Emtaq 100/Emtaq 300

Quetiapine fumarate.

Quetiapine fumarate tablets 100 mg: White to off white coloured, round shaped, biconvex, film-coated tablets debossed with '56' on one side and 'I' on the other side.
Quetiapine fumarate tablets 300 mg: White to off white coloured, capsule shaped, biconvex, film-coated tablets debossed with '45' on one side and 'I' on the other side.
Each Film-Coated Tablet contains: Quetiapine Fumarate equivalent to 100 mg or 300 mg of Quetiapine.
Quetiapine is described chemically as (i) Ethanol, 2-[2-(4-dibenzo[b,f] [1,4]thiazepin-11-yl-1- piperazinyl) ethoxy]-, (E)-2-butenedioate (2:1) (salt); (ii) 2-[2-(4-Dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl) ethoxy] ethanol fumarate (2:1) salt & (i) Bis [2-[2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl] ethoxy] ethanol]fumarate & (i) 2- [2-(4 -Dibenzo [b,f] [1,4] thiazepin-11-yl-1- piperazinyl) ethoxy] ethanol fumarate (ii) 11-[4-[2-(2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b,f] [1,4] thiazepine fumarate. The molecular formula is (C₂₁H₂₅N₃O₂S)2·C₄H₄O₄ and the molecular weight is 883.1.
Quetiapine is a white to off-white powder., and pKa value is very slightly soluble in water, hence pKa value is not determined. Soluble in Dimethyl formamide and Glacial acetic acid; sparingly soluble in methanol.
Excipients/Inactive Ingredients: Quetiapine Tablets contain the following inactive ingredients: Lactose Monohydrate (HMS Impalpable), Calcium Hydrogen Phosphate Dihydrate (Unmilled Di-Tab), Microcrystalline Cellulose (Avicel PH101), Sodium starch Glycolate (Primojel), Povidone (Plasdone K-29/32), Purified water, Sodium starch Glycolate (Primojel), Magnesium stearate, Opadry white 03B28796.

Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines. ATC code: N05A H04.
Pharmacology: Pharmacodynamics: Mechanism of action: Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine 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 D₂ receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Emtaq 100/Emtaq 300 compared to typical antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anti-cholinergic (muscarinic) effects. Inhibition of NET and partial agonist action at 5HT_1A sites by norquetiapine may contribute to Emtaq 100/Emtaq 300's therapeutic efficacy as an antidepressant.
Pharmacodynamic effects: Quetiapine 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 typical 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 mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration.
Clinical efficacy: Schizophrenia: Clinical trials have demonstrated that Emtaq 100/Emtaq 300 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 doses greater than 800 mg/day have not been evaluated.
In three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of quetiapine, there were no differences between the Emtaq 100/Emtaq 300 and placebo treatment groups in the incidence of EPS or concomitant use of anti-cholinergics. 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 anti-cholinergics. The long-term efficacy of Quetiapine XR tablets 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.
Bipolar disorder: 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 divalproex, there were no differences between the Emtaq 100/Emtaq 300 and placebo treatment groups in the incidence of EPS or concomitant use of anti-cholinergics.
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 Emtaq 100/Emtaq 300's effectiveness in preventing subsequent manic or depressive episodes. Emtaq 100/Emtaq 300 data in combination with divalproex or lithium in acute 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.
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 XR tablets 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 XR tablets 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 XR tablets 300 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 Emtaq 100/Emtaq 300 in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with Emtaq 100/Emtaq 300 was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed). Emtaq 100/Emtaq 300 was administered twice-daily totaling 400 mg to 800 mg a day as combination therapy to lithium or valproate.
In a 6-week, randomised, study of lithium and Quetiapine versus placebo and Quetiapine in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was 2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs. 68% in the placebo add-on group).
In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to switching to lithium, the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.
Clinical Safety: In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients compared to those treated with placebo in short-term, placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for Quetiapine XR tablets and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for Quetiapine XR tablets and 2.3% for placebo. In both bipolar depression and MDD, 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 short-term, fixed-dose (50 mg/d to 800 mg/d), placebo-controlled studies (ranging from 3 to 8 dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in any treatment group. weeks), the mean weight gain for quetiapine-treated patients ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo treated patients. The percentage of quetiapine treated patients who gained ≥7% of body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily doses), compared to 3.7% for placebo treated patients. A 6-week, randomised, study of lithium and Quetiapine XR tablets versus placebo and Quetiapine XR tablets in adult patients with acute mania indicated that the combination of Quetiapine XR tablets with lithium leads to more adverse events (63% versus 48% in Quetiapine XR tablets in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the Quetiapine XR tablets with lithium add-on group (12.7%) compared to the Quetiapine XR tablets with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (≥7%) at the end of treatment compared to patients in the placebo add-on group (4.7%). Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were randomized to quetiapine or placebo. For patients who were randomized to quetiapine, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomized period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomized to placebo, the mean weight gain during the open label period was 2.39 kg, and by week 48 of the randomized period the mean weight gain was 0.89 kg, compared to open label baseline. 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. 1.9% of patients treated with quetiapine compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5-<1.0 x 10⁹/L was the same (0.2%) in patients treated with quetiapine as with placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator) in patients with a baseline neutrophil count ≥1.5 x 10⁹/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 10⁹/L was 2.9% and to <0.5 x 10⁹/L was 0.21% in patients treated with quetiapine. Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. The incidences of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For about 2/3 of 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.
Cataracts/lens opacities: In a clinical trial to evaluate the cataractogenic potential of Emtaq 100/Emtaq 300 (200-800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in Emtaq 100/Emtaq 300 (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.
Pharmacokinetics: Absorption: Quetiapine is well absorbed and extensively metabolised following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine. The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range.
Distribution: Quetiapine is approximately 83% bound to plasma proteins.
Biotransformation: 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. In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.
Quetiapine and several of its metabolites (including norquetiapine) 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 co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.
Elimination: The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
Special populations: Gender: The kinetics of quetiapine do not differ between men and women.
Elderly: The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
Renal impairment: 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), but the individual clearance values are within the range for normal subjects.
Hepatic impairment: The mean quetiapine plasma clearance decreases with approx. 25% in persons with known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients.
Paedriatic population: Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose-normalised plasma levels of the parent compound quetiapine, in children and adolescents (10-17 years of age) were in general similar adults, though Cmax in children was at the higher end of the range observed in respectively, compared to adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13-17 years).

Quetiapine is indicated for: For treatment of schizophrenia; For the treatment of bipolar disorder; For the treatment of moderate to severe manic episodes in bipolar disorder; For the treatment of major depressive episodes in bipolar disorder; For the prevention of recurrence of manic or depressed episodes in patients with bipolar disorder who previously responded to quetiapine treatment.

Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear information on the appropriate dosage for their condition.
It can be administered with or without food.
Adult: For the treatment of schizophrenia: For the treatment of schizophrenia, it 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 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 moderate to severe manic episodes in bipolar disorder: For the treatment of manic episodes associated with bipolar disorder, it 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/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 major depressive episodes in bipolar disorder: Quetiapine should be administered once daily at bedtime. 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. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group. Individual patients may benefit from a 600 mg dose. Doses greater than 300 mg should be initiated by physicians experienced in treating bipolar disorder. 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.
For preventing recurrence in bipolar disorder: For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have responded to quetiapine for acute treatment of bipolar disorder should continue therapy at the same dose. The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice daily.
Elderly: As with other antipsychotics, Emtaq 100/Emtaq 300 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.
Paediatric population: It is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group.
Renal impairment: Dosage adjustment is not necessary in patients with renal impairment.
Hepatic impairment: Quetiapine is extensively metabolised by the liver. Therefore, it 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 with 25 mg/day. The dosage should be increased daily with increments of 25-50 mg/day until an effective dosage, depending on the clinical response and tolerability of the individual patient.

