Seroquel 25 mg, 100 mg, 200 mg, 300 mg, Tablet

SEROQUEL is indicated for the treatment of schizophrenia. SEROQUEL is also indicated for the treatment of manic episodes associated with a bipolar disorder. Safety and efficacy beyond 12 weeks have not been demonstrated.

Posology 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 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 150-750 mg per day. For the treatment of manic episodes associated with bipolar disorder, the total daily dose for the first 4 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 the clinical response and tolerability of the individual patient, within the range of 200-800 mg/day. The usual effective dose is in the range of 400-800 mg/day.

Special Populations Elderly: 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 25-50 mg, to an effective dose, which is likely to be lower than that in younger patients. Renal and hepatic impairment: The oral clearance of SEROQUEL is reduced by approximately 25 % in patients with renal or hepatic impairment. SEROQUEL 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 25-50 mg, to an effective dose.

• SEROQUEL is contraindicated in patients who are hypersensitive to any component of this medicine.
• Pregnancy and lactation, as safety has not been demonstrated.
• Safety and efficacy in children and adolescents have not been demonstrated.
• Advanced liver and renal function impairment, as safety has not been demonstrated.

Suicide/suicidal thoughts or clinical worsening: Depression 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. Other psychiatric conditions for which SEROQUEL is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may co-morbid with major depression disorder. The same precaution observed when treating patients with major depressive disorder should therefore be observed when treating with other psychiatric disorders. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

Neutropenia and agranulocytosis: Severe neutropenia (<0,5 X 10 9 /L) without infection has been uncommonly reported in short-term placebo-controlled monotherapy clinical trials with SEROQUEL. There have been reports of agranulocytosis (severe neutropenia with infection) among all patients treated with SEROQUEL during clinical trials (rare) as well as post-marketing reports (including fatal cases). Most of these cases of severe neutropenia have occurred within the first two months of starting therapy with quetiapine. 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. There have been cases of agranulocytosis in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate. SEROQUEL should be discontinued in patients with a neutrophil count <1,0 X 10 9 /L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1,5 X 10 9 /L) (see section 4.8).

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. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics such as SEROQUEL, 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 such as SEROQUEL, should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics such as SEROQUEL, should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic such as SEROQUEL, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Lipids: Increases in triglycerides and cholesterol and decreases in HDL have been observed with SEROQUEL (see section 4.8). Lipid changes should be managed as clinically appropriate.

Metabolic factors: In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.

Pancreatitis: Pancreatitis has been reported in clinical trials and during the post marketing experience. Among the post marketing reports, while not all cases were confounded by risk factors, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see section 4.4 Lipids), gallstones and alcohol consumption.

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; this is more common in elderly patients than in younger patients.

In patients who have a history of or are at risk of sleep apnoea and are receiving concomitant central nervous system (CNS) depressants, SEROQUEL should be used with caution.

Dysphagia: Dysphagia (see section 4.8) and aspiration have been reported with SEROQUEL. SEROQUEL should be used with caution in patients at risk for aspiration pneumonia.

Constipation and intestinal obstruction: Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with SEROQUEL (see section 4.8). This includes fatal reports in patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medications that decrease intestinal motility and/or may not report symptoms of constipation. Patients with intestinal obstruction/ileus should be managed with close monitoring and urgent care.

Seizures: Caution is recommended when treating patients with a history of seizures.

Tardive dyskinesia and Extrapyramidal Symptoms (EPS): There is a potential for SEROQUEL to cause tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, discontinuation of SEROQUEL should be considered. In placebo-controlled clinical trials of adult patients with schizophrenia and bipolar mania, the incidence of extrapyramidal symptoms was no different from that of placebo across the recommended therapeutic dose range. This predicts that SEROQUEL has less potential than typical 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 section 4.8).

Neuroleptic malignant syndrome: Neuroleptic malignant syndrome has been associated with SEROQUEL 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.

QT prolongation: In clinical trials, SEROQUEL was not associated with a persistent increase in QTc intervals. However, in post marketing experience there were cases reported of QT prolongation with overdose. As with other antipsychotics, caution should be exercised when SEROQUEL is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when SEROQUEL is prescribed either with medicines known to increase QT interval or with concomitant neuroleptics, especially for patients with increased risk of QT prolongation, i.e. the elderly, patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia, or hypomagnesaemia (see section 4.5).

Cardiomyopathy and Myocarditis: Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience. Treatment with SEROQUEL should be reassessed in patients with suspected cardiomyopathy or myocarditis.

Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Acute Generalised Exanthematous Pustulosis (AGEP), Erythema multiforme (EM) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) are potentially life-threatening adverse drug reactions that have been reported during SEROQUEL exposure. SCARs commonly present with one or more of the following symptoms: extensive cutaneous rash which may be pruritic or associated with pustules, exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia or neutrophilia. Discontinue SEROQUEL if severe cutaneous adverse reactions occur.

Withdrawal: Acute withdrawal symptoms such as insomnia, nausea, and vomiting 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 section 4.8).

Misuse and abuse: Cases of misuse and abuse have been reported. Caution may be needed when prescribing SEROQUEL to patients with a history of alcohol or drug abuse.

Elderly patients with dementia: SEROQUEL is not approved for the treatment of patients with dementia-related psychosis. 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. 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 from a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between SEROQUEL treatment and death in elderly patients with dementia.

Anticholinergic (muscarinic) effects: Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to adverse drugs reactions (ADRs) reflecting anticholinergic effects when SEROQUEL is used at recommended doses, when used concomitantly with other medications having anticholinergic effects, and in the setting of overdose. SEROQUEL should be used with caution in patients receiving medications having anticholinergic (muscarinic) effects. SEROQUEL should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or narrow angle glaucoma (see section 4.5, 4.8, 4.9, and 5.1).

Lactose: SEROQUEL contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, or glucose-galactose malabsorption should not take SEROQUEL.

Given the primary central nervous system effects of SEROQUEL, SEROQUEL should be used with caution in combination with other centrally acting medicines and alcohol. Caution should be exercised when SEROQUEL is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval (see section 4.4). Caution should be exercised treating patients receiving other medications having anti-cholinergic (muscarinic) effects (see section 4.4). 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 SEROQUEL were not significantly altered following co-administration with the antipsychotics risperidone or haloperidol. However, co-administration of SEROQUEL and thioridazine caused increases in clearance of SEROQUEL. SEROQUEL did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. In a multiple dose trial in patients to assess the pharmacokinetics of SEROQUEL given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of SEROQUEL. This increase in clearance reduced systemic SEROQUEL exposure (as measured by AUC) to an average of 13 % of the exposure during administration of SEROQUEL 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 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 clearance of SEROQUEL. 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, 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 SEROQUEL. The pharmacokinetics of SEROQUEL was not altered following co-administration with cimetidine a known P450 enzyme inhibitor. The pharmacokinetics of SEROQUEL 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 SEROQUEL given before and during treatment with ketoconazole, co-administration of ketoconazole resulted in an increase in mean C max and AUC of SEROQUEL of 235 % and 522 %, respectively, with a corresponding decrease in mean oral clearance of 84 %. The mean half-life of SEROQUEL increased from 2,6 to 6,8 hours, but the mean t max was unchanged. Due to the potential for an interaction of similar magnitude in a clinical setting, the dosage of SEROQUEL should be reduced during concomitant use of SEROQUEL and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors). There have been reports of false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken SEROQUEL. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.

Pregnancy SEROQUEL is contraindicated during pregnancy and lactation, as safety has not been demonstrated. Following some pregnancies in which quetiapine was used, neonatal withdrawal symptoms have been reported.

Breastfeeding There have been published reports of quetiapine excretion into human breast milk, however the degree of excretion was not consistent.

SEROQUEL may cause somnolence which may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility is known.

a. Summary of the safety profile The most commonly reported adverse drug reactions (ADRs) with SEROQUEL (u226510 %) are somnolence, dizziness, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms.

