Servitel, 100 mg 60 pcs.

Pharmgroup: antipsychotic (neuroleptic).
Pharmacological action: Quetiapine is an atypical antipsychotic drug. Quetiapine and its active metabolite N-dezalkyl quetiapine interact with brain neutrotransmitter receptors. Quetiapine and N-desalkyl quetiapine exhibit high affinity for the 5NT2 sstrotonin receptors and brain dopamine receptors types D1 and D2. The higher selectivity for 5HT2 serotonin receptors than for D2 dopamine receptors accounts for the major clinical antipsychotic properties of quetiapine and the low frequency of extrapyramidal side effects. In addition, N-desalkyl quetiapine has a high affinity for the norepinephrine transporter. Quetiapine and N-desalkyl quetiapine have a high affinity for histamine and alpha1 adrenoreceptors and a lower affinity for alpha2 adrenoreceptors and serotonin type 5NT1 receptors.
Quetiapine has no appreciable affinity for cholinergic muscarinic and benzodiazepine receptors. Quetiapine exhibits antipsychotic activity in standard tests. The specific contribution of the metabolite N-dezalkyl quetiapine to the pharmacological activity of quetiapine has not been established.
Results of studies of extrapyramidal symptoms (EPS) in animals have revealed that quetiapine causes mild catalepsy at doses that effectively block dopamine D2 receptors. Quetiapine causes a selective reduction in the activity of mesolimbic A10-dopaminergic neurons compared to A9-nigrostriate neurons involved in motor function.
Clinical studies (using quetiapine at doses of 75-750 mg/day) found no difference between quetiapine and placebo in the incidence of extrapyramidal symptoms and concomitant use of anticholinergic drugs. Quetiapine does not cause long-term increases in plasma prolactin concentrations.
Quetiapine is effective in the treatment of both positive and negative symptoms of schizophrenia. It maintains long-term clinical improvement in those patients in whom a positive effect developed at the beginning of treatment. The duration of effects of quetiapine on 5NT2 and D2 receptors is less than 12 hours after drug administration.
Pharmacokinetics: When taken orally, quetiapine is well absorbed from the gastrointestinal tract and is actively metabolized in the liver. Food intake does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine is bound to blood plasma proteins.
The equilibrium molar concentration of the active metabolite N-dezalkyl quetiapine is 35% of the equilibrium molar concentration of quetiapine. The elimination period of vetiapine and N-dezalkyl vetiapine is approximately 7 and 12 hours, respectively. Pharmacokinetics of vetiapine and N-dezalkyl vetiapine are linear, no differences in pharmacokinetic parameters are observed in men and women. CYP3A4 has been found to be the key isoenzyme of cytochrome P450-mediated metabolism of quetiapine. N-dsalkyl quetiapine is formed with the participation of CYP3A4 isoenzyme.
Mean clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.
Mean plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2), but individual clearance values are within values consistent with healthy volunteers. In patients with impaired liver function (e.g., compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Because quetiapine is extensively metabolized in the liver, patients with hepatic impairment may have increased plasma concentrations of quetiapine, requiring dose adjustments.
On average, less than 5% of the molar dose fraction of free quetiapine and N-desalkyl plasma quetiapine is excreted with the urine. Approximately 73% of quetiapine is excreted overnight and 21% is excreted via the intestine. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or through the intestine.
In a study of the pharmacokinetics of quetiapine at various doses, administration of quetiapine prior to or concomitantly with ketoconazole resulted in an average increase in the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of quetiapine of 235% and 522%, respectively, and a decrease in quetiapine clearance of, on average, 84%. The half-life of quetiapine increased, but the mean time to reach maximum concentration (tmax) did not change. Quetiapine and some of its metabolites, including N-desalkyl quetiapine, have weak inhibitory activity against cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and WA4, but only at concentrations 10-50 times higher than those observed at the commonly used effective dose of 300-450 mg/day. Based on in vitro results, we should not expect that concomitant use of quetiapine with other drugs will result in clinically significant inhibition of cytochrome P450-mediated metabolism of other drugs.

Indications

– for the treatment of schizophrenia;
– for the treatment of manic episodes in the structure of bipolar disorder.
The drug Servitel is not indicated for the prevention of manic episodes in bipolar disorder.

