Ketilept tablets p / o 100mg, No. 60

• acute and chronic psychoses, including schizophrenia;

• treatment of manic episodes in the structure of bipolar disorder;

• treatment of moderate to severe depressive episodes in the structure of bipolar disorder.

KetileptЃ should be taken orally, with or without food.

For adults with acute and chronic psychoses, including schizophrenia, the drug is prescribed 2 times / day. The total daily dose in the first 4 days of therapy is 50 mg (1st day), 100 mg (2nd day), 200 mg (3rd day) and 300 mg (4th day). Starting from the 4th day, the usual effective daily dose of KetileptЃ is 300 mg to 450 mg.

Depending on the clinical effect and tolerability in each patient, the dose can be selected (varied) in the range from 150 mg to 750 mg / day. The maximum recommended daily dose is 750 mg.

For the treatment of acute manic episodes in the structure of bipolar disorder, the drug is prescribed 2 times / day. The total daily dose in the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4). Further dose selection up to 800 mg / day by the 6th day is possible with an increase of no more than 200 mg / day. Depending on the clinical response and tolerance in each patient, the dose can be adjusted in the range from 200 mg to 800 mg / day.

The usual effective dose ranges from 400 to 800 mg / day.

The maximum recommended daily dose is 800 mg.

For the treatment of depressive episodes in the structure of bipolar disorder, the drug is prescribed 1 time / day at night. The daily dose in the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). The recommended dose is 300 mg / day. The maximum recommended daily dose is 600 mg.

Supportive therapy

It is advisable to use the lowest dose to maintain remission. Patients should be evaluated periodically to determine the need for supportive therapy.

Resumption of an interrupted course of treatment in patients who previously received quetiapine:

If therapy is resumed less than 1 week after discontinuation of KetileptЃ, the drug can be continued at a dose adequate for maintenance therapy. When resuming therapy in patients who have not received KetileptЃ for more than 1 week, the rules for the initial selection of the dose should be followed and the effective dose should be established according to the patient's clinical response.

The recommended initial dose in elderly patients is 25 mg / day, then the dose should be increased by 25-50 mg / day until an effective dose is reached, which is usually lower than in young patients. Similarly, more careful dose selection and lower doses are recommended for debilitated patients or those prone to hypotensive reactions.

Patients with renal and hepatic insufficiency are recommended to start therapy with 25 mg / day, then increase the dose daily by 25-50 mg until an effective dose is reached, depending on the patient's clinical response and individual tolerance.

The efficacy and safety of quetiapine in children and adolescents has not been established.

Active ingredient: quetiapine fumarate - 115.13 mg, which corresponds to the content of quetiapine - 100 mg

Excipients : microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, colloidal anhydrous silicon dioxide.

Shell composition: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol), iron dye yellow oxide, iron dye red oxide.

• pregnancy;

• lactation period (breastfeeding);

• childhood (efficacy and safety have not been established);

• hypersensitivity to the components of the drug.

The drug is used with caution in patients with hepatic insufficiency, a history of seizures, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; in elderly patients.

Clinical and pharmacological group: Antipsychotic drug (neuroleptic)

Pharmaco-therapeutic group: Antipsychotic (neuroleptic) agent

pharmachologic effect

An antipsychotic drug (neuroleptic). Shows a higher affinity for serotonin 5-HT2 receptors than for dopamine D1 and D2 receptors in the brain. It also has a higher affinity for histamine and ? 1-adrenergic receptors and less in relation to ? 2-adrenergic receptors. No noticeable affinity of quetiapine for m-choline and benzodiazepine receptors was found.

In standard tests, quetiapine exhibits antipsychotic activity.

The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes mild catalepsy at a dose that effectively blocks dopamine D2 receptors.

Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons compared to A9 nigrostriatal neurons involved in motor function.

In clinical studies (at a dose of 75-750 mg / day), no differences were found between the use of quetiapine and placebo in the incidence of EPS and in the concomitant use of anticholinergic drugs.

Quetiapine does not cause a prolonged increase in the concentration of prolactin in the blood plasma. In numerous studies with a fixed dose, there were no differences in the concentration of prolactin when using quetiapine or placebo.

In clinical trials, quetiapine has been shown to be effective in treating both positive and negative symptoms of schizophrenia.

The effect of quetiapine on 5-HT2 and D2 receptors lasts up to 12 hours after taking the drug.

Pharmacokinetics

Suction

When administered orally, quetiapine is well absorbed from the gastrointestinal tract. Food intake does not significantly affect the bioavailability of quetiapine.

