot Topics  |  Search

Data Sheet

Seroquel

Quetiapine fumarate 25 mg, 100 mg, 150 mg, 200 mg, 300 mg

Presentation

SEROQUEL 25 mg is presented as a peach coloured round, biconvex, film-coated tablet containing quetiapine fumarate delivering a dose of 25 mg of quetiapine free base. The tablets are 6 mm in diameter and are compressed to a weight of 100 mg. SEROQUEL and the strength are impressed on one side and the tablet is plain on the other.

SEROQUEL 100 mg is presented as a yellow coloured round, biconvex, film-coated tablet containing quetiapine fumarate delivering a dose of 100 mg of quetiapine free base. The tablets are 8.5 mm in diameter and are compressed to a weight of 250 mg. SEROQUEL and the strength are impressed on one side and the tablet is plain on the other.

SEROQUEL 150 mg is presented as a pale yellow coloured round, biconvex, film-coated tablet containing quetiapine fumarate delivering a dose of 150 mg of quetiapine free base. The tablets are 10 mm in diameter and are compressed to a weight of 375 mg. SEROQUEL and the strength are impressed on one side and the tablet is plain on the other. [Not available in New Zealand]

SEROQUEL 200 mg is presented as a white coloured round, biconvex, film-coated tablet containing quetiapine fumarate delivering a dose of 200 mg of quetiapine free base. The tablets are 11 mm in diameter and are compressed to a weight of 500 mg. SEROQUEL and the strength are impressed on one side and the tablet is plain on the other.

SEROQUEL 300 mg is presented as a white coloured capsule-shaped (19 mm x 7.62), film-coated tablet containing quetiapine fumarate delivering a dose of 300 mg of quetiapine free base. The tablets are compressed to a weight of 750 mg. The tablet is impressed with SEROQUEL on one side and the strength on the other.

Uses

Actions

Mechanism of action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, N-desalkyl quetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and N-desalkyl quetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1 and D2 receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to Dopamine2 receptors which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effects (EPS) liability of SEROQUEL. Additionally, N-desalkyl quetiapine has high affinity for the norepinephrine transporter (NET). Quetiapine and N-desalkyl quetiapine also have high affinity at histaminergic and adrenergic alpha1 receptors, with a lower affinity at adrenergic alpha2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.

Pharmacodynamic effects

Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviourally or electrophysiologically and elevates dopamine metabolite concentrations, a neurochemical index of dopamine D2 receptor blockade.

In pre-clinical tests predictive of EPS, quetiapine is unlike standard antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2 receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2 receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the A10 mesolimbic but not the A9 nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naïve Cebus monkeys after acute and chronic administration. The results of these tests predict that SEROQUEL should have minimal EPS liability, and it has been hypothesised that agents with a lower EPS liability may also have a lower liability to produce tardive dyskinesia.

The extent to which the N-desalkyl quetiapine metabolite contributes to the pharmacological activity of SEROQUEL in humans is not known.

Clinical efficacy

Clinical trials have demonstrated that SEROQUEL is effective when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study which identified that for quetiapine, 5HT2 and Dopamine2 receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

Unlike many other antipsychotics, SEROQUEL does not produce sustained elevations in prolactin, which is considered a feature of atypical agents. In a multiple fixed-dose clinical trial, there were no differences in prolactin levels at study completion, for SEROQUEL across the recommended dose range, and placebo.

Schizophrenia:

In clinical trials, SEROQUEL has been shown to be effective in the treatment of both positive and negative symptoms of schizophrenia. In comparative clinical trials, SEROQUEL has been shown to be as effective as standard antipsychotic agents such as chlorpromazine and haloperidol.

In three 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 or concomitant use of anticholinergics. A placebo-controlled trial evaluating fixed doses of SEROQUEL across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anticholinergics.

Bipolar mania:

In clinical trials, SEROQUEL has been shown to be effective as monotherapy or as adjunct therapy in reducing manic symptoms in patients with bipolar mania. Efficacy has been demonstrated up to 12 weeks in the monotherapy setting. In the adjunct setting, there are no efficacy data beyond 6 weeks. The mean last week median dose of SEROQUEL in responders, was approximately 600 mg and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.

