Serdolect

/ Lundbeck

Sertindole is administered orally as one daily dosage with or without meals. In patients where sedation is required, a benzodiazepine may be co-administered.
Note: ECG monitoring is required before and during treatment with sertindole. Clinical studies have shown that sertindole prolongs the QT interval to a greater extent than some 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.
Titration: Initially 4 mg sertindole daily is administered to all patients. The dose should be increased by increments of 4 mg after 4-5 days on each dose until the optimal daily maintenance dose, within the range of 12-20 mg, is reached. Due to the 1-blocking activity of sertindole, symptoms of postural hypotension may occur during the initial dose-titration period. A starting dose of 8 mg or a rapid increase in dose carries a significantly increased risk of postural hypotension.
Maintenance: Dependent on individual patient response, the dose may be increased to 20mg/day. Only in exceptional cases should the maximum dose of 24mg be considered, as clinical trials have not demonstrated consistently improved efficacy above 20mg and the risk of QT prolongation may be increased at the upper end of the dose range. The blood pressure of the patients should be monitored during titration and early maintenance treatment.
Elderly: A pharmacokinetic study showed no difference between young and elderly subjects. However, only limited clinical trial data exist for patients greater than 65 years of age. Treatment should only be initiated after a thorough cardiovascular examination. Slower titration and lower maintenance doses are recommended in elderly patients.
Children & adolescents under the age of 18: Serdolect is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Reduced renal function: Sertindole can be given at the usual dosage to patients with renal impairment. The pharmacokinetics of sertindole is not affected by haemodialysis.
Reduced hepatic function: Patients with mild/moderate hepatic impairment require slower titration and a lower maintenance dose.
Re-titration of sertindole in patients for whom treatment has previously been discontinued: When restarting sertindole treatment in patients who have had an interval of less than one week without sertindole, re-titration of sertindole is not required and their maintenance dose can be re-introduced. Otherwise the recommended titration schedule should be followed. An ECG should be taken prior to re-titration of sertindole.
Switching from other antipsychotics: Treatment with sertindole can be initiated according to the recommended titration schedule concomitantly with cessation of other oral antipsychotics. For patients treated with depot antipsychotics, sertindole is initiated in place of the next depot injection.
For full details see prescribing information.

Sertindole is indicated for the treatment of schizophrenia. Due to cardiovascular safety concerns, sertindole should only be used for patients intolerant to at least one other antipsychotic agent. Sertindole should not be used in emergency situations for urgent relief of symptoms in acutely disturbed patients.

Hypersensitivity to sertindole or any of the excipients. Sertindole is contraindicated in patients with known uncorrected hypokalaemia, and those with known uncorrected hypomagnesaemia. Sertindole is contraindicated in patients with a history of clinically significant cardiovascular disease, congestive heart failure, cardiac hypertrophy, arrhythmia, or bradycardia (<50 beats per minute). Furthermore, sertindole should not be initiated in patients with congenital long QT syndrome or a family history of this disease, or in patients with known acquired QT interval prolongation (QTc above 450 msec in males and 470 msec in females). Sertindole is contraindicated in patients receiving drugs known to significantly prolong the QT interval. Relevant classes include:  Class Ia and III antiarrhythmics (e.g. quinidine, amiodarone sotalol, dofetilide), Some antipsychotics (e.g. thioridazine), Some macrolides (e.g. erythromycin), Some antihistamines (e.g. terfenadine, astemizole), Some quinolone antibiotics (e.g. gatifloxacin, moxifloxacin). The list is not exhaustive. Other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) are also contraindicated. Co-administration of sertindole is contraindicated with drugs known to potently inhibit hepatic cytochromeP450 3A enzymes. Relevant classes include:  Systemic treatment with ‘azole’ antifungal agents (e.g. ketoconazole, itraconazole), Some macrolide antibiotics (e.g. erythromycin, clarithromycin), HIV protease inhibitors (e.g. indinavir), Some calcium channel blockers (e.g. diltiazem, verapamil ). The above list is not exhaustive. Other individual drugs known to potently inhibit CYP3A enzymes (e.g. cimetidine) are also contraindicated. Sertindole is contraindicated in patients with severe hepatic impairment.

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 approximately3 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. 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.
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. 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. 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 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. Sertindole should be used with caution in patients who are known to be poor CYP2D6 metabolisers. 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.
Elderly patients: Sertindole is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in elderly patients with dementia.
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 be used with care in patients above 65 years of age. Treatment should only be initiated after a thorough cardiovascular examination 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 movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, a gradual withdrawal is recommended.
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.
For full details see prescribing information.