Active ingredient

Composition

1 Tablet:
– quetiapine hemifumarate 28.78 mg, which corresponds to the quetiapine content of 25 mg
– quetiapine hemifumarate 115.13 mg, which corresponds to the quetiapine content of 100 mg
– quetiapine hemifumarate 230.27 mg, which corresponds to the quetiapine content of 200 mg
Excipients: hypromellose, calcium hydrophosphate dihydrate, lactose monohydrate, corn starch. Compounds: Hypromellose, calcium hydrophosphate dihydrate, lactose monohydrate, corn starch, sodium carboxymethyl starch, magnesium stearate, microcrystalline cellulose, talcum, colloidal silicon dioxide.

How to take, the dosage

Adults:
Treatment of schizophrenia
Servitel® is prescribed 2 times a day. The daily dose for the first 4 days of therapy is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg. Starting on day 4, the dose should be adjusted to a clinically effective dose, which is usually between 300 and 450 mg/day. Depending on clinical effect and individual patient tolerance, the dose may vary between 150 and 750 mg/day. The maximum recommended daily dose is 750 mg. Treatment of manic episodes in the structure of bipolar disorder Servitel® is used as monotherapy or as adjuvant therapy to stabilize mood.
Servitel® is prescribed 2 times daily. The daily dose for the first 4 days of therapy is: Day 1 – 100 mg, Day 2 – 200 mg, Day 3 – 300 mg, Day 4 – 400 mg. By the 6th day of therapy, the daily dose can be increased to 800 mg. The daily dose should not exceed 200 mg per day.
Depending on the clinical effect and individual tolerance of a patient, the dose may vary from 200 to 800 mg/day. Usually the effective dose is 400 to 800 mg/day. The maximum recommended daily dose is 800 mg.
Elderly:
In elderly patients, the initial dose of quetiapine is 25 mg/day. The dose should be increased daily by 25-50 mg until an effective dose is reached, which is likely to be lower than in younger patients. Patients with renal or hepatic impairment
In patients with renal or hepatic impairment, it is recommended that quetiapine therapy be started at 25 mg/day. It is recommended that the dose of Servitel be increased daily by 25-50 mg until an effective dose is achieved.

Interaction

Concomitant administration of drugs with strong inhibitory effect on CYP3A4 isoenzyme (such as azole antifungals and macrolide antibiotics) may increase plasma concentration of quetiapine. In a study of pharmacokinetics of quetiapine in different dosages, administration of quetiapine before or at the same time as ketoconazole led to a 5-8-fold increase in maximum concentration (Cmax) and area under the curve “concentration-time” (AUC) of quetiapine, as well as to a decrease in clearance of quetiapine. The half-life of vetiapine increased, but the average time to reach the maximum concentration Tmax did not change. In such cases, lower doses of vetiapine should be used.
Special attention should be paid to elderly and impaired patients. The risk-benefit ratio for each patient must be assessed individually. Therefore, co-administration of vvetiapine and CYP3A4 cytochrome inhibitors is contraindicated. It is also not recommended to take vetiapine together with grapefruit juice. Concomitant administration of quetiapine with drugs that induce the liver enzyme system, such as carbamazepine, may decrease the plasma concentration of the drug, which may require increasing the dose of quetiapine, depending on the clinical effect. In a study of the pharmacokinetics of quetiapine in different dosages, when administered before or simultaneously with carbamazepine (a hepatic enzyme inducer) resulted in a significant increase in the clearance of quetiapine. This increase in clearance of quetiapine decreased AUC by an average of 13% compared to the use of quetiapine without carbamazepine.
Simultaneous administration of quetiapine with another inducer of microsomal liver enzymes, phenytoin, also resulted in increased clearance of quetiapine. If quetiapine and phenytoin (or other hepatic enzyme inducers such as barbiturates, rifampicin) are concomitantly prescribed, the dose of quetiapine may need to be increased. It may also be necessary to reduce the dose of quetiapine when phenytoin or carbamazepine or another hepatic enzyme inducer is withdrawn or replaced with a drug that does not induce hepatic microsomal enzymes (e.g., valproic acid).
Pharmacokinetics of lithium preparations are not altered by concomitant administration of quetiapine.
No clinically significant changes in valproic acid and quetiapine pharmacokinetics have been observed when valproate semisodium and quetiapine are co-administered. Quetiapine did not cause induction of hepatic enzyme systems involved in phenazone metabolism.
Pharmacokinetics of quetiapine does not change significantly when concomitantly administered with antipsychotic drugs – risperidone or haloperidol. However, concomitant administration of quetiapine and thioridazine resulted in increased clearance of quetiapine.
Pharmacokinetics of quetiapine does not change significantly with concomitant use of cimetidine, which is a cytochrome P450 inhibitor. Quetiapine pharmacokinetics did not change significantly with concomitant administration of antidepressant imipramine (CYP2D6 isoenzyme inhibitor) or fluoxetine (CYP3A4 and CYP2D6 isoenzyme inhibitor).
Pharmacokinetic studies to study interaction of quetiapine with drugs used for cardiovascular diseases were not conducted. Caution should be exercised when combining quetiapine with drugs that can cause electrolyte imbalance and QTc interval prolongation.
Caution should be exercised when combining quetiapine with other drugs affecting the central nervous system and with alcohol, as this may increase the risk of quetiapine side effects.