In four placebo-controlled trials, evaluating doses of SEROQUEL up to 800 mg/day for the treatment of bipolar mania, two each in monotherapy and as adjunct therapy to lithium or sodium valproate, there were no differences between the SEROQUEL and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.

Bipolar depression:

In two clinical trials, which included patients who are bipolar I, bipolar II and patients with and without rapid cycling courses, SEROQUEL has been shown to be effective in patients with bipolar depression at doses of 300 and 600 mg/day, however, no additional benefit was seen with the 600 mg dose.

In both studies, SEROQUEL was superior to placebo in reduction of Montgomery-Asberg Depression Scale (MADRS) total score. The antidepressant effect of SEROQUEL was significant at Day 8 (Week 1) and was maintained through the end of the studies (Week 8). Treatment with either SEROQUEL 300 or 600 mg at bedtime reduced depressive symptoms and anxiety symptoms in patients with bipolar depression. There were fewer episodes of treatment emergent mania with either dose of SEROQUEL than with placebo.

For the 300 mg dose group, statistically significant improvements over placebo were seen in reductions in suicidal thinking as measured by MADRS item 10 and overall quality of life and satisfaction related to various areas of functioning, as measured using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q).

In two placebo-controlled trials, evaluating doses of SEROQUEL 300 and 600 mg/day for treatment of bipolar depression, the incidence of EPS was higher in the SEROQUEL treatment groups compared to the placebo treatment groups The concomitant use of anticholinergics was similar across treatment groups.

There are currently no efficacy or safety data beyond 8 weeks.

Bipolar Maintenance

The efficacy of SEROQUEL in the maintenance treatment of bipolar disorder was established in 2 placebo-controlled trials in 1326 patients who met DSM-IV criteria for bipolar I disorder. The trials included patients whose most recent mood episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stablised on SEROQUEL in combination with mood stabiliser (lithium or valproate) for a minimum of 12 weeks in order to be randomised. In the randomisation phase, patients either continued treatment with SEROQUEL (administered twice daily totalling 400 to 800 mg per day) in combination with mood stabiliser (lithium or valproate) or received placebo in combination with mood stabiliser (lithium or valproate) for up to 104 weeks.

In each study, SEROQUEL was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), the primary endpoint. The risk reductions were 67% and 74%.

Maintenance treatment with SEROQUEL was superior to placebo in increasing the time to recurrence of a depressive event. Patients on SEROQUEL also had a lower risk of experiencing a depressive event prior to week 28 and week 52 compared to patients on placebo.

Similarly, maintenance treatment with SEROQUEL was superior to placebo in increasing the time to recurrence of a manic event. Patients on SEROQUEL also had a lower risk of experiencing a manic event prior to week 28 and week 52 compared to patients on placebo.

Efficacy was demonstrated to be independent of the nature of the most recent episode (manic, mixed or depressed), the mood stabiliser (lithium or valproate), rapid cycling course, gender, age or ethnicity.

In two bipolar maintenance placebo-controlled trials, comparing the efficacy and safety of SEROQUEL (administered twice daily totalling 400 to 800 mg per day) in combination with mood stabilisers (lithium or valproate), the incidence of EPS from randomisation to end of treatment in the SEROQUEL treatment group was similar to the placebo treatment group. The concomitant use of anticholinergics was similar across treatment groups.

Pharmacokinetics

Quetiapine is well absorbed and extensively metabolised following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food. Quetiapine is approximately 83% bound to plasma proteins. Steady-state peak molar concentrations of the active metabolite N-desalkyl quetiapine are 35% of that observed for quetiapine. The elimination half lives of quetiapine and N-desalkyl quetiapine are approximately 7 and 12 hours, respectively.

The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear across the approved dosing range. The kinetics of quetiapine does not differ between men and women.

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m2) and in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects. The average molar dose fraction of free quetiapine and the active human plasma metabolite N-desalkyl quetiapine is <5% excreted in the urine.

Quetiapine is extensively metabolised by the liver with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces. The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with hepatic impairment (stable alcoholic cirrhosis). Since quetiapine is extensively metabolised by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed in these patients (see DOSAGE AND ADMINISTRATION).