In clinical trials, adverse events with an incidence greater than 1% associated with the use of sertindole and significantly different from placebo were (listed in order of decreasing frequency): rhinitis/nasal congestion, abnormal ejaculation (decreased ejaculatory volume), dizziness, dry mouth, postural hypotension, weight gain, peripheral oedema, dyspnoea, paraesthesia, and prolonged QT interval.
Extrapyramidal Symptoms (EPS): The incidences of patients treated with sertindole reporting EPS-related adverse events were similar to those of patients treated with placebo. In placebo-controlled clinical trials, the number of patients requiring anti-EPS medication was the same in the group receiving sertindole as in the group of placebo-treated patients. Some of the adverse drug reactions will appear at the beginning of treatment and disappear with continuous treatment, e.g., postural hypotension. The list below shows adverse reactions sorted by system organ class and frequency: Very common ( 1/10); Common ( 1/100, < 1/10); Uncommon ( 1/1,000, < 1/100); Rare ( 1/10,000, < 1/1,000); Very rare ( 1/10,000), not known (cannot be estimated from the available data).
Investigations: Common: red blood cells urine positive, white blood cells urine positive.
Cardiac disorders: Common: Peripheral oedema, prolonged QT interval.
Nervous system disorders: Common: Dizziness, paraesthesia.
Respiratory, thoracic and mediastinal disorders: Very common: Rhinitis/nasal congestion. Common: Dyspnoea. Gastrointestinal disorders: Common: Dry mouth.
Metabolism and nutritional disorders: Common: Dizziness, Paraesthesia.
Vascular disorders: Common: Postural hypotension.
Pregnancy, puerperium and perinatal conditions: Unknown: Drug withdrawal syndrome neonatal.
Reproductive system & breast disorders: Very common: Ejaculation disorder. Common: Abnormal ejaculation (decreased ejaculatory volume).
For full details see prescribing information.

Increases in the QT interval related to sertindole treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval. Co-administration of such drugs is therefore contraindicated. Such an interaction may occur e.g. between quinidine and sertindole. In addition to the effects on QT interval prolongation, CYP2D6 is markedly inhibited by quinidine. Sertindole is extensively metabolised by the CYP2D6 and CYP3A isozymes of the cytochrome P450 system. CYP2D6 is polymorphic in the population and both isozymes can be inhibited by a variety of psychotropic and other drugs.
CYP2D6: The plasma concentration of sertindole is increased by a factor of 2 – 3 in patients concurrently taking fluoxetine or paroxetine (both potent CYP2D6 inhibitors), sertindole should therefore only be used concomitantly with these or other CYP2D6 inhibitors with extreme caution. 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.
CYP3A: Minor increases (25%) in sertindole plasma concentrations have been noted for macrolide antibiotics (e.g. erythromycin, a CYP3A inhibitor) and calcium channel antagonists (diltiazem, verapamil). However, the consequences could be greater in CYP2D6 poor metabolisers since elimination of sertindole by both CYP2D6 and CYP3A would be affected. Because it is not possible to routinely identify patients who are poor metabolisers of CYP2D6, the concomitant administration of CYP3A inhibitors and sertindole is contraindicated, as this may lead to significant increases in sertindole levels. The metabolism of sertindole may be significantly enhanced by agents known to induce CYP isozymes, notably rifampicin, carbamazepine, phenytoin and phenobarbital, which can decrease the plasma concentrations of sertindole by a factor of 2 to 3. Reduced antipsychotic efficacy in patients receiving these drugs or other inducing agents may require the dose of sertindole to be adjusted to the upper dosage range.
For full details see prescribing information.

Pregnancy: The safety of sertindole for use during pregnancy has not been established. Sertindole was not teratogenic in animal reproduction studies. A peri/postnatal study in rats showed a decrease in offspring fertility at a dose within the therapeutic range for humans. Consequently, sertindole should not be used during pregnancy. Neonates exposed to antipsychotics (including Serdolect) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Lactation: Studies in nursing mothers have not been performed. Sertindole is expected to be excreted in breast milk. If treatment with sertindole is considered necessary, discontinuation of breast-feeding should be considered.
Fertility: Oral administration of sertindole was shown to impair male fertility in mice and rats at systemic exposures similar to or less than that anticipated in humans at the maximum recommended clinical dose. The adult male fertility impairment, which was reversible, was likely to be due to α1- adrenoceptor antagonism. Offspring of sertindole-treated female rats have also shown reduced mating and fertility. In humans, adverse events such as hyperprolactinaemia, galactorrhoea, erectile dysfunction, ejaculation disorder and ejaculation failure have been reported. These events may have a negative impact on female and/or male sexual function and fertility. If clinical significant hyperprolactinaemia, galactorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.

Experience with sertindole in acute overdose is limited. Fatal cases have occurred. However, patients taking estimated dosages up to 840 mg have recovered without sequelae. Reported signs and symptoms of overdose were somnolence, slurred speech, tachycardia, hypotension, and transient prolongation of the QT interval. Cases of Torsade de Pointes have been observed, often in combination with other drugs known to induce TdP.
Treatment: In case of acute overdose, establishment of an airway and maintenance of adequate oxygenation should be ensured. Continuous monitoring of ECG and vital signs should commence immediately. If the QTc interval is prolonged, it is recommended that the patient be monitored until the QTc interval has normalised. A half-life of sertindole of 2 to 4 days should be taken into account. Intravenous access should be established, and the administration of activated charcoal with laxative should be considered. The possibility of multiple drug involvement should be considered. There is no specific antidote to sertindole and it is not dialysable, therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, adrenaline and dopamine should be used with caution, since  stimulation combined with 1 antagonism associated with sertindole may worsen hypotension. If antiarrhythmic therapy is administered, agents such as quinidine, disopyramide, and procainamide carry a theoretical hazard of QT interval-prolonging effects that might be additive to those of sertindole. In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.