Core Safety Profile

Active substance: Zotepine Pharmaceutical form(s)/strength: Por. tbl. obd, 25mg, 50mg, 100mg P-RMS: CZ/H/PSUR/0025/001 Date of FAR: 05.12.2011

4.2 Posology and method of administration

Children: /.../ is not recommended for use in children (under 18 years of age).

Adults: Doses above 100 mg three times daily are not recommended because they may increase the risk of seizure.

Elderly patients and patients with established hepatic and/or renal impairment: The starting dose of /.../ should be reduced to 25 mg twice daily in the elderly and patients with established renal and/or hepatic impairment. Titration should be gradual, based on tolerability and efficacy up to a maximum of 75 mg twice daily.

4.3 Contraindications

/.../ should not be used in patients with a known hypersensitivity to zotepine or any of its excipients.

/.../ should not be used in patients suffering from acute intoxication with CNS depressants including alcohol.

As with other uricosuric agents, due to the increased risk of renal stone formation, /.../ should not be used in patients with acute gout.

Nursing mothers taking /.../ should not breast-feed.

4.4 Special warnings and precautions for use

Increased Mortality in Elderly people with Dementia An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical 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. /.../ should be used with caution in patients with risk factors for stroke.

/.../ is known to lower the seizure threshold and PMS data have shown a clear dose-related proconvulsive effect. /.../ should not be used to treat patients with a personal or close family history of epilepsy unless the individual benefit outweighs the risk. Data from controlled clinical trials indicate that the seizure rate associated with /.../treatment when used up to a maximum total daily dose of 300 mg is about 1%. At total daily doses above the recommended maximum of 300 mg there is an appreciable increase in the incidence of seizures. It is therefore recommended that total daily doses above 300 mg are not used. High doses of other antipsychotics should not be co-prescribed with zotepine as this may further lower the seizure threshold. Caution should be exercised when withdrawing concomitantly prescribed CNS depressants.

Clinical trials showed a dose related QTc interval prolongation. Caution is therefore advised in relation to the use of /.../ in patients at risk of arrhythmias such as patients with coronary heart disease, patients taking other drugs known to cause QTc prolongation or those at risk of hypokalaemia. When

2/7 treating patients from these groups, it is recommended that an ECG is performed prior to initiation of treatment, to enable the exclusion of those patients with a pre-existing QTc prolongation. In addition to measuring the ECG prior to treatment, electrolytes should also be measured (calcium, potassium and sodium) and any imbalances corrected and periodically monitored, particularly at each dose escalation. Further ECG monitoring should be carried out at each dose escalation. /.../ is associated with an increase in heart rate and should be used with caution in patients who suffer from angina pectoris due to coronary artery disease.

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 /.../ and preventive measures undertaken

In common with other antipsychotics isolated reports of Neuroleptic Malignant Syndrome (NMS) have occurred during treatment with /.../. This potentially fatal syndrome includes muscle rigidity, stupor, hyperpyrexia, labile pulse or blood pressure, elevation of plasma creatine kinase, myoglobinaemia and acute renal failure. If NMS occurs all antipsychotic drugs including /.../ should be discontinued immediately and expert advice sought.

As with all compounds that possess 1-adrenergic blocking properties, /.../ may cause orthostatic hypotension, especially during initiation of therapy and increase in dosage. Patients should be advised to rise slowly from the recumbent position and blood pressure should be measured periodically as with other antipsychotics. A dose reduction or more gradual titration should be considered if orthostatic hypotension occurs. Anaesthesia may increase the risk of hypotension. /.../ should be used with caution in patients with known severe cardiovascular disease including severe hypertension or severely restricted cardiac output.

As with other antipsychotic drugs a reduction in white cell count can occur. Extensive clinical usage of /.../ suggests that this poses minimal risk to patient safety. If a reduction in white cell count is suspected (e.g. infection) then a white cell count should be performed and specialist advice sought if appropriate.