Distribution

Plasma protein binding is approximately 83%.

Metabolism

Quetiapine is extensively metabolized in the liver. It has been established that CYP3A4 is a key enzyme in the CYP-mediated metabolism of quetiapine.

The main metabolites in plasma do not have pronounced pharmacological activity. Quetiapine and some of its metabolites have a weak inhibitory activity against the isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, but only at a concentration 10-50 times higher than the concentration observed at the usual effective dose of 300-450 mg / day.

Withdrawal

T1 / 2 is about 7 hours. Approximately 73% of quetiapine is excreted in the urine and 21% in the feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or feces.

Pharmacokinetics in special clinical situations

The mean plasma clearance of quetiapine is approximately 25% lower in patients with severe renal insufficiency (CC <30 ml / min / 1.73 m2) and in patients with liver damage (stabilized alcoholic cirrhosis), but individual clearance values ??are within the range corresponding to healthy people ...

In a study of the pharmacokinetics of quetiapine in different dosages, when prescribing quetiapine before taking ketoconazole or simultaneously with ketoconazole, it led to an increase, on average, of Cmax and AUC of quetiapine by 235% and 522% , respectively, and also led to a decrease in quetiapine clearance, on average, by 84%. T1 / 2 of quetiapine increased, but the mean time to reach Cmax did not change.

Based on in vitro results, concomitant administration of quetiapine with other drugs should not be expected to result in clinically significant inhibition of CYP-mediated metabolism of other drugs.

The average clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.

The pharmacokinetics of quetiapine is linear, there are no differences in pharmacokinetic parameters in men and women.

Indications

• acute and chronic psychoses, including schizophrenia;

• treatment of manic episodes in the structure of bipolar disorder;

• treatment of moderate to severe depressive episodes in the structure of bipolar disorder.

Dosage regimen

KetileptЃ should be taken orally, with or without food.

For adults with acute and chronic psychoses, including schizophrenia, the drug is prescribed 2 times / day. The total daily dose in the first 4 days of therapy is 50 mg (1st day), 100 mg (2nd day), 200 mg (3rd day) and 300 mg (4th day). Starting from the 4th day, the usual effective daily dose of KetileptЃ is 300 mg to 450 mg.

Depending on the clinical effect and tolerability in each patient, the dose can be selected (varied) in the range from 150 mg to 750 mg / day. The maximum recommended daily dose is 750 mg.

For the treatment of acute manic episodes in the structure of bipolar disorder, the drug is prescribed 2 times / day. The total daily dose in the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4). Further dose selection up to 800 mg / day by the 6th day is possible with an increase of no more than 200 mg / day. Depending on the clinical response and tolerance in each patient, the dose can be adjusted in the range from 200 mg to 800 mg / day.

The usual effective dose ranges from 400 to 800 mg / day.

The maximum recommended daily dose is 800 mg.

For the treatment of depressive episodes in the structure of bipolar disorder, the drug is prescribed 1 time / day at night. The daily dose in the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). The recommended dose is 300 mg / day. The maximum recommended daily dose is 600 mg.

Supportive therapy

It is advisable to use the lowest dose to maintain remission. Patients should be evaluated periodically to determine the need for supportive therapy.

Resumption of an interrupted course of treatment in patients who previously received quetiapine:

If therapy is resumed less than 1 week after discontinuation of KetileptЃ, the drug can be continued at a dose adequate for maintenance therapy. When resuming therapy in patients who have not received KetileptЃ for more than 1 week, the rules for the initial selection of the dose should be followed and the effective dose should be established according to the patient's clinical response.

The recommended initial dose in elderly patients is 25 mg / day, then the dose should be increased by 25-50 mg / day until an effective dose is reached, which is usually lower than in young patients. Similarly, more careful dose selection and lower doses are recommended for debilitated patients or those prone to hypotensive reactions.

Patients with renal and hepatic insufficiency are recommended to start therapy with 25 mg / day, then increase the dose daily by 25-50 mg until an effective dose is reached, depending on the patient's clinical response and individual tolerance.

The efficacy and safety of quetiapine in children and adolescents has not been established.

Side effect

The most common side effects of quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia. According to the summary data of clinical studies, the number of patients who stopped taking the drug due to side effects was approximately the same in the groups receiving placebo and quetiapine. As with the use of other antipsychotics, fainting, neuroleptic malignant syndrome, leukopenia, neutropenia, and peripheral edema have been noted while taking quetiapine.