In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. N-desalkyl quetiapine is primarily formed and eliminated via CYP3A4.

Quetiapine and several of its metabolites (including N-desalkyl quetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that coadministration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug.

Indications

SEROQUEL is indicated for the:

Dosage And Administration

Adults

For the treatment of acute and chronic psychoses, including schizophrenia:

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

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 range of 300-450 mg/day. However, this may be adjusted, depending on the clinical response and tolerability of the individual patient, within the range 150 to 750 mg/day.

For the treatment of manic episodes associated with bipolar disorder:

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

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/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.

For the treatment of depressive episodes associated with bipolar disorder:

SEROQUEL should be administered once daily at bedtime, with or without food.

The usual dose is 300 mg/day. The 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). SEROQUEL can be titrated to 400 mg on Day 5 and up to 600 mg by Day 8.

Antidepressant efficacy was demonstrated with SEROQUEL at 300 mg and 600 mg however no additional benefit was seen in the 600 mg group. (See CLINICAL EFFICACY - BIPOLAR DEPRESSION and ADVERSE EFFECTS).

For the maintenance treatment of bipolar I disorder in combination with mood stabilisers

Patients who have responded to SEROQUEL in combination therapy with a mood stabiliser for acute treatment of bipolar disorder should continue on SEROQUEL therapy at the same dose.

The SEROQUEL dose can be re-adjusted depending on clinical response and tolerability of the individual patient.

Efficacy was demonstrated with SEROQUEL (administered twice daily totalling 400 mg to 800 mg a day) as combination therapy with a mood stabiliser.

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 not been evaluated in children and adolescents.

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 daily in increments of 25-50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.

Contraindications

SEROQUEL is contraindicated in patients who are hypersensitive to any component of this product.

Warnings And Precautions

Concomitant Illness

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.

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 (see ADVERSE EFFECTS).

Extrpyramidal Symptoms (EPS) And Tardive Dyskinesia

In placebo-controlled clinical trials for schizophrenia and bipolar mania, the incidence of EPS was no different from that of placebo across the recommended therapeutic dose range. This predicts that SEROQUEL has less potential than standard antipsychotic agents to induce tardive dyskinesia in schizophrenia and bipolar mania patients. In short-term, placebo-controlled clinical trials for bipolar depression, the incidence of EPS was higher in SEROQUEL treated patients than in placebo treated patients (see ADVERSE EFFECTS). In long-term, placebo-controlled clinical trials for bipolar maintenance, the incidence of EPS was similar in patients treated with SEROQUEL or placebo. However, 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. 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.

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 EFFECTS.

Withdrawal

Acute withdrawal symptoms such as nausea, vomiting and insomnia have very rarely been described after abrupt cessation of antipsychotic drugs including SEROQUEL. Gradual withdrawal is advisable.

Hyperglycaemia and Diabetes Mellitus

Increases in blood glucose and hyperglycaemia, and occasional reports of diabetes, have been observed in clinical trials with quetiapine. Although a causal relationship with diabetes has not been established, patients who are at risk for developing diabetes are advised to have appropriate clinical monitoring. Similarly, patients with existing diabetes should be monitored for possible exacerbation (see ADVERSE EFFECTS).

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 baseline 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.

Safety Experience in Elderly Patients with Dementia-related psychosis

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in quetiapine-treated patients was greater than placebo treated patients (5.5% vs. 3.2 %, respectively). This difference was not statistically significant. Risk factors that may predispose this patient population to increased mortality when treated with quetiapine include age > 75 years, or presence of pulmonary conditions (e.g. pneumonia, with or without aspiration). The data does not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.

Interactions

Also see INTERACTIONS section.

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.

Use in Pregnancy

The safety and efficacy of SEROQUEL during human pregnancy have not been established. Therefore, SEROQUEL should only be used during pregnancy if the benefits justify the potential risks.

Use in Lactation

The degree to which quetiapine is excreted into human milk is unknown. Women who are breast-feeding should therefore be advised to avoid breast-feeding while taking SEROQUEL.