Caution should be exercised when prescribing /.../ to patients with established hepatic impairment. Weekly monitoring of Liver Function Tests is recommended for at least the first 3 months of therapy in patients with hepatic impairment.

A lower starting dose, gradual titration and a reduced maximum daily dose should be used in the elderly, renally or hepatically impaired patients (See Section 4.2).

As with other antipsychotics, patients should be advised of the possibility for weight gain and given dietary advice.

Isolated reports of tardive dyskinesia have occurred during clinical trials and marketing experience but no causality has been established. If tardive

3/7 dyskinesia does occur the discontinuation or reduction in dose of all antipsychotic drugs should be considered.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia, have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore gradual withdrawal is advisable.

/.../ possesses anticholinergic properties and should be used with caution in patients with prostatic hypertrophy, retention of urine, narrow angle glaucoma and paralytic ileus.

/.../ has uricosuric properties and thus, in the unlikely event of treating a patient with a history of gout or hyperuricaemia, /.../ should be started with care, maintaining a good urine output until serum uric acid returns to normal levels. As with all uricosurics, /.../ should not be started within three weeks of the resolution of an episode of acute gout. There is a theoretical risk of increased urate renal stone formation and /.../ should not be used in patients with a history of nephrolithiasis. In practice this risk appears to be low.

As with other antipsychotics, thermoregulation of the body may be adversely affected by treatment with /.../ giving rise to hyperpyrexia or hypothermia.

Theoretically /.../ may cause a deterioration in patients with Parkinson’s disease.

Caution should be exercised in treating patients with tumours of the adrenal medulla, e.g. phaeochromocytoma or neuroblastoma.

/.../ contains glucose and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

/.../ contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

/.../ is a CNS depressant, therefore it should be used with caution in combination with other CNS depressant drugs. Antipsychotics are known to lower the seizure threshold and PMS data for /.../ have shown a clear dose- related proconvulsive effect. If co-prescription of high doses of other antipsychotics is considered necessary, the prescriber should be aware that this may further lower the seizure threshold.

As /.../ possesses significant α1-blocking properties, caution should be exercised when it is co prescribed with hypotensive agents, including some anaesthetic agents. Through its effect on α adrenoceptors, the simultaneous administration of adrenaline may lead to a fall in blood pressure. Theoretically the effects of α methyldopa, guanethidine and clonidine may be reduced.

4/7 In a desipramine co-administration study no clinical interaction was found with respect to the CYP 2D6 isoenzyme suggesting that antidepressants and other drugs dependent on this isoenzyme are unlikely to interact with /.../.

Co-administration with fluoxetine or diazepam leads to increased plasma concentrations of zotepine and norzotepine, and caution is advised when these drugs are co-prescribed.

No specific clinical interaction studies have been conducted with anticonvulsants or lithium.

Food taken with a single oral dose of /.../ delayed by 30% the appearance of /.../ in plasma but had no effect on the extent of absorption of /.../; the effect of food is unlikely to be significant on chronic administration.

4.6 Fertility, pregnancy and lactation

Use in Pregnancy: The drug plasma concentrations (AUC) in the animal reproduction studies were generally lower than those seen in patients. Whilst animal studies have shown no teratogenic effects in rats and rabbits, some indirect prolactin- and CNS-mediated effects were observed in rats including reduced fertility in females and increased neonatal mortality. The use of /.../ during human pregnancy has not been investigated, therefore, /.../ should not be used during pregnancy unless the benefits to the mother outweigh the potential risk to the baby. Women of child-bearing potential should employ adequate contraception whilst taking /.../.

Lactation: There is evidence that /.../ and its metabolites may be secreted in the milk of lactating rats, and a case report indicates similar secretion may occur in humans. Therefore, women taking /.../ should not breast-feed.

4.7 Effects on ability to drive and use machines

/.../ may cause sedation and/or impair mental alertness. Patients should be advised not to drive or operate machinery, during treatment, until their susceptibility has been established.

4.8 Undesirable effects

The following adverse events have been reported on at least four occasions in association with /.../ therapy in clinical trials and spontaneously during extensive clinical usage (over 1.98 million patients treated).