Adverse events observed when taking quetiapine and classified by body systems are listed in the following order: very often (> 1/10); often (<1/10 and> 1/100); infrequently (<1/100 and> 1/1000); rarely (<1/1000); very rare (<1/10 000).

From the hematopoietic system: often - leukopenia3; infrequently - eosinophilia; very rarely - neutropenia 3.

From the side of metabolism: often - an increase in body weight4, an increase in serum transaminases (ALT, ACT) 5; infrequently - an increase in the level of GGT5, total cholesterol, triglycerides after a meal; very rarely - hyperglycemia 1.7, diabetes mellitus 1.7.

From the side of the nervous system: very often - dizziness1.6, drowsiness2; often - headache, anxiety, psychomotor agitation, tremors, fainting1,6; infrequently - epileptic seizures 1 .

From the side of the cardiovascular system: often - tachycardia 1.6, orthostatic hypotension 1.6.

From the respiratory system: often - rhinitis, pharyngitis.

From the digestive system: often - dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.

Reproductive system disorders: rarely - priapism.

Allergic reactions: sometimes - hypersensitivity.

Others: often - mild asthenia, peripheral edema; back pain, chest pain, low-grade fever, myalgia, dry skin, decreased visual acuity; rarely - neuroleptic malignant syndrome 1.

1 See the section 'Special instructions'.

2 Drowsiness is possible, especially during the first 2 weeks of treatment, which usually disappears with continued use of KetileptЃ.

3 In controlled clinical trials of quetiapine, there have been no cases of persistent severe neutropenia or agranulocytosis. During the observation period after registration of the drug, leukopenia and / or neutropenia passed after the termination of the administration of quetiapine. Potential risk factors for leukopenia and / or neutropenia include a pre-existing decrease in white blood cell counts and a history of drug-induced leukopenia and / or neutropenia.

4 The increase in body weight is mainly observed in the first weeks of treatment.

5 In some patients, during the use of quetiapine, an asymptomatic increase in the activity of serum transaminases (ALT, ACT) or GGT was noted, which usually disappears with continued therapy with quetiapine.

6 Like other antipsychotics with alpha1-adrenergic blocking activity, KetileptЃ can cause orthostatic hypotension with dizziness, tachycardia and (in some patients) fainting, especially during the initial period of dose selection.

7 In very rare cases, hyperglycemia and worsening of pre-existing diabetes mellitus have been noted during the use of quetiapine.

Contraindications for use

• pregnancy;

• lactation period (breastfeeding);

• childhood (efficacy and safety have not been established);

• hypersensitivity to the components of the drug.

The drug is used with caution in patients with hepatic insufficiency, a history of seizures, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; in elderly patients.

Application during pregnancy and lactation

Category C. The safety and efficacy of quetiapine during pregnancy has not been established.

The use of KetileptЃ during pregnancy is possible only when the intended benefit to the mother outweighs the potential risk to the fetus.

It is not known whether quetiapine is excreted in breast milk. If it is necessary to use KetileptЃ during lactation (breastfeeding), the question of stopping breastfeeding should be resolved.

Application for violations of liver function

The drug is used with caution in patients with hepatic insufficiency.

Patients with hepatic insufficiency are recommended to start therapy with 25 mg / day, then daily increase the dose by 25-50 mg until an effective dose is reached, depending on the patient's clinical response and individual tolerance.

Application for impaired renal function

Patients with renal insufficiency are recommended to start therapy with 25 mg / day, then daily increase the dose by 25-50 mg until an effective dose is reached, depending on the patient's clinical response and individual tolerance.

Application in children

Contraindication: childhood (efficacy and safety have not been established).

Use in elderly patients

The drug is used with caution in elderly patients.

special instructions

Cardiovascular diseases

KetileptЃ should be used with caution in patients with diagnosed cardiovascular diseases, vascular diseases of the brain, or other conditions predisposing to arterial hypotension.

KetileptЃ can cause orthostatic hypotension, especially in the initial period of dose adjustment; it occurs more often in the elderly than in younger patients.

There was no relationship between taking quetiapine and an increase in the QTc interval. However, when prescribing quetiapine simultaneously with drugs that prolong the QTc interval, caution must be exercised, especially in elderly patients.

Seizures

Ќе вы¤влено различий в частоте развити¤ судорог у пациентов, принимающих  етилептЃ или плацебо. ќднако, также как и при терапии другими антипсихотическими препаратами, рекомендуетс¤ соблюдать осторожность при лечении пациентов с наличием судорожных приступов в анамнезе.