Effect on Ability to Drive and Use Machines

Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility is known.

Adverse Effects

The most commonly reported Adverse Drug Reactions (ADRs) with Seroquel are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.

As with other antipsychotics, weight gain, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral oedema, have been associated with Seroquel.

The incidences of ADRs associated with Seroquel therapy, are tabulated below according to the format recommended by the Council for International Organisations of Medical Sciences (CIOMS III Working Group; 1995).

Frequency System Organ Class Event
Very Common
(≥10%)		 Nervous system disorders Dizziness1, 5
Somnolence2
Gastrointestinal disorders Dry Mouth
Common
(≥1% - <10%)		 Blood and lymphatic system disorders Leukopenia
Cardiac disorders Tachycardia1, 5
Gastrointestinal disorders Constipation
Dyspepsia
General disorders and administration site conditions Mild asthenia
Peripheral oedema
Investigations Weight gain4
Elevations in serum transaminases (ALT, AST)5
Neutrophil count decreased Blood glucose increased to hypergylcaemic level8
Nervous system disorders Syncope1, 5
Respiratory, thoracic, and mediastinal disorders Rhinitis
Vascular disorders Orthostatic hypotension1, 5
Uncommon
(≥0.1% - <1%)		 Blood and lymphatic system disorders Eosinophilia
Immune system disorders Hypersensitivity
Investigations Elevations in gamma-GT levels4
Elevations in non-fasting serum triglyceride levels
Elevations in total cholesterol
(predominantly LDL cholesterol)
Nervous system disorders Seizure1
Restless legs syndrome
Rare
(0.01% - <0.1%)		 General disorders and administration site conditions Neuroleptic malignant synrome1
Reproductive system and breast disorders Priapism
Very Rare
(<0.01%)		 Immune system disorders Anaphylactic reaction6

 

  1. See WARNINGS AND PRECAUTIONS
  2. Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of Seroquel
  3. Occurs predominantly during the early weeks of treatment.
  4. Asymptomatic elevations in serum transaminase (ALT, AST) or gamma-GT levels have been observed in some patients administered SEROQUEL. These elevations were usually reversible on continued SEROQUEL treatment.
  5. As with other antipsychotics with alpha1 adrenergic blocking activity, SEROQUEL may induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period.
  6. The inclusion of anaphylactic reaction is based on post marketing reports.
  7. In all placebo-controlled monotherapy trials 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 SEROQUEL, 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 was 0.21% in patients treated with SEROQUEL and 0% in placebo treated patients and the incidence ≥0.5 -<1.0 x 109/L was 0.75% in patients treated with SEROQUEL and 0.11% in placebo-treated patients.
  8. Fasting blood glucose ≥126 mg/dL or a non fasting blood glucose ≥200 mg/dL on at least one occasion.

In placebo-controlled clinical trials in schizophrenia and bipolar mania the incidence of EPS was no different to placebo (schizophrenia: SEROQUEL 10.9%, placebo 11.3%; bipolar mania SEROQUEL 15.7%, placebo 15.2%). (see WARNINGS AND PRECAUTIONS). In two short-term studies in bipolar depression the incidence of EPS from the combined data was 11.8% for SEROQUEL compared to 5.5% for placebo (see WARNINGS AND PRECAUTIONS). In these studies, the incidence of the individual adverse events (eg, 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 two long-term studies in bipolar maintenance, the incidence of EPS from randomisation to end of treatment for the combined data was 7.9% for SEROQUEL in combination with a mood stabiliser (lithium or valproate).compared to 6.9% for placebo in combination with a mood stabiliser (lithium or valproate) (see WARNINGS AND PRECAUTIONS).

Exacerbation of pre-existing diabetes mellitus, and diabetic ketoacidosis, have occurred very rarely with quetiapine therapy. The causal association with quetiapine has not been established (see WARNINGS AND PRECAUTIONS).

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 SEROQUEL treatment, with no further reduction during long-term treatment. 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. Smaller decreases in total T3 and reverse T3 were seen only at higher doses. Levels of TBG were unchanged and in general reciprocal increases in TSH were not observed, with no indication that SEROQUEL causes clinically relevant hypothroidism.

