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Pharmacological properties

the neuropharmacological profile of sertindole antipsychotic action is due to selective blockade of mesolimbic dopaminergic neurons and a balanced inhibitory effect on central dopamine d2– and serotonin 5-nt2 receptors, as well as on α1-adrenergic receptors. in animal pharmacology studies, sertindole suppressed spontaneously active dopamine neurons in the mesolimbic ventral region of the brain with a selectivity of 100 compared to dopamine neurons in substancia nigra pars compacta. the reason for the occurrence of motor side effects of many antipsychotics is the inhibition of the activity of substancia nigra pars compacta. antipsychotic drugs are known to increase plasma prolactin levels due to blockade of dopamine receptors. Prolactin levels in patients taking sertindole remain within normal limits for both short and long (1 year) treatment. sertindole does not affect m-cholinergic receptors and histamine H1 receptors.

Pharmacokinetics

Absorption

Sertindole is well absorbed, the maximum concentration after oral administration is achieved after about 10 hours. Bioavailability when taking different doses of the drug is equivalent. Eating or aluminum-magnesium antacids almost does not affect the absorption of the drug.

Distribution

The volume of distribution after increasing the dose of sertindole is approximately 20 l / kg. Sertindole binds to plasma proteins by 99.5%, mainly with albumin and α1-glycoprotein. In patients taking the drug at the recommended dose, 90% of the measured concentrations are 140 ng / ml (320 nmol / L). Sertindole penetrates red blood cells with a blood / plasma ratio of 1. Sertindole easily penetrates the BBB and the placental barrier.

Metabolism

Two metabolites are determined in human blood plasma: dehydrosertindole (oxidation of the imidazolidine ring) and norsertindole (N-alkylation). The concentrations of dehydrocertindole and norsertindole are respectively 80 and 40% against the background of equilibrium concentration. The activity of sertindole primarily depends on the main compound, and metabolites do not have a pronounced pharmacological activity in humans.

Excretion

Sertindole and its metabolites are eliminated very slowly with the complete restoration of 50-60% of the radiolabeled oral dose on the 14th day after administration. Approximately 4% in the form of unchanged substance and 1% of metabolites excreted in the urine. The main part of the unchanged substance and metabolites is excreted in the feces, which is the main route of excretion.

Indications

Schizophrenia. taking into account the caution regarding cardiovascular safety, sertindole is prescribed only to those patients whose treatment with at least one of the other antipsychotics was not effective enough and / or was accompanied by hypersensitivity reactions to the drug. sertindole should not be used in emergency situations to quickly stop the symptoms of exacerbation of the disease.

Application

Sertindole is administered orally 1 time per day, regardless of food intake.

In patients in need of sedation, benzodiazepine can be used at the same time.

It is necessary to monitor the ECG at the beginning and during treatment with sertindole (see SPECIAL INSTRUCTIONS). Clinical trials have shown the ability of sertindole to significantly extend the Q – T interval compared to some other antipsychotic drugs. When using the drug, safety warnings must be strictly observed (see SPECIAL INSTRUCTIONS).

Dose selection. Treatment of all patients should begin with 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 α1-adrenoreceptors, therefore, during the initial period of dose titration, symptoms of postural hypotension may be observed. An initial dose of 8 mg or a rapid increase in dose significantly increases 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 in clinical trials there was no increase in the effectiveness of the drug with 20 mg / day, and the prolongation of the Q – T interval can increase with the use of the drug in higher doses.

During dose titration and at the beginning of maintenance therapy, blood pressure should be monitored.

Repeated dose selection in patients whose sertindole was previously discontinued. With a break in taking Sertindole for 1 week, there is no need to re-select the dose, and the previously used maintenance dose may be the same. In other cases, it is necessary to adhere to the recommended method of dose selection. Before repeated titration of a dose of sertindole, ECG monitoring should be performed.

Transition from other antipsychotics. Sertindole treatment can be started according to the recommended dose selection sequence after stopping other oral antipsychotics. For patients who have been treated with injectable depot antipsychotic drugs, sertindole is prescribed instead of the next injection.

The duration of treatment is determined individually depending on the course of the disease and the condition of the patient.

Contraindications

Hypersensitivity to sertindole or other components of the drug. established uncorrectable hypokalemia, hypomagnesemia.

Clinically significant cardiovascular diseases in the anamnesis: congestive heart failure, myocardial hypertrophy, arrhythmia or bradycardia (50 beats / min). Syndrome of a congenital extended Q – T interval (including in a family history), acquired syndrome of an extended Q – T interval (450 ms in men and 470 ms in women).

Severe liver disease.

Side effects

When using sertindole in clinical trials, side effects whose frequency exceeded 1% and significantly differed from placebo are listed in decreasing order of frequency: rhinitis / nasal congestion, ejaculation disturbance (decrease in ejaculate volume), dizziness, dry mouth, postural hypotension, increase body mass, peripheral edema, dyspnea, paresthesia and prolongation of the q – t interval (see special instructions).

The incidence of extrapyramidal symptoms, as well as the need for medical intervention for the development of this side effect, was the same in patients taking sertindole and placebo. Some side effects may appear at the beginning and disappear with continued treatment, such as postural hypotension.

Disorders from the metabolism and metabolism
Infrequently Hyperglycemia
Disorders of the nervous system
Often Dizziness, paresthesia
Infrequently Syncope, convulsions, movement disorders (especially tardive dyskinesia)
Rarely Malignant antipsychotic syndrome
Disorders of the cardiovascular system
Often Peripheral edema

Postural hypotension

Infrequently Torsade de Pointes Arrhythmia
Respiratory system disorders
Often Rhinitis, nasal congestion
Often Dyspnoea
Gastrointestinal Disorders
Often Dry mouth
Reproductive system disorders
Often Violation of ejaculation (decrease in ejaculate volume)
Survey data
Often Weight gain, Q – T interval prolongation, erythrocyturia and leukocyturia

special instructions

The cardiovascular system. clinical results confirm the ability of sertindole to significantly extend the q – t interval compared with other antipsychotics.the average prolongation q – t increases with the use of the drug at a dose of 20 and 24 mg. prolongation of the q – t interval can lead to arrhythmias such as torsade de pointes (potentially lethal polymorphic ventricular tachycardia) and sudden death.

However, clinical and non-clinical data cannot confirm that sertindole is a more arrhythmogenic drug than other antipsychotics. Sertindole is used in patients whose treatment with at least one of the other antipsychotics has been found to be insufficiently effective and / or accompanied by hypersensitivity reactions to the drug.

When using the drug should be guided by safety warnings.

ECG monitoring is mandatory before and during sertindole treatment.

Sertindole is contraindicated if, when measured at rest, the Q – T interval is 450 ms in men or 470 ms in women.

ECG monitoring should be carried out at the beginning of treatment, when an equilibrium concentration of the drug in the blood plasma is reached after approximately 3 weeks of therapy or the use of a dose of 16 mg and again after 3 months of treatment. During maintenance treatment, an ECG should be performed every 3 months.

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