b. Tabulated summary of adverse reactions System Organ Class Frequency Event Blood and lymphatic system disorders Common ( u22651 % - <10 %) Leukopenia a, x Very rare Neutropenia ab Immune system disorders Uncommon ( u22650,1 % - <1 %) Hypersensitivity (angioedema, anaphylaxis f , urticaria/rash) Metabolism and nutrition disorders Common ( u22651 % - <10 %) Increased appetite Psychiatric disorders Common ( u22651 % - <10 %) Abnormal dreams and nightmares Rare ( u22650,01 % - <0,1 %) Somnambulism and other related events Nervous system disorders Very common ( u2265 10 %) Dizziness a, e, q Somnolence b, q Extrapyramidal symptoms a, p Common ( u22651 % - <10 %) Dysarthria Uncommon ( u22650,1 % - <1 %) Seizure a Syncope a, e, q Restless legs syndrome Tardive dyskinesia a Confusional state Eye disorders Common ( u22651 % - <10 %) Vision blurred s Cardiac disorders Common ( u22651 % - <10 %) Tachycardia a, e Palpitations t Uncommon ( u22650,1 % - <1 %) Bradycardia y Vascular disorders Common ( u22651 % - < 10 %) Orthostatic hypotension a, e, q Respiratory, thoracic, and mediastinal disorders Common ( u22651 % - <10 %) Dyspnoea t Uncommon ( 0,1 % - <1 %) Rhinitis Gastrointestinal disorders Very common ( u2265 10 %) Dry mouth Common ( u22651 % - <10 %) Constipation Dyspepsia Vomiting v Uncommon ( u22650,1 % - <1 %) Dysphagia a, i Rare ( u22650,01 % - <0,1 %) Intestinal obstruction/Ileus Hepatobiliary disorders Rare ( u22650,01 % - <0,1 %) Hepatitis (with or without jaundice) Skin and subcutaneous tissue disorders Not known Drug reaction with eosinophilia and systemic symptoms (DRESS) Acute Generalized Exanthematous Pustulosis (AGEP) Erythema multiforme (EM) Cutaneous vasculitis Musculoskeletal and connective tissue disorders Very rare Rhabdomyolysis Renal and urinary disorders Uncommon ( u22650,1 % - <1 %) Urinary retention Reproductive system and breast disorders Rare ( u22650,01 % - <0,1 %) Priapism Galactorrhoea General disorders and administration site conditions Very common ( u2265 10 %) Withdrawal (discontinuation) symptoms a, j Common ( u2265 1 % - < 10 %) Asthenia Peripheral oedema Irritability Pyrexia Rare ( u2265 0,01 % - <0,1 %) Neuroleptic malignant syndrome a Hypothermia Unknown Neonatal withdrawal aa Investigations Very common ( u2265 10 %) Elevations in serum triglyceride levels a, k Elevations in total cholesterol a, l Decreases in HDL cholesterol a, r Weight gain c Decreased haemoglobin s Common ( u2265 1 % - <10 %) Elevations in serum alanine aminotransferase (ALT) d Elevations in gamma-GT Levels d Neutrophils count decreased a, g Eosinophils increased w Blood glucose increased to hyperglycaemic level a, h Elevations in serum prolactin o Decreases in Total T 4 u Decreases in Free T 4 u Decreases in Total T 3 u Increases in TSH u Uncommon ( u22650,1 % - <1 %) Elevations in serum aspartate aminotransferase (AST) d Platelet count decreased n Decreases in Free T 3 u Rare (0,01 % - <0,1 %) Elevations in blood creatinine phosphokinase m Agranulocytosis z a See section 4.4 b Somnolence may occur, usually during the first 2 weeks of treatment and generally, resolves with the continued administration of SEROQUEL. c Based on u22657 % increase in body weight from baseline. Occurs predominantly during the early weeks of treatment. d Asymptomatic elevations (shift from normal to u22653X ULN at any time) in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in patients administered SEROQUEL. These elevations were usually reversible on continued SEROQUEL treatment. e SEROQUEL may induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose- titration period. f The inclusion of anaphylactic reaction is based on post-marketing reports. g In all short-term placebo-controlled monotherapy trials among patients with a baseline neutrophil count u22651,5 X 10 9 /L, the incidence of at least one occurrence of neutrophil count 0,5 - <1,0 x 10 9 /L was 0,2 % in patients treated with quetiapine and 0,2 % 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 10 9 /L, among patients with a baseline neutrophil count u22651,5 X 10 9 /L, the incidence of at least one occurrence of neutrophil count <0,5 X 10 9 /L was 0,21 % in patients treated with quetiapine and 0 % in placebo treated patients. h Fas ting blood glucose u2265126 mg/dL or a non - fasting blood glucose u2265200 mg/dL on at least one occasion.

In clinical trials, experience with SEROQUEL in overdosage is limited. In post-marketing experience, there have been very rare reports of overdose of SEROQUEL alone resulting in death or coma. In post marketing experience, there were cases reported of QT prolongation with overdose (see section 4.4). In general, reported signs and symptoms were those resulting from an exaggeration of the medicineu2019s known pharmacological effects, i.e. drowsiness, sedation, tachycardia, hypotension and anticholinergic effects.

Management of overdose There is no specific antidote to SEROQUEL. Treatment is symptomatic and supportive. In this context, published reports in the setting of anti-cholinergic symptoms describe a reversal of severe CNS effects, including coma and delirium, with administration of intravenous physostigmine (1-2 mg), under continuous ECG monitoring. In cases of quetiapine overdose refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine induced alpha blockade).