The adverse events occurring in each body system are classified according to the following frequency estimates: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Infections and infestations: Very common: infection. Common: flu syndrome.

5/7 Blood and lymphatic system disorders: Very common: leucocytosis, leucopenia. Common: abnormal blood cells, anaemia, thrombocythaemia. Uncommon: thrombocytopenia.

Immune system disorders: Uncommon: allergic reaction.

Endocrine disorders: Common: prolactin increased. Uncommon: inappropriate lactation.

Metabolism and nutrition disorders: Common: hyperglycaemia, hypoglycaemia, hyperlipidaemia, hypouricaemia.

Psychiatric disorders: Very common: agitation, anxiety, depression, insomnia. Common: confusion, hostility, libido decreased, nervousness. Uncommon: delirium.

Nervous system disorders: Very common: dizziness, extrapyramidal syndrome (akathisia, dyskinesia, dystonias, Parkinsonism), headache, somnolence. Common: convulsions, dysautonomia, speech disorder, syncope. Uncommon: amnesia, ataxia, CNS stimulation, coma, hypaesthesia, myoclonus, neuroleptic malignant syndrome.

Eye disorder: Very common: blurred vision. Common: conjunctivitis.

Ear and labyrinth disorders: vertigo

Cardiac disorder: Very common: tachycardia. Common: arrhythmia. Uncommon: bradycardia, palpitations. Frequency unknown: cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs.

Vascular disorders: Very common: hypotension. Common: hypertension, postural hypotension. Very rare: shock.

Respiratory, thoracic and mediastinal disorders: Very common: rhinitis. Common: cough increase, dyspnoea. Uncommon: epistaxis.

Gastrointestinal disorders: Very common: constipation, dry mouth, dyspepsia, salivation increased. Common: abdominal pain, anorexia, appetite increased, diarrhoea, nausea, vomiting. Uncommon: Abdominal enlargement, ileus.

Skin and subcutaneous tissue disorders: Very common: sweating. Common: acne, dry skin, rash. Uncommon: alopecia, photosensitivity.

Musculoskeletal and connective tissue disorders: Common: arthralgia, joint disease, myalgia. Uncommon: myasthenia.

Renal and urinary disorders: Common: urinary incontinence. Uncommon: retention of urine.

Pregnancy, puerperium and perinatal conditions: Uncommon: menstrual disorder.

6/7 Reproductive system and breast disorder: Common: impotence, Uncommon: abnormal ejaculation.

General disorders and administration site conditions: Very common: asthenia, chills, pain. Common: chest pain, fever, malaise, oedema, thirst. Uncommon: facial oedema, hypothermia.

Investigations: Very common: changes in ESR, EEG abnormal, elevated liver function tests, weight increase. Common: creatinine increased, ECG abnormality, weight loss.

4.9 Overdose

Symptoms of Overdose: Overdose may result in exaggerated pharmacological effects which include hypotension, tachycardia, arrhythmias, agitation, pronounced extrapyramidal motor effects, hypothermia, hyperthermia, seizures, respiratory depression, stupor or even coma.

In the event of overdosage, the possibility of multiple drug involvement should be considered.

Management of Overdose: There is no specific antidote to /.../, therefore appropriate supportive measures should be instituted. A clear airway should be established and maintained, and adequate oxygenation and ventilation ensured. Gastric lavage (after endotracheal intubation if the patient is unconscious) and administration of activated charcoal should be considered. Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures. If sympathomimetic agents are used for vascular support, adrenaline and dopamine should not be used, since beta-stimulation

combined with 1-antagonism associated with /.../ may worsen hypotension. Cardiac arrhythmias may respond to correction of circulatory and metabolic disturbance, however, if persistent or life-threatening, appropriate antiarrhythmic treatment may be considered. In the case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Seizures may be treated with intravenous diazepam, preferably in emulsion form (artificial respiration equipment and expertise should be available in the event of respiratory depression). Close medical supervision and monitoring should continue until the patient recovers.

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