ZENAXEL

Posology Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear information on the appropriate dosage for their condition. Other quetiapine-containing products may be available.

The physician should prescribe the most appropriate dosage form, presentation and strength according to age, weight and dose.

Dosage equivalence for the syringe:

Measured Amount (ml) Amount of quetiapine (mg) 1 ml 25 mg 2 ml 50 mg 4 ml 100 mg Note that the total volume of the syringe is 5 ml.

Dose equivalence for the cup:

Measured Amount (ml) Amount of quetiapine (mg) 6 ml 150 mg 8 ml 200 mg 9 ml 225 mg 12 ml 300 mg 15 ml 375 mg 16 ml 400 mg 24 ml 600 mg Note that the total volume of the dosing cup is 20 ml. Adults For the treatment of schizophrenia For the treatment of schizophrenia, Zenaxel 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, Zenaxel 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 Zenaxel 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. 1). 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. It is important that the lowest effective dose is used for maintenance therapy.

Elderly As with other antipsychotics, Zenaxel 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 Zenaxel 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. 2. Renal impairment Dosage adjustment is not necessary in patients with renal impairment.

Hepatic impairment Quetiapine is extensively metabolised by the liver. Therefore, Zenaxel 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. Method of administration For oral use. Zenaxel can be administered with or without food.

6.

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 below (Table 1) according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995). Table 1 ADRs associated with quetiapine therapy 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).

SOC Very common Common Uncommon Rare Very Rare Not known Blood and lymphatic system disorders Decrease d haemogl obin22 Leucopoeni a 1, 28, Decreased neutrophil count, Eosinophils increased27 Neutropenia1, Thrombocyto penia, Anaemia, Platelet count decreased13 Agranulocytosi s26 Immune system disorders Hypersensitiv ity (including allergic skin reactions) Anaphylacti c reaction5 Endocrine disorders Hyperprolac tinaemia 15, Decreases in total T4 24, Decreases in free T424, Decreases in total T324, Increases in TSH24 Decreases in free T324, Hypothyroidi sm21 Inappropriat e antidiuretic hormone secretion Metabolis m and nutritional disorders Elevatio ns in serum triglyceri de levels 10, 30 Elevatio ns in total cholester ol (predomi nantly LDL Increased appetite, blood glucose increased to hyperglycae mic levels6, 30 Hyponatraem ia 19, Diabetes Mellitus 1,5, Exacerbation of preexisting diabetes Metabolic syndrome 29 cholester ol)11, 30 Decrease s in HDL cholester ol 17, 30, Weight gain 8, 30 Psychiatri c disorders Abnormal dreams and nightmares, Suicidal ideation and suicidal behaviour20 Somnambulism and related reactions such as sleep talking and sleep related eating disorder Nervous system disorders Dizzines s 4, 16, Somnole nce 2, 16, Headach e, Extrapyr amidal symptom s 1, 21 Dysarthria Seizure 1, Restless legs syndrome, Tardive dyskinesia 1, 5,Syncope 4, 16 Confusional state Cardiac disorders Tachycardia 4, QT Prolongation 1, 12, 18 Cardiomyopa thy and SOC Very common Common Uncommon Rare Very Rare Not known Palpitations 23 Bradycardia 32 myocarditis Eye disorders Vision blurred Vascular disorders Orthostatic hypotension 4, 16 Venous thromboemboli sm1 Stroke 33 Respirator y, thoracic and mediastin al disorders Dyspnoea 23 Rhinitis Gastrointe stinal disorders Dry mouth Constipatio n, Dyspepsia, Vomiting 25 Dysphagia7 Pancreatitis 1, Intestinal obstruction/Ille us Hepato- biliary disorders Elevations in serum alanine aminotransf erase (ALT)3, Elevations in gamma- GT levels 3 Elevations in serum aspartate aminotransfer ase (AS)3 Jaundice5, Hepatitis Skin and subcutane ous tissue disorders Angioedem a5, StevensJohn son syndrome5 Toxic Epidermal Necrolysis, Erythema Multiforme Acute Generalised Exanthemato us Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Cutaneous vasculitis Musculosk eletal and connective tissue disorders Rhabdomyo lysis Renal and urinary disorders Urinary retention Pregnancy , puerperiu m Drug withdrawal syndrome neonatal31 And perinatal conditions Reproduct ive system and breast disorders Sexual dysfunction Priapism, Galactorrhoea, Breast SOC Very common Common Uncommon Rare Very Rare Not known swelling, Menstrual disorder General disorders and administration site conditions Withdrawal (discontinuati on) symptoms 1, 9 Mild asthenia, Peripheral oedema, Irritability, Pyrexia Neuroleptic malignant syndrome1, Hypothermia Investigations Elevations in blood creatine phosphokinase14 1.

4 2. Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of quetiapine. 3. Asymptomatic elevations (shift from normal to > 3 x ULN at any time) in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in some patients administered quetiapine.

These elevations were usually reversible on continued quetiapine treatment. 4. 4).

As Zenaxel has several indications, the safety profile should be considered with respect to the individual patient's diagnosis and the dose being administered. Paediatric population 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.

8), 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.

8). 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.

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) 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.

8). 1). 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. Tardive dyskinesia If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. 8). 8). In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity.

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 […]

1. 5).