Special Warning : אזהרת שימוש

4.4      Special warnings and precautions for use
Cardiovascular
Clinical studies have shown that sertindole prolongs the QT interval to a greater extent than some other antipsychotics. The mean QT prolongation is greater at the upper end of the recommended dose range (20 and 24 mg). Prolongation of the QTc interval in some drugs is associated with the ability to cause Torsade de Pointes-type (TdP) arrhythmia (a potentially fatal polymorphic ventricular tachycardia) and sudden death. However, clinical and non-clinical data have been unable to confirm whether sertindole is more arrhythmogenic than other antipsychotics. Sertindole should therefore only be used for patients intolerant to at least one other antipsychotic agent.


Prescribing physicians should comply fully with the required safety measures.
ECG monitoring:
-   ECG monitoring is mandatory prior to and during treatment with sertindole.
-   Sertindole is contraindicated if a QTc interval of more than 450 msec in males or       470 msec in females is observed at baseline.
-   ECG monitoring should be conducted at baseline, upon reaching steady state after approximately 3 weeks or when reaching 16 mg and again after 3 months of treatment.
During maintenance therapy an ECG is required every 3 months.
-   During maintenance treatment, ECG measurements should take place prior to and after any increase in dose.
-   An ECG is recommended after the addition or increase of dosage of concomitant medication that may increase the sertindole concentration (see section 4.5).
-   If a QTc interval of more than 500 msec is observed during treatment with sertindole, treatment with sertindole should be discontinued.
-   For patients with symptoms such as palpitations, convulsions, or syncope that could indicate the occurrence of arrhythmias, the prescriber should initiate urgent evaluation, including an ECG.
-   ECG monitoring is ideally conducted in the morning and the Bazett or Fridericia formulae for calculating the QTc interval are preferred.
The risk of QT prolongation is increased in patients receiving concomitant treatment with drugs that prolong the QTc interval or drugs that inhibit sertindole metabolism (see section 4.3).

Baseline serum potassium and magnesium levels should be measured before commencing treatment with sertindole in patients at risk of significant electrolyte disturbances. Low serum potassium and magnesium should be corrected before proceeding with treatment. Monitoring of serum potassium is recommended for patients experiencing vomiting, diarrhoea, treatment with potassium-depleting diuretics, or other electrolyte disturbances.


Due to the α 1 -blocking activity of sertindole, symptoms of postural hypotension may occur during the initial dose-titration period.

Antipsychotic drugs may inhibit the effects of dopamine agonists. Sertindole should be used cautiously in patients with Parkinson’s disease.

Some SSRIs, like fluoxetine and paroxetine (potent CYP2D6 inhibitors), may increase the plasma levels of sertindole by a factor of 2 - 3. Sertindole should therefore only be used concomitantly with these drugs with extreme caution, and only if the potential benefit outweighs the risk. A lower maintenance dose of sertindole may be needed and careful ECG monitoring should be undertaken before and after any dose adjustment of these drugs (see section 4.5).


Sertindole should be used with caution in patients who are known to be poor CYP2D6 metabolisers (see section 4.5).

Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with sertindole. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.



Increased Mortality in Elderly people with Dementia
Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated.
There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Serdolect is not licensed for the treatment of dementia-related behavioural disturbances.

Risk of cerebrovascular adverse events
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. Sertindole should be used with caution in patients with risk factors for stroke.

In view of the increased risk of significant cardiovascular disease in the elderly, sertindole should only be used with care in patients above 65 years of age. Treatment should only be initiated after a thorough cardiovascular examination (see section 4.2)

Venous thromboembolism
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 sertindole and preventive measures undertaken.

Reduced hepatic function
Patients with mild/moderate hepatic dysfunction should be closely observed. Slower titration and a lower maintenance dose are recommended.

Tardive dyskinesia
Tardive dyskinesia is thought to be caused by dopamine receptor hypersensitivity in the basal ganglia as a result of chronic receptor blockade by antipsychotics. A low incidence (comparable to that of placebo) of extrapyramidal symptoms during treatment with sertindole has been seen in clinical studies. However, long-term treatment with antipsychotic compounds (especially at high dosages) is associated with the risk of tardive dyskinesia. If signs of tardive dyskinesia appear, dosage reduction or drug discontinuation should be considered.

Seizures
Sertindole should be used with caution in patients with a history of seizures.

Neuroleptic Malignant Syndrome
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. The management of NMS should include immediate discontinuation of antipsychotic drugs.

Withdrawal
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, a gradual withdrawal is advisable.

Excipients
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not receive this medicine.




Effects on Driving

4.7      Effects on ability to drive and use machines
Sertindole is not sedative, however, patients should be advised not to drive or operate machinery until their individual susceptibility is known.