Special Instructions

Sleepiness:
Sleepiness and related symptoms, such as sedation, may be noted during therapy with quetiapine. In clinical studies involving depressed patients with bipolar disorder, somnolence generally developed within the first three days of therapy. The severity of this side effect was generally mild to moderate. If severe somnolence develops, patients with depression in the structure of bipolar disorder may require more frequent visits to the physician within 2 weeks from the onset of somnolence or until the severity of symptoms decreases. In some cases, discontinuation of quetiapine therapy may be necessary. Patients with cardiovascular diseases
Caution should be exercised when prescribing quetiapine to patients with cardiovascular and cerebrovascular diseases, and other conditions predisposing to hypotension. Against the background of quetiapine therapy, orthostatic hypotension may occur, especially in the initial period of dose adjustment (it is observed more often in elderly patients than in young ones). If orthostatic hypotension occurs, dose reduction or slower titration may be required. QT interval prolongation
No relationship between quetiapine administration and QT interval prolongation has been found. However, prolongation of the QT interval has been observed in overdose of the drug.
Caution should be exercised when prescribing quetiapine to patients with cardiovascular disease and previously noted QT interval prolongation, as well as when concomitant use with QT interval prolongers, other neuroleptics, especially in the elderly, patients with congenital QT interval prolongation syndrome, chronic heart failure, myocardial hypertrophy, hypokalemia or hypomagnesemia.
Tardive dyskinesia:
With long-term use of quetiapine, there is a potential for the development of tardive dyskinesia. If symptoms of tardive dyskinesia occur, it is recommended to reduce the dose of the drug Servitel or gradually discontinue it.
Severe neutropenia:
Severe neutropenia (neutrophil count < 0.5*109/L) has been infrequently reported in clinical trials of quetiapine. Most cases of severe neutropenia occurred several months after the start of quetiapine therapy. No dose-dependent effect was detected. Leukopenia and/or neutropenia resolved after discontinuation of quetiapine treatment. A possible risk factor for the occurrence of neutropenia is a previous decrease in the leukocyte count and a history of drug-induced neutropenia. In patients with neutrophil counts < 1.0*109/l, quetiapine should be discontinued. The patient should be monitored for possible symptoms of infection and neutrophil levels should be monitored (until the level of 1.5*109/l increases).
Hyperglycemia:
Hyperglycemia or worsening of diabetes in patients with a history of diabetes mellitus may develop during quetiapine administration. Clinical monitoring of patients with diabetes mellitus and patients with risk factors for diabetes mellitus is recommended.
Lipid levels:
Quetiapine administration may increase triglyceride and cholesterol concentrations.
Elderly patients with dementia:
Quetiapine is not indicated for treatment of psychosis associated with dementia. Some atypical neuroleptics in randomized placebo-controlled trials increased the risk of cerebrovascular complications in patients with dementia. The mechanism of this increased risk is not understood. A similar risk of increased incidence of cerebrovascular complications cannot be ruled out for other antipsychotic medications or other patient groups. Quetiapine should be used with caution in patients at risk for stroke.