Management of overdose: Symptoms: In general, reported signs and symptoms were those resulting from an exaggeration of the active substance's known pharmacological effects, i.e. drowsiness and sedation, tachycardia, hypotension and anti-cholinergic effects. Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma and death. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. 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. Based on public literature, patients with delirium and agitation and a clear anti-cholinergic syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as standard treatment, because of potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in severe poisonings and if possible to perform within one hour of ingestion. The administration of activated charcoal should be considered. 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. Close medical supervision and monitoring should be continued until the patient recovers.

Hypersensitivity to the active substance or to any of the excipients of this product.

As this medicine has several indications, the safety profile should be considered with respect to the individual patient's diagnosis and the dose being administered.
Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated.
Suicide/suicidal thoughts or clinical worsening: Depression 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 addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated. Other psychiatric conditions for which quetiapine is prescribed can also be associated with an increased risk of suicide related events. In addition, these conditions may be co-morbid with major depressive episodes The same precautions observed when treating patients with major depressive episodes should therefore be observed when treating patients 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. A meta analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients (younger than 25 years of age) who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively). A population-based retrospective study of quetiapine for the treatment of patients with major depressive disorder showed an increased risk of self-harm and suicide in patients aged 25 to 64 years without a history of self-harm during use of quetiapine with other antidepressants.
Metabolic Risk: Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose (see hyperglycaemia as follows) and lipids, which was seen in clinical studies, patients' metabolic parameters should be assessed at the time of treatment initiation and changes in these parameters should be regularly controlled for during the course of treatment. Worsening in these parameters should be managed as clinically appropriate.
Extrapyramidal Symptoms: In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder.
The use of quetiapine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment.
Somnolence and dizziness: Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. 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. 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.
Orthostatic hypotension: Quetiapine treatment has been associated with orthostatic hypotension and related dizziness which, like somnolence has onset usually during the initial dose-titration period. This could increase the occurrence of accidental injury (fall), especially in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.
Sleep apnoea syndrome has been reported in patients using quetiapine. In patients receiving concomitant central nervous system depressants and who have a history of or are at risk for sleep apnoea, such as those who are overweight/obese or are male, quetiapine should be used with caution.
Seizures: In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. No data is available about the incidence of seizures in patients with a history of seizure disorder. As with other antipsychotics, caution is recommended when treating patients with a history of seizures.
Neuroleptic Malignant Syndrome: Neuroleptic malignant has been associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.
Severe neutropenia and agranulocytosis: Severe neutropenia (neutrophil count <0.5 x 10⁹/L) has been 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, some cases were fatal. Possible risk factors for neutropenia include pre-existing low white blood cell count (WBC). Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 10⁹/L).
Neutropenia should be considered in patients presenting with infection or fever, particularly in the absence of obvious predisposing factor(s), and should be managed as clinically appropriate. Patients should be advised to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g. fever, weakness, lethargy, or sore throat) at any time during therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.
Anti-cholinergic (muscarinic) effects: Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to ADRs reflecting anti-cholinergic effects when quetiapine is used at recommended doses, when used concomitantly with other medications having anticholinergic effects, and in the setting of overdose. Quetiapine should be used with caution in patients receiving medications having anti-cholinergic (muscarinic) effects. Quetiapine 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.
Interactions: 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).
Weight: Weight gain has been reported in patients who have been treated with quetiapine, and should be monitored and managed as clinically appropriate as in accordance with utilised antipsychotic guidelines. Weight should be monitored regularly.
Hyperglycaemia: Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.
Lipids: Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with quetiapine. Lipid changes should be managed as clinically appropriate.
QT prolongation: In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. In postmarketing, QT prolongation was reported with quetiapine at the therapeutic doses and in overdose. 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 either with medicines known to increase QT interval or with concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.
Cardiomyopathy and myocarditis: Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience, however, a causal relationship to quetiapine has not been established. Treatment with quetiapine should be reassessed in patients with suspected cardiomyopathy or myocarditis.
Withdrawal: Acute 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.
Dysphagia: Dysphagia has been reported with quetiapine. Quetiapine 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 quetiapine. 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.
Venous thromboembolism (VTE): Cases of venous thromboembolism (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 and preventive measures undertaken.
Pancreatitis: Pancreatitis has been reported in clinical trials and during post marketing experience. Among 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, gallstones, and alcohol consumption.
Additional Information: Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3.
Lactose: Quetiapine tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Misuse and abuse: Cases of misuse and abuse have been reported. Caution may be needed when prescribing quetiapine to patients with a history of alcohol or drug abuse.
Use in Children: Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. Clinical trials with quetiapine have shown that in addition to the known safety profile identified in adults, certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope), or may have different implications for children and adolescents (extrapyramidal symptoms and irritability) and one was identified that has not been previously seen in adult studies (increases in blood pressure). Changes in thyroid function tests have also been observed in children and adolescents.
Furthermore, the long-term safety implications of treatment with quetiapine on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.
In placebo-controlled clinical trials with children and adolescent patients, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania and bipolar depression.
Use in the Elderly: Elderly patients with dementia-related psychosis: Quetiapine 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 antipsychotics, 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.
Elderly patients with Parkinson's disease (PD)/parkinsonism: A population-based retrospective study of quetiapine for the treatment of patients with MDD, showed an increased risk of death during use of quetiapine in patients aged >65 years. This association was not present when patients with PD were removed from the analysis. Caution should be exercised if quetiapine is prescribed to elderly patients with PD.

