Summary of Product Characteristics Updated 01-Jul-2013 | Accord-UK Ltd
For the treatment of schizophrenia:Quetiapine should be administered twice a day.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 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:Quetiapine should be administered twice a day.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.
For the treatment of depressive episodes in bipolar disorder:Quetiapine should be administered once daily at bedtime as this may reduce the likelihood of day time sedation. 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). The recommended daily dose is 300 mg. Depending on the patients' response quetiapine may be titrated up to 600mg daily. Antidepressant efficacy was demonstrated at 300mg and 600mg/day, however no additional benefit was seen in the 600mg/day group, above 300mg daily during short-term treatment (see section 5.1). In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered. When treating depressive episodes in bipolar disorder, treatment should be initiated by physicians experienced in treating bipolar disorder.
ElderlyAs with other antipsychotics, quetiapine 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 - 50% in elderly subjects when compared to younger patients.Efficacy and safety has not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder.
Children and adolescentsThe safety and efficacy of quetiapine have not been evaluated in children and adolescents.
Renal impairmentDose adjustments are not necessary in patients with renal impairment
Hepatic impairmentQuetiapine is extensively metabolised by the liver, and therefore should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with known hepatic impairment should be started on 25mg/day. The dose should be increased daily, in increments of 25 to 50mg, to an effective dose, depending on the clinical response and tolerability of the individual patient.
Suicide/suicidal thoughts or clinical worseningDepression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.In clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients less than 25 years of age who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively).
SomnolenceQuetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see section 4.8). In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.
Cardiovascular diseaseQuetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Quetiapine may induce orthostatic hypotension, especially during the initial dose-titration period and therefore dose reduction or more gradual titration should be considered if this occurs.
SeizuresIn controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section 4.8).
Tardive dyskinesiaIf signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered (see section 4.8).
Neuroleptic malignant syndromeNeuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.
Severe NeutropeniaSevere neutropenia (neutrophil count <0.5 X 109/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine. There was no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine. 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). (See section 5.1).
LipidsIncreases in triglycerides and cholesterol have been observed in clinical trials with quetiapine (see section 4.8). Lipid increases should be managed as clinically appropriate.
Extrapyramidale symptomsIn placebo controlled clinical trials quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder (see section 4.8).
InteractionsSee also section 4.5.Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).
HyperglycaemiaHyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with quetiapine. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8.).
Venous Thromboembolism (VTE)Cases of VTE have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Quetiapine Tablets and preventive measures undertaken.
QT ProlongationIn clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. However, with overdose (see section 4.9) 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 (see section 4.5).
WithdrawalAcute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable (see section 4.8).
Elderly patients with dementia-related psychosisQuetiapine is not approved for the treatment of dementia-related psychosis.An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled 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.In a meta-analysis of atypical antipsychotic drugs, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However in two 10-week placebo-controlled quetiapine studies in the same patient population (n=710); mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died of a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.
Additional informationQuetiapine data in combination with divalproex or lithium in moderate to severe manic episodes is limited; however, combination therapy was well tolerated (see section 4.8 and 5.1). The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6. There are no combination data available beyond week 6.
OtherThis medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy:The safety and efficacy of quetiapine during human pregnancy have not been established (see section 5.3). Up to now there are no indications for harmfulness in animal tests, possible effects on the foetal eye have not been examined, though. Therefore, quetiapine should only be used during pregnancy if the benefits justify the potential risks. Following pregnancies in which quetiapine was used, neonatal withdrawal symptoms were observed.Neonates exposed to antipsychotics (including Quetiapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
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 quetiapine.