ѕоздн¤¤ дискинези¤

 етилептЃ, как и другие антипсихотические средства, при длительном применении может вызывать позднюю дискинезию. ¬ случае возникновени¤ признаков и симптомов поздней дискинезии следует рассмотреть вопрос о снижении дозы или отмене препарата.

«локачественный нейролептический синдром

«локачественный нейролептический синдром может быть св¤зан с проводимым антипсихотическим лечением.  линические про¤влени¤ синдрома включают в себ¤ гипертермию, измененный ментальный статус, мышечную ригидность, нестабильность вегетативной нервной системы, увеличение уровн¤  ‘ . ¬ таких случа¤х  етилептЃ следует отменить и провести соответствующее лечение.

–еакции внезапной отмены

—имптомы острой отмены (в т.ч. тошнота, рвота, бессонница) описаны в очень редких случа¤х после резкого прекращени¤ приема антипсихотических препаратов в высоких дозах. ¬озможны рецидивы симптомов психоза и по¤вление расстройств, св¤занных с непроизвольными движени¤ми (акатизи¤, дистони¤, дискинези¤). ѕоэтому в случае необходимости прекращени¤ приема препарата рекомендуетс¤ постепенное снижение дозы.

Ќепереносимость лактозы

ѕри составлении диеты дл¤ пациентов с непереносимостью лактозы следует учитывать, что таблетки, покрытые пленочной оболочкой 25 мг, 100 мг, 150 мг, 200 мг и 300 мг содержат лактозы соответственно 4.42 мг, 17.05 мг, 25.47 мг, 34.1 мг и 50.94 мг. ѕрепарат не следует назначать пациентам с редкими наследственными нарушени¤ми толерантности к галактозе, наследственным дефицитом лактазы lapp или синдромом нарушени¤ всасывани¤ глюкозы-галактозы.

ѕринима¤ во внимание, что кветиапин, главным образом, вли¤ет на ?Ќ—, препарат следует примен¤ть с осторожностью в комбинации с другими препаратами, обладающими угнетающим действием на ?Ќ—, или алкоголем.

”становлена св¤зь между применением кветиапина в низких дозах и снижением уровней гормонов щитовидной железы (“4 и свободный “4). ћаксимальное снижение наступало на прот¤жении первых 2 или 4 недель приема кветиапина, но при длительном курсе лечени¤ дальнейшего снижени¤ не происходило. ѕочти во всех случа¤х прекращение приема кветиапина приводило к восстановлению уровней “4 и свободного “4 независимо от продолжительности курса лечени¤. ћенее значительное снижение “3 и реверсивного “3 наблюдалось только при применении кветиапина в более высоких дозах. ”ровни ““v и “—v (тироксин-св¤зывающего глобулина) оставались неизменными.  линически выраженный гипотиреоз не обнаружен.

 ак и другие антипсихотические средства, кветиапин может вызвать удлинение интервала QTc, но в клинических испытани¤х этот эффект не был посто¤нным.

¬ли¤ние на способность управлени¤ транспортными средствами и механизмами

¬следствие вли¤ни¤ на ?Ќ—  етилептЃ может вызывать сонливость. ѕоэтому на первых этапах лечени¤, в течение индивидуально определ¤емого периода времени, следует запретить пациенту управление механическими транспортными средствами или опасными механизмами. ¬ дальнейшем степень ограничений устанавливаетс¤ индивидуально.

ѕередозировка

?анные о передозировке кветиапина ограничены.

—имптомы: сонливость, чрезмерна¤ седаци¤, тахикарди¤, снижение ј?.  райне редко сообщалось о случа¤х т¤желой передозировки кветиапина, приводивших к смерти или коме.

Ћечение: специфических антидотов кветиапина нет. ѕровод¤т симптоматическую терапию и меропри¤ти¤, направленные на поддержание функции дыхани¤, сердечно-сосудистой системы, обеспечение адекватной оксигенации и вентил¤ции.

ћедицинское наблюдение следует продолжать до полного выздоровлени¤ пациента.

Ћекарственное взаимодействие

“ребуетс¤ особа¤ осторожность при назначении  етилептЃ в сочетании с другими препаратами, действующими на ?Ќ—.

–езультаты исследовани¤ in vitro показали, что кветиапин и 9 его метаболитов in vivo ¤вл¤ютс¤ слабыми ингибиторами метаболических процессов, опосредованных изоферментами системы цитохрома –450 (1ј2, 2—9, 2—19, 2D6 и 3ј4). CYP3A4 ¤вл¤етс¤ главным ферментом, осуществл¤ющим опосредованный –450 метаболизм кветиапина.

