Realiquel 25 mg/100 mg/150 mg/200 mg/300 mg Film-Coated Tablets

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

Realiquel should be administered twice daily, with or without food. Adults: 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 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 in some patients within the range 150 to 750 mg/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 u2013 800 mg/day. The usual effective dose is in the range of 400 u2013 800 mg/day. Elderly: Realiquel should be used with caution in the elderly, especially during the initial dosing period. Elderly patients should be started on Realiquel 25 mg/day. The dose should be increased daily, in increments of 25 to 50 mg, to an effective dose, which is likely to be lower than that in younger patients. Renal and hepatic impairment: The oral clearance of Realiquel is reduced by approximately 25 % in patients with renal or hepatic impairment. Realiquel 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 Realiquel 25 mg/day. The dose should be increased daily in increments of 25 to 50 mg to an effective dose.

• Realiquel is contraindicated in patients who are hypersensitive to quetiapine or any of the ingredients of Realiquel.
• 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 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, medical practitioners 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. 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. Close supervision of patients and in particular those at high risk should accompany medicine 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.

Metabolic risk: Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose (see Hyperglycaemia and diabetes mellitus), patientsu2019 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: Realiquel has been associated with an increased incidence of extrapyramidal symptoms. The use of Realiquel 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.

Tardive dyskinesia: There is a potential for Realiquel to cause tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, discontinuation of Realiquel should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment.

Somnolence: Realiquel treatment has been associated with somnolence and related symptoms, such as sedation. Somnolence may occur, usually during the first 2 weeks of treatment and generally resolves with the continued administration of Realiquel.

Orthostatic hypotension: Realiquel 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. Realiquel 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: Sleep apnoea syndrome has been reported in patients using Realiquel. 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, Realiquel should be used with caution.

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

Neuroleptic malignant syndrome: Neuroleptic malignant syndrome has been associated with Realiquel treatment. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, Realiquel should be discontinued and appropriate medical treatment given.

Severe neutropenia and agranulocytosis: Severe cases of neutropenia (neutrophil count < 0,5 x 109/litre) have been reported with Realiquel. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with Realiquel. There is no apparent dose relationship. Some cases were fatal. Possible risk factors for neutropenia include pre-existing low white blood cell count and history of medicine induced neutropenia. However, some cases have occurred in patients without pre-existing risk factors. Realiquel should be discontinued in patients with a neutrophil count < 1,0 x 109/litre. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1,5 x 109/litre). 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 Realiquel therapy. Such patients should have a white blood cell count and an absolute neutrophil count performed promptly, especially in the absence of predisposing factors.

Anti-cholinergic (muscarinic) effects: Realiquel should be used with caution in patients receiving medicines having anti-cholinergic (muscarinic) effects. Realiquel 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.

Weight: Weight gain has been reported in patients who have been treated with Realiquel, and should be monitored and managed as clinically appropriate. Weight gain occurs predominantly during the early weeks of treatment.

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 Realiquel. Patients with an established diagnosis of diabetes mellitus who are started on Realiquel, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg. obesity, family history of diabetes) who are starting treatment with Realiquel, should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with Realiquel, should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when Realiquel, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect medicine.

Lipids: Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed with Realiquel. Lipid changes should be managed as clinically appropriate.

QT prolongation: QT prolongation has been reported with quetiapine at the therapeutic doses. Caution should be exercised when Realiquel is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when Realiquel 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. Treatment with Realiquel should be reassessed in patients with suspected cardiomyopathy or myocarditis.

Withdrawal: Acute withdrawal symptoms such as nausea, headache, diarrhoea, dizziness, irritability, vomiting and insomnia have been described after abrupt cessation of Realiquel. Gradual withdrawal over a period of at least one to two weeks is advisable.

Elderly patients with dementia-related psychosis: Realiquel 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. Realiquel should be used with caution in patients with risk factors for stroke. Where the use of antipsychotics in the elderly is considered essential, the lowest effective dose should be used. These patients should be carefully monitored to avoid or reduce hypotension, gait disturbances, oversedation and complications associated with hyperglycemia.

Dysphagia: Dysphagia has been reported with quetiapine. Realiquel 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 Realiquel. Patients with intestinal obstruction/ileus should be managed with close monitoring.

Venous thromboembolism (VTE): Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicines. 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 Realiquel and preventive measures undertaken.

Pancreatitis: Pancreatitis has been reported in patients treated with Realiquel.

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

Lactose: Realiquel tablets contain lactose. Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take Realiquel.

Given the primary central nervous system effects of quetiapine, Realiquel should be used with caution in combination with other centrally acting medicines and alcohol. CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of Realiquel. The pharmacokinetics of Realiquel was not altered following co-administration with cimetidine a known P450 enzyme inhibitor. The pharmacokinetics of Realiquel was not significantly altered following co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor). In an interaction study in healthy volunteers, co-administration of Realiquel (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. Due to the potential for an interaction of similar magnitude in a clinical setting, the dosage of Realiquel should be reduced during concomitant use of Realiquel and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors). It is also not recommended to take Realiquel with grapefruit juice. The co-administration of Realiquel with strong hepatic enzyme inducers such as carbamazepine or phenytoin and other hepatic enzyme inducers (e.g., barbiturates, rifampicin etc.) substantially decreases Realiquel plasma concentrations, which could affect the efficacy of Realiquel therapy. As a consequence of this interaction, in each patient, consideration for a higher dose of Realiquel, depending on clinical response, should be considered. It should be noted that the recommended maximum daily dose of Realiquel 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. Increased doses of Realiquel may be required to maintain control of psychotic symptoms in patients where Realiquel and hepatic enzyme inducers are co-administered. The dose of Realiquel may need to be reduced if phenytoin or carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g. sodium valproate). The pharmacokinetics of Realiquel was not significantly altered following co-administration with the antipsychotics risperidone or haloperidol. However, co-administration of Realiquel and thioridazine caused increases in clearance of Realiquel. The pharmacokinetics of lithium was not altered when co-administered with Realiquel. A study showed an increase in side effects such as somnolence, extrapyramidal effects and weight gain. The pharmacokinetics of sodium valproate and Realiquel were not altered to a clinically relevant extent when co-administered. Formal interaction studies with commonly used cardiovascular medicinal products have not been performed. Caution should be exercised when Realiquel is used concomitantly with medicines 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 Realiquel. Confirmation of screening results by an appropriate chromatographic technique is recommended. Realiquel did not induce the hepatic enzyme systems involved in the metabolism of antipyrine.