The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine (≥10%) are somnolence, dizziness, headache, 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.
The incidences of ADRs associated with quetiapine therapy, are tabulated as follows (Table 1) according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).
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), very rare (<1/10,000) and not known (cannot be estimated from the available data). (See Table 1.)

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Platelets ≤100 x 10⁹/L on at least one occasion.
Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.
Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34 pmol/L) females at any time. May lead to falls HDL cholesterol: <40 mg/dL (1.025 mmol/L) males; <50 mg/dL (1.282 mmol/L) females at any time.
Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec increase. In placebo-controlled trials with quetiapine the mean change and the incidence of patients who have a shift to a clinically significant level is similar between quetiapine and placebo.
Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation.
Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in haemoglobin at any time was -1.50 g/dL. These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in total T₄, free T₄, total T₃ and free T₃ are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mIU/L at any time. Based upon the increased rate of vomiting in elderly patients (≥65 years of age). Based on shift in neutrophils from ≥1.5 x 10⁹ L at baseline to <0.5 x 10⁹/L at any time during treatment and based on patients with severe neutropenia (<0.5 x 10⁹/L) and infection during all quetiapine clinical trials. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in eosinophils are defined as >1 x 10⁹ cells/L at any time. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in WBCs are defined as ≤3 x 10⁹ cells/L at any time. Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine. In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies quetiapine.
May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with quetiapine.
Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with quetiapine treatment.
Paediatric population: The same ADRs described previously for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher frequency category in children and adolescent patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population.
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). (See Table 2.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Given the primary central nervous system effects of quetiapine, quetiapine should be used with caution in combination with other centrally acting medicinal products and alcohol.
Caution should be exercised treating patients receiving other medications having anti-cholinergic (muscarinic) effects.
Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.
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, which could affect the efficacy of quetiapine therapy. Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. 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).
The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).
The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%.
The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine.
The pharmacokinetics of lithium were not altered when co-administered with quetiapine.
In a 6-week, randomised, study of lithium and Quetiapine XR tablets versus placebo and Quetiapine XR tablets in adult patients with acute mania, a higher incidence of extrapyramidal related events (in particular tremor), somnolence, and weight gain were observed in the lithium add-on group compared to the placebo add-on group.
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered. A retrospective study of children and adolescents who received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the monotherapy groups.
Formal interaction studies with commonly used cardiovascular medicinal products have not been performed.
Caution should be exercised when quetiapine is used concomitantly with medicinal products known to cause electrolyte imbalance or to increase QT interval.
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.

Store at temperatures not exceeding 30°C.

Antipsychotics

N05AH04 - quetiapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.

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