An analysis of the use of atypical neuroleptics for the treatment of psychosis associated with dementia in elderly patients revealed an increased mortality rate in the group of patients receiving the drugs in this group compared to the placebo group. No causal relationship was found between quetiapine treatment and the risk of increased mortality in elderly patients with dementia.
Seizures:
No difference was found in the incidence of seizures in patients receiving quetiapine or placebo. However, as with therapy with other antipsychotics, caution is advised when treating patients with a history of seizures. Malignant neuroleptic syndrome
Malignant neuroleptic syndrome may develop while taking antipsychotic drugs, including quetiapine. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, instability of the autonomic nervous system, and increased concentration of creatine phosphokinase. In such cases, quetiapine should be withdrawn and appropriate treatment should be given.
Acute reactions associated with withdrawal of the drug Servitel:
The following acute reactions (withdrawal syndrome) may be observed during abrupt withdrawal of quetiapine – nausea, vomiting, insomnia, headache, dizziness and irritability. Therefore, withdrawal of the drug is recommended gradually over at least one or two weeks.
Suicidal/suicidal thoughts or clinical deterioration:
Depression is associated with an increased risk of suicidal thoughts, self-injury and suicide in children, adolescents and young adults (younger than 24 years). This risk persists until the onset of marked remission. Because it may take several weeks or more before a patient’s condition improves from the start of treatment, patients should be under close medical supervision until improvement occurs. According to generally accepted clinical experience, the risk of suicide may increase in the early stages of remission.
Other psychiatric disorders for which quetiapine is prescribed are also associated with an increased risk of suicide-related events. In addition, such conditions may be comorbid with a depressive episode. Thus, the precautions used in the therapy of patients with a depressive episode should also be taken when treating patients with other psychiatric disorders. Patients with a history of suicidal events, as well as patients clearly expressing suicidal thoughts before starting therapy, are at increased risk of suicidal intentions and suicide attempts and should be carefully monitored during treatment. Patients with hepatic impairment
Quetiapine is extensively metabolized in the liver. Therefore, caution should be exercised when using quetiapine in patients with hepatic impairment, especially at the beginning of therapy.
Interaction with other medicinal products:
Also see “Interaction with other medicinal products”. The use of quetiapine in combination with strong inducers of the liver enzyme system, such as carbamazepine and phenytoin, reduces the concentration of quetiapine in plasma and may reduce the effectiveness of quetiapine therapy. Administration of quetiapine to patients receiving hepatic enzyme system inducers is possible only if the expected benefit of quetiapine therapy exceeds the risk associated with withdrawal of the liver enzyme inducer drug. Changes in the dose of microsomal enzyme inducers should be gradual. If necessary, they may be replaced by drugs that do not induce microsomal enzymes (e.g., valproic acid preparations).
Taking into account the effect of quetiapine on the central nervous system, quetiapine should be taken with caution in combination with other drugs that have a depressing effect on the central nervous system, or alcohol.
Effect on the ability to drive vehicles and mechanisms:
Quetiapine may cause drowsiness, so during treatment patients are not recommended to drive vehicles, as well as it is not recommended to work with mechanisms that pose a danger.