The safety of Realiquel in pregnant and lactating women has not been established (see section 4.3). Pregnancy: Realiquel is contraindicated in lactation. Lactation: Realiquel is contraindicated in lactation. Fertility: The effects of quetiapine on human fertility have not been assessed.

Realiquel 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.

The most commonly reported adverse drug reactions (ADRs) with Realiquel (u2265 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 side effects associated with Realiquel therapy, are given below:

Blood and the lymphatic system disorders: Frequent: Decreased haemoglobin, leucopenia, decreased neutrophil count, increased eosinophils. Less frequent: Neutropenia, thrombocytopenia, anaemia, decreased platelet count, agranulocytosis.

Immune system disorders: Less frequent: Hypersensitivity (angioedema, anaphylaxis, urticaria/rash).

Endocrine disorders: Frequent: Hyperprolactinaemia, decreases in total T4, decreases in free T4, decreases in total T3, increases in TSH. Less frequent: Decreases in free T3, hypothyroidism, inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: Frequent: Elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, increased appetite, blood glucose increased to hyperglycaemic levels. Less frequent: Hyponatraemia, diabetes mellitus, exacerbation of pre-existing diabetes, metabolic syndrome.

Psychiatric disorders: Frequent: Abnormal dreams and nightmares, suicidal ideation and suicidal behaviour. Less frequent: Somnambulism and related reactions such as sleep talking and sleep related eating disorder.

Nervous system disorders: Frequent: Headache, somnolence, dizziness, anxiety, extrapyramidal symptoms (akathisia, cogwheel rigidity, hypertonia, hypokinesia, neck rigidity and tremor), dysarthria. Less frequent: Seizure, restless leg syndrome, tardive dyskinesia, syncope.

Eye disorders: Frequent: Dry eyes, asymptomatic changes in lenses of the eyes with long term use, blurred vision.

Ear and labyrinth disorders: Less frequent: Ear pain.

Cardiac disorders: Frequent: Tachycardia, palpitations. Less frequent: QT prolongation, bradycardia, chest pain.

Vascular disorders: Frequent: Orthostatic hypotension (associated with dizziness, tachycardia and syncope in some patients). Less frequent: Venous thromboembolism. Frequency unknown: Stroke.

Respiratory, thoracic and mediastinal disorders: Frequent: Dyspnoea. Less frequent: Rhinitis.

Gastro-intestinal disorders: Frequent: Constipation, dry mouth, dyspepsia, vomiting. Less frequent: Abdominal pain, diarrhoea, dysphagia, pancreatitis, intestinal obstruction/ileus.

Hepato-biliary disorders: Frequent: Elevations in serum alanine aminotransferase (ALT), elevations in gamma - GT levels. Less frequent: Elevations in serum aspartate aminotransferase (AST), jaundice, hepatitis.

Skin and subcutaneous tissue disorders: Less frequent: Angioedema, Stevens-Johnson syndrome. Frequency unknown: Toxic epidermal necrolysis, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Musculoskeletal, connective tissue and bone disorders: Less frequent: Myalgia, back pain, rhabdomyolysis.

Renal and urinary disorders: Less frequent: Urinary tract infection, urinary retention.

Pregnancy, puerperium and perinatal conditions: Frequency unknown: Substance withdrawal syndrome neonatal.

Reproductive system and breast disorders: Less frequent: Sexual dysfunction, priapism, galactorrhoea, breast swelling, menstrual disorder.

General disorders: Frequent: Withdrawal symptoms, mild asthenia, peripheral oedema, irritability, pyrexia. Less frequent: Neuroleptic malignant syndrome, hypothermia.

Investigations: Less frequent: Elevations in blood creatine phosphokinase. Elevations in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in patients administered Realiquel. These elevations were usually reversible on continued Realiquel treatment. Realiquel treatment was associated with dose-related decreases in thyroid hormone levels, particularly total T4 and free T4. The reduction in total and free T4 was maximal within the first 2 to 4 weeks of Realiquel treatment, with no further reduction during long-term treatment. There was no evidence of clinically significant changes in TSH concentration over time. In nearly all cases, cessation of Realiquel treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. Smaller decreases in total T3 and reverse T3 were seen only at higher doses. Levels of TBG were unchanged and in general, reciprocal increases in TSH were not observed, with any indication that Realiquel causes clinically relevant hypothyroidism.

In clinical trials, experience with Realiquel in overdosage is limited. In general, reported signs and symptoms were those resulting from an exacerbation of Realiquelu2019s known pharmacological effects, i.e. drowsiness, sedation, tachycardia and hypotension. There is no specific antidote to Realiquel. Treatment is symptomatic and supportive.