Pharmacological properties
Pharmacodynamics. The neuropharmacological profile of the antipsychotic action of sertindole is due to selective blockade of mesolimbic dopaminergic neurons and a balanced inhibitory effect on central dopamine D2 and serotonin 5-HT2 receptors, as well as on α1-adrenoreceptors. In a pharmacological study on animals, sertindole inhibited spontaneously active dopamine neurons in the mesolimbic ventral region of the brain with a selectivity coefficient of 100 compared with dopamine neurons in the substantia nigra pars compacta. The cause of the motor side effects of many antipsychotics is considered to be inhibition of the activity of the substantia nigra pars compacta. It is known that antipsychotics increase the level of prolactin in the blood plasma, due to the blockade of dopamine receptors. The level of prolactin in patients taking sertindole remains within normal limits both during short and long (1 year) courses of treatment. Sertindole does not affect m-cholinoreceptors and histamine H1 receptors.
Pharmacokinetics
absorption
Sertindole is well absorbed, with peak plasma concentrations occurring approximately 10 hours after oral administration. Bioavailability is equivalent across doses. Food or aluminum-magnesium antacids have little effect on absorption.
distribution
The volume of distribution after increasing the dose of sertindole is approximately 20 l/kg. Sertindole is 99.5% bound to plasma proteins, mainly albumin and α 1 glycoprotein. In patients taking the drug at the recommended dose, 90% of the measured concentrations are 140 ng / ml (320 nmol / l). Sertindole penetrates into erythrocytes with a blood / plasma ratio of 1. Sertindole easily penetrates the blood-brain barrier and the placental barrier.
metabolism
Two metabolites are identified in human plasma: dehydrosertindole (oxidation of the imidazolidine ring) and norsertindole (N-alkylation). The concentrations of dehydrosertindole and norsertindole are 80 and 40%, respectively, of the equilibrium concentration. The activity of sertindole depends primarily on the parent compound, and the metabolites do not have pronounced pharmacological activity in humans.
excretion
Sertindole and its metabolites are eliminated very slowly with complete recovery of 50-60% of the radiolabeled oral dose by the 14th day after administration. Approximately 4% as unchanged drug and 1% as metabolites are excreted in the urine. The majority of unchanged drug and metabolites are excreted in the feces, which is the major route of excretion.
Indication
Schizophrenia. Given the caution regarding cardiovascular safety, sertindole should only be prescribed to patients whose treatment with at least one other antipsychotic agent has been insufficiently effective and/or has been accompanied by hypersensitivity reactions to the drug. Sertindole should not be used in emergency situations for the rapid relief of symptoms of an exacerbation of the disease.
Application
Sertindole is administered orally once a day, regardless of meals.
In patients requiring sedation, a benzodiazepine may be used concurrently.
ECG monitoring is necessary at the beginning and during treatment with Sertindole (see Precautions). Clinical trials have shown that sertindole can significantly prolong the QT interval compared to some other antipsychotics. When using the drug, it is necessary to strictly follow the Precautions (see Precautions).
Dose selection. Treatment of all patients should be initiated at a dose of sertindole 4 mg/day. The dose is increased by adding 4 mg every 4-5 days to the optimal daily maintenance dose of 12-20 mg. Sertindole blocks α 1 -adrenoceptors, therefore, symptoms of postural hypotension may occur during the initial dose titration period. An initial dose of 8 mg or rapid dose increases significantly increase the risk of postural hypotension.
Maintenance dose. Depending on the individual sensitivity of the patient, the dose may be increased to 20 mg/day. Only in exceptional cases is it possible to use the maximum dose of 24 mg, since clinical trials have not shown an increase in the effectiveness of the drug when using 20 mg/day, and QT interval prolongation may increase when using the drug in higher doses.
Blood pressure should be monitored during dose titration and at the beginning of maintenance therapy.
Re-selection of the dose in patients whose sertindole use has previously been stopped. If a break in taking sertindole for 1 week is not necessary to re-selection of the dose, and the previously used maintenance dose may be unchanged. In other cases, the recommended method of dose selection should be followed. ECG monitoring should be performed before re-titrating the dose of sertindole.
Switching from other neuroleptics. Sertindole treatment can be started according to the recommended dose selection sequence after stopping other oral neuroleptics. In patients who have been treated with injectable depot neuroleptics, sertindole is prescribed instead of the next injection.
The duration of treatment is determined individually depending on the course of the disease and the patient's condition.
Contraindication
Clinically significant cardiovascular disease in history: congestive heart failure, myocardial hypertrophy, arrhythmia or bradycardia (50 beats / min). Congenital long QT syndrome (including family history), acquired long QT syndrome (450 ms in men and 470 ms in women).
Severe liver disease.
Side effects
When using sertindole in clinical studies, side effects that occurred at an incidence greater than 1% and were significantly different from placebo are listed in order of decreasing frequency: rhinitis/nasal congestion, ejaculation disorder (decreased ejaculate volume), dizziness, dry mouth, postural hypotension, weight gain, peripheral edema, dyspnea, paresthesia, and QT prolongation (see Special Instructions).
The incidence of extrapyramidal symptoms, as well as the need for medical intervention for this side effect, was similar in patients taking sertindole and placebo. Some side effects may appear at the beginning and disappear with continued treatment, for example, postural hypotension.
| Metabolic and metabolic disorders |
| Not often | hyperglycemia |
| Nervous system disorders |
| often | Dizziness, paresthesia |
| Not often | Syncope, seizures, movement disorders (especially tardive dyskinesia) |
| rarely | Neuroleptic malignant syndrome |
| Cardiovascular system disorders |
| often | peripheral edema postural hypotension |
| Not often | Torsade de Pointes type arrhythmia |
| Respiratory system disorders |
| Very often | Rhinitis, nasal congestion |
| often | dyspnea |
| Gastrointestinal disorders |
| often | Dry mouth |
| Reproductive system disorders |
| often | Ejaculation disorders (reduced ejaculate volume) |
| survey data |
| often | Weight gain, QT prolongation, erythrocyturia and leukocyturia |
|
Special instructions
Cardiovascular system. Clinical studies have shown that sertindole significantly prolongs the QT interval compared to other neuroleptics. The mean QT prolongation increases with doses of 20 and 24 mg. QT prolongation can lead to torsade de pointes (a potentially fatal polymorphic ventricular tachycardia) and sudden death.
However, clinical and non-clinical data do not support the idea that sertindole is more arrhythmogenic than other neuroleptics. Sertindole is used in patients whose treatment with at least one other antipsychotic agent has been insufficiently effective and/or has been accompanied by hypersensitivity reactions to the drug.
When using the drug, safety precautions should be followed.
ECG monitoring is mandatory before starting and during treatment with Sertindole.
Sertindole is contraindicated if the QT interval measured at rest is 450 ms in men or 470 ms in women.
ECG monitoring should be performed at the beginning of treatment, when a stable plasma concentration of the drug is achieved after approximately 3 weeks of therapy or at a dose of 16 mg, and again after 3 months of treatment. During maintenance treatment, ECG monitoring should be performed every 3 months.
During support