¬ли¤ние других лекарственных средств на  етилептЃ

‘енитоин: одновременное применение препарата  етилептЃ с фенитоином приводит к повышению клиренса кветиапина в плазме, т.к. фенитоин индуцирует изофермент 3ј4 цитохрома –450. —очетание кветиапина (по 250 мг 3 раза/сут) и фенитоина (по 100 мг 2 раза/сут) в 5 раз повышало средний клиренс кветиапина после приема внутрь.

?л¤ коррекции симптомов шизофрении у пациентов, получающих одновременно кветиапин и фенитоин, могут потребоватьс¤ повышенные дозы препарата  етилептЃ или других индукторов печеночных ферментов (в т.ч. карбамазепина, барбитуратов, рифампицина, v —). ¬ этих случа¤х требуетс¤ осторожность при отмене фенитоина и/или переходе на вальпроат, который не обладает фермент-индуцирующими свойствами.

 арбамазепин: одновременное применение препарата  етилептЃ с карбамазепином значительно повышает клиренс кветиапина, что ведет к снижению системную экспозиции кветиапина. ¬следствие такого взаимодействи¤ может потребоватьс¤ применение более высоких доз препарата  етилептЃ.

»нгибиторы CY–3ј: одновременное применение препарата  етилептЃ с кетоконазолом (по 200 мг/сут в течение 4 дней), сильным ингибитором изофермента CY–3ј, снижает клиренс кветиапина после приема внутрь на 84%, в результате чего концентраци¤ кветиапина в плазме крови повышаетс¤, в среднем, на 235%. Ќеобходима осторожность при сочетании препарата  етилептЃ с кетоконазолом и другими ингибиторами изоферментов системы цитохрома –450, противогрибковыми препаратами из группы азолов и антибиотиками из группы макролидов (в т.ч. итраконазолом, флуконазолом, эритромицином); следует соответственно снижать дозу кветиапина.

?иметидин: ежедневное регул¤рное введение циметидина (по 400 мг 3 раза/сут в течение 4 дней), который ¤вл¤етс¤ неспецифическим ингибитором ферментов, приводило к 20%-ному снижению среднего клиренса кветиапина (по 150 мг 3 раза/сут) из плазмы после приема внутрь. ѕри одновременном применении препарата  етилептЃ с циметидином нет необходимости измен¤ть дозу первого.

“иоридазин: тиоридазин (по 200 мг 2 раза/сут) на 65% повышал клиренс кветиапина (по 300 мг 2 раза/сут) из плазмы после приема внутрь.

–исперидон и галоперидол: одновременное применение кветиапина (по 300 мг 2 раза/сут) с антипсихотическим средством галоперидол (по 7.5 мг 2 раза/сут) или рисперидон (по 3 мг 2 раза/сут) не измен¤ло фармакокинетику кветиапина в равновесном состо¤нии.

‘луоксетин и имипрамин: одновременное применение кветиапина (по 300 мг 2 раза/сут) с антидепрессантом и ингибитором CYP3A4 и CYP2D6 флуоксетином (по 60 мг 1 раз/сут) или известным ингибитором CYP2D6 имипрамином (по 75 мг 2 раза/сут) не измен¤ло равновесную фармакокинетику кветиапина.

¬ли¤ние препарата  етилептЃ на другие лекарственные средства

јнтипирин: многократное ежедневное введение кветиапина (до 750 мг/сут при 3-кратном приеме) не вызывало клинически значимых изменений клиренса антипирина или его метаболитов. Ёто свидетельствует о том, что кветиапин не обладает существенным угнетающим действием на печеночные ферменты, участвующие в метаболизме антипирина, опосредованном цитохромом –450.

Lithium: the simultaneous use of quetiapine (250 mg 3 times / day) with lithium did not affect any pharmacokinetic parameters of lithium in the equilibrium state.

Lorazepam: the mean clearance of lorazepam after oral administration (single dose of 2 mg) decreased by 20% while taking quetiapine (250 mg 3 times / day).

Smoking did not affect the plasma clearance of quetiapine.

Since clinical studies have shown that quetiapine potentiates the cognitive and motor effects of ethanol in patients with psychosis, alcohol should not be taken during the course of KetileptЃ treatment.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25 ? C.

Shelf life

The shelf life is 5 years.

Terms of sale

The drug is available with a prescription.