|The frequencies of adverse events are ranked according to the following: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100, rare (≥1/10,000, <1/1000) and very rare (<1/10,000).|
|Blood and lymphatic system disorders|
|Immune system disorders|
|Very rare:||Anaphylactic reaction 6|
|Metabolism and nutritional disorders|
|Very rare:||Diabetes Mellitus 1, 5, 6|
|Common:||Abnormal dreams and nightmares|
|Nervous system disorders|
|Very Common:||Dizziness 4, 17, somnolence 2, 17, headache|
|Common:||Syncope 4, 17, Extrapyramidal symptoms1, 13|
|Uncommon:||Seizure 1, Restless legs syndrome, Dysarthria|
|Very rare||Tardive dyskinesia6|
|Common:||Orthostatic hypotension 4, 17|
|Unknown:||Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs.|
|Respiratory, thoracic and mediastinal disorder|
|Very common:||Dry mouth|
|Very rare:||Hepatitis 6|
|Skin and subcutaneous tissue disorders|
|Very rare:||Angioedema 6, Stevens-Johnson syndrome 6|
|Pregnancy, puerperium and perinatal conditions|
|Not Known:||Drug withdrawal syndrome neonatal|
|Reproductive system and breast disorders|
|General disorders and administration site conditions|
|Very common||Withdrawal (discontinuation) symptoms 1, 10|
|Common:||Mild asthenia, peripheral oedema, irritability|
|Rare:||Neuroleptic malignant syndrome 1|
|Very common||Elevations in serum triglyceride levels 11 Elevations in total cholesterol (predominantly LDL cholesterol) 12 Weight gain9|
|Common:||Elevations in serum transaminases (ALT, AST) 3, decreased neutrophil count, blood glucose increased to hyperglycaemic levels 7|
|Uncommon:||Elevations in gamma-GT levels 3, Platelet count decreased 14|
|Rare:||Elevations in blood creatine phosphokinase 15|
Mechanism of actionQuetiapine 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 5-HT2 and dopamine D1 and D2 receptors. It is this combination of receptor antagonism with a higher selectivity for serotonin 5-HT2 receptors relative to D2 receptors which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal symptom (EPS) liability of quetiapine. 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 α1 receptors, with a lower affinity at adrenergic α2 and serotonin 5-HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.
Pharmacodynamic effectsQuetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of 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. It produces only weak catalepsy at effective dopamine D2 receptor-blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the 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 quetiapine 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 (see section 4.8).The extent to which the N-desalkyl quetiapine metabolite contributes to the pharmacological activity of quetiapine in humans is not known.
Clinical efficacyIn three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of quetiapine, there were no differences between the quetiapine and placebo groups in the incidence of EPS or concomitant use of anticholinergics. A placebo-controlled trial evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anticholinergics.In four placebo-controlled clinical trials, evaluating doses of quetiapine up to 800 mg/day for the treatment of moderate to severe manic episodes, two each in monotherapy and as combination therapy to lithium or valproic acid, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. There are no data from long-term studies to demonstrate quetiapine's effectiveness in preventing subsequent manic or depressive episodes. Quetiapine data in combination with valproic acid or lithium in moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6. There are no combination data available beyond week 6.The mean last week median dose of quetiapine in responders was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400 to 800 mg per day.In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, quetiapine immediate release 300 mg and 600 mg was significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline. There was no difference in magnitude of effect between the patients who received 300 mg quetiapine immediate release and those who received 600 mg dose.In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on quetiapine immediate release 300 mg or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.In two recurrence prevention studies evaluating quetiapine in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with quetiapine was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event ( manic, mixed or depressed). Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate. Clinical trials have demonstrated that quetiapine is effective in schizophrenia and mania 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 D2 receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.The long-term efficacy of quetiapine in prevention of schizophrenic relapses has not been verified in blinded clinical trials. In open label trials, in patients with schizophrenia, quetiapine was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response, suggesting some long-term efficacy.In placebo-controlled monotherapy trials in 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 all clinical trials (placebocontrolled, open-label, active comparator; 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 quetiapine and 0% in placebo treated patients and the incidence ≥ 0.5 - < 1.0 X 109/L was 0.75% in patients treated with quetiapine and 0.11% in placebo-treated patients.
Tablet core:Cellulose, microcrystallineCalcium hydrogen phosphate dihydrateSodium starch glycolate (Type A)Povidone Lactose monohydrate Magnesium stearate
Tablet coating:Polyvinyl alcohol-part hydrolysed Titanium dioxide (E171) MacrogolTalcIron Oxide Yellow (E172)
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