Contraindications

– hypersensitivity to any of the components of the drug Servitel;
– co-administration with cytochrome P450 inhibitors (antifungal drugs of azole group, erythromycin, clarithromycin, nefazodone, protease inhibitors);
– lactase deficiency, glucose-galactose malabsorption, lactose intolerance;
– psychosis in elderly patients with dementia;
– children under 18;
– lactation;
– pregnancy.
With caution:
In patients with cardiovascular and cerebrovascular disease or other conditions predisposing to arterial hypotension; old age; hepatic insufficiency; seizures in the anamnesis.

Side effects

The most common side effects when taking quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.
Administration of quetiapine, as well as other antipsychotic drugs, may be accompanied by an increase in body weight, fainting, development of malignant neuroleptic syndrome, leukopenia, neutropenia and peripheral edema.
The frequency of adverse reactions is given as the following gradation: very frequently (≥ 1/10); frequently (≥ 1/100, < 1/10); infrequently (≥ 1/1000, < 1/100); rarely (≥ 1/10000, < 1/1000); very rarely (< 1/10000), including cases whose frequency is not known.
Central nervous system: very common – somnolence2, dizziness4, headache; common – dysarthria, unusual and nightmarish dreams, syncope4, extrapyramidal symptoms; infrequent – seizures’, restless legs syndrome; very rare – tardive dyskinesia6.
Cardiovascular system: frequently – orthostatic hypotension4, tachycardia4.
Gastrointestinal tract: very frequently – dry mouth; frequently – constipation, dyspepsia; infrequently – dysphagia; rarely – jaundice6; very rarely – hepatitis6.
Respiratory system: frequent – rhinitis.
Blood system: frequent – leukopenia1; infrequent – eosinophilia; frequency is not known – neutropenia.
Immune system: infrequent – hypersensitivity reactions; very rare – anaphylactic reactions.6
Skin: very rare – angioedema6, Stevens-Johnson syndrome6.
Metabolic disorders: very rare – diabetes mellitus1,5,6
Changes in laboratory and instrumental parameters: very often – increased concentration of triglycerides, total cholesterol (mainly low-density lipoprotein cholesterol); common – weight gain, increased liver transaminases activity (aspartate aminotransferase (ACT) and alanine aminotransferase (ALT))3, decreased neutrophil count, hyperglycemia7; infrequent – increased creatine phosphokinase activity, not associated with malignant neuroleptic syndrome, thrombocytopenia.
Other: very common – withdrawal syndrome; common – asthenia, peripheral edema, blurred vision; rare – priapism, malignant neuroleptic syndrome.
1. See Special Precautions.
2. Sleepiness usually occurs within the first 2 weeks of starting therapy and usually resolves with continued quetiapine.
3. Asymptomatic increases in serum ACT, ALT and gamma glutamyl transpeptidase (GGT) activity may occur, usually reversible with continued quetiapine administration.
4. Like other antipsychotics, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia and in some cases, fainting, especially at the beginning of therapy.
5. There are very rare cases of decompensation of diabetes mellitus.
6. Frequency of this side effect was estimated on the basis of the results of post-marketing observation.
7. Increase of fasting blood glucose concentration ≥ 126 mg/dL (≥ 7.0 mmol/L) or blood glucose after a meal ≥ 200 mg/dL (≥ 11.1 mmol/L) at least during a single use.
QT interval prolongation, ventricular arrhythmias, sudden death, cardiac arrest, and bidirectional ventricular tachycardia are considered side effects inherent to neuroleptics.
Quetiapine therapy is associated with a small dose-dependent decrease in thyroid hormone concentrations, particularly total thyroxine (T4) and free T4. The maximum decrease of total and free T4 was registered at the 2nd and 4th weeks of quetiapine therapy with no further decrease of hormone concentrations during long-term treatment. Thereafter, there were no signs of clinically significant changes in the concentration of thyrotropic hormone. In almost all cases, total and free T4 concentrations returned to baseline after discontinuation of quetiapine therapy regardless of the duration of treatment. A slight decrease in total triiodothyronine (Tz) and inverse Tz was observed only with high doses. Thyroxine-binding globulin (TSH) levels remained unchanged, no increase in thyrotropic hormone (TSH) levels was noted.

Overdose

The data on quetiapine overdose are limited. Cases of quetiapine administered in doses greater than 20 g have been described without fatal consequences and with complete recovery. Extremely rare cases of quetiapine overdose resulting in death or coma have been reported.
In patients with a history of severe cardiovascular disease, the risk of side effects from overdose may increase.
Symptoms: the symptoms noted in overdose were mainly a consequence of an increase in the known pharmacological effects of the drug, such as drowsiness and excessive sedation, tachycardia and decreased blood pressure.
Treatment: there are no specific antidotes to quetiapine. In cases of severe intoxication, symptomatic therapy should be considered, and measures aimed at maintaining respiratory function, cardiovascular system, ensuring adequate oxygenation and ventilation of the lungs are recommended. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal and laxatives may facilitate excretion of unabsorbed quetiapine, but the effectiveness of these measures has not been studied. Close medical observation should continue until the patient’s condition improves.

Pregnancy use

Safety and efficacy of the drug Servitel in pregnancy has not been established, so the drug is prescribed only if the benefit to the mother exceeds the risk to the fetus.
If the use of the drug during lactation is necessary, breastfeeding should be stopped.

Similarities