Interactions

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 were not altered when co-administered with SEROQUEL.

The pharmacokinetics of sodium valproate and SEROQUEL were not altered to a clinically relevant extent when co-administered.

The pharmacokinetics of quetiapine were 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 750 mg/day, for the treatment of acute and chronic psychoses including schizophrenia, and 800 mg/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 were 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). In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, co-administration of ketoconazole resulted in an increase in mean Cmax and AUC of quetiapine of 235% 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. Due to the potential for an interaction of a similar magnitude in a clinical setting, the dosage of SEROQUEL should be reduced during concomitant use of quetiapine and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors).

Overdosage

In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed reported no adverse events or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone.

In postmarketing experience, there have been very rare reports of overdose with quetiapine alone resulting in death or coma.

Patients with pre-existing severe cardiovascular disease may be at increased risk of the effects of overdose (See WARNINGS AND PRECAUTIONS).

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.

There is no specific antidote to quetiapine. In cases of severe intoxication, 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.

Close medical supervision and monitoring should be continued until the patient recovers.

Pharmaceutical Precautions

Shelf-life

3 years

Storage Conditions

Store below 30°C.

List of excipients

Core

Coating

Medicine Classification

Prescription Medicine.

Package Quantities

SEROQUEL STARTER PACK is presented as a PVC/aluminium foil blister pack containing 25 mg x 6 tablets and 100 mg x 2 tablets.

SEROQUEL 25 mg tablets are presented in a PVC/aluminium foil blister pack containing 6 tablets or 60 (6 x 10) tablets.

SEROQUEL 100 mg tablets are presented in a PVC/aluminium foil blister pack containing 60 (6 x 10) tablets or 100 (10 x 10) tablets.

SEROQUEL 150 mg tablets are presented in a PVC/aluminium foil blister pack containing 60 (6 x 10) tablets. Not available in New Zealand

SEROQUEL 200 mg tablets are presented in a PVC/aluminium foil blister pack containing 60 (6 x 10) tablets or 100 (10 x 10) tablets.

SEROQUEL 300 mg tablets are presented in a PVC/aluminium foil blister pack containing 60 (6 x 10) tablets or 100 (10 x 10) tablets.

Further Information

Acute Toxicity Studies

Quetiapine has low acute toxicity. Findings in mice and rats after oral (500 mg/kg) or intraperitoneal (100 mg/kg) dosing were typical of an effective neuroleptic agent and included decreased motor activity, ptosis, loss of righting reflex, fluid around the mouth and convulsions.

Repeat-dose Toxicity Studies

In multiple-dose studies in rats, dogs and monkeys, anticipated central nervous system effects of an antipsychotic drug were observed with quetiapine (e.g. sedation at lower doses and tremor, convulsions or prostration at higher exposures).

Hyperprolactinaemia, induced through the dopamine D2 receptor antagonist activity of quetiapine or its metabolites, varied between species but was most marked in the rat, and a range of effects consequent to this were seen in the 12-month study, including mammary hyperplasia, increased pituitary weight, decreased uterine weight and enhanced growth of females.

Reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction, were seen in mouse, rat and monkey.

Thyroid follicular cell hypertrophy and concomitant changes in plasma thyroid hormone levels occurred in rat and monkey.

Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.

Transient increases in heart rate, unaccompanied by an effect on blood pressure, occurred in dogs.

Posterior triangular cataracts seen after 6 months in dogs at 100 mg/kg/day were consistent with inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in Cynomolgus monkeys dosed up to 225 mg/kg/day, nor in rodents. Monitoring in clinical studies did not reveal drug-related corneal opacities in man.

No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.

Carcinogenicity studies

In the rat study (doses 0, 20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia.

In 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.

Reproduction Studies

Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, 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.

Quetiapine had no teratogenic effects.

Mutagenicity studies

Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen.

Name And Address

AstraZeneca Limited
303 Manukau Road, Epsom
P O Box 1301
AUCKLAND

Telephone: (09) 623-6300

Date Of Preparation

19 September 2007

CDS June 2007

Copyright - No part may be reproduced by any process without the prior written permission of AstraZeneca Limited