Zylaxera, tablets 10 mg 28 pcs

– Hisophrenia: acute episodes and supportive therapy.

Bipolar disorder type I: manic episodes and maintenance therapy to prevent relapse in patients with bipolar disorder type I who have recently had a manic or mixed episode.

Addition to therapy with lithium or valproic acid to treat manic or mixed episodes within type I bipolar disorder with or without psychotic symptoms and maintenance therapy to prevent relapse in patients with type I bipolar disorder.

– Addition to antidepressant therapy for major depressive disorder.

Indications

· Schizophrenia: acute attacks and maintenance therapy.

· Bipolar I disorder: manic episodes and maintenance therapy to prevent relapse in patients with bipolar I disorder who have recently had a manic or mixed episode.

·Adjunct therapy with lithium or valproic acid to treat manic or mixed episodes of bipolar I disorder with or without psychotic symptoms and maintenance therapy to prevent relapse in patients with bipolar I disorder.

·Adjunct to antidepressant therapy for major depressive disorder.

Pharmacological effect

antipsychotic (neuroleptic)

Special instructions

Cardiovascular diseases (coronary heart disease [CHD] or previous myocardial infarction, chronic heart failure [CHF] or conduction disorders), cerebrovascular diseases, conditions predisposing to the development of arterial hypotension (dehydration, hypovolemia, use of antihypertensive drugs) due to the possibility of developing orthostatic hypotension, convulsive seizures or diseases in which possible convulsions, increased risk of developing hyperthermia (for example, intense physical activity, overheating, use of m-anticholinergics, dehydration, since antipsychotics can interfere with thermoregulation), in patients with an increased risk of aspiration pneumonia due to the risk of developing impaired motor function of the esophagus and aspiration, obesity or diabetes mellitus in a family history, in patients with a high risk of suicide (psychotic illnesses, bipolar disorders, major depressive disorder), in persons aged 18-24 years due to the risk of developing suicidal behavior.

Contraindicated in persons under the age of 18 years (efficacy and safety have not been established).

Patients with kidney failure

No dose adjustment is required when prescribing Zilaxer® to patients with renal failure.

Patients with liver failure

No dose adjustment is required when prescribing Zilaxer® to patients with liver failure.

Use in patients over 65 years of age

Dose adjustment is usually not required. However, due to increased sensitivity in patients in this population, the use of lower initial doses should be considered.

When using antipsychotics (neuroleptics), the therapeutic effect develops from several days to several weeks. During this period, it is necessary to monitor the patient’s condition.

Suicidal behavior

Suicidal behavior is often observed in psychotic and mood disorders. In some cases, suicidal behavior occurs at the beginning of treatment or when changing antipsychotic drugs, including the use of aripiprazole. Treatment with antipsychotics in high-risk patients should be carried out under close supervision. Epidemiological studies have shown no increased risk of suicidal behavior with aripiprazole compared with other antipsychotics in adult patients with schizophrenia or bipolar disorder. There are insufficient data to assess the risk in younger patients (<18 years of age), but the risk of suicide is known to persist during the first 4 weeks of treatment with atypical antipsychotics, including aripiprazole.

Cardiovascular diseases

Aripiprazole should be used with caution in patients with diseases of the cardiovascular system (myocardial infarction or history of coronary artery disease, heart failure, conduction disorders), cerebrovascular disorders, risk factors for the development of arterial hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or arterial hypertension, including progressive and malignant.

When using antipsychotics, venous thrombosis may develop. Because patients receiving such drugs may have predisposing factors for venous thromboembolism, patients should be carefully assessed before starting treatment with aripiprazole to identify all possible risk factors and preventive measures should be taken during treatment.

QT prolongation

In clinical studies, the incidence of QT prolongation in patients treated with aripiprazole was comparable to the placebo group. However, as with other antipsychotics, caution should be exercised when prescribing aripiprazole in patients with a family history of QT prolongation.

Tardive dyskinesia

In clinical studies lasting 1 year or less, infrequent cases of tardive dyskinesia were observed during treatment with aripiprazole. If a patient develops objective or subjective symptoms of tardive dyskinesia during treatment with Zilaxera®, a dose reduction or discontinuation of the drug is indicated. Such symptoms may persist for some time or even worsen after treatment is stopped.

Neuroleptic malignant syndrome

NMS is a potentially lethal complex of symptoms that develops during the use of antipsychotics. In clinical studies of aripiprazole, cases of NMS were rare. NMS is manifested by increased body temperature, muscle rigidity, mental disorders and instability of the autonomic nervous system (instability of pulse and blood pressure, tachycardia, sweating and arrhythmias). In addition, increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis) and acute renal failure may occur. However, increased creatine phosphokinase and rhabdomyolysis do not necessarily indicate the development of NMS.

If symptoms of NMS or unexplained fever occur without additional clinical manifestations of NMS, all antipsychotics, including Zilaxera®, should be discontinued.

Convulsions

In clinical studies of aripiprazole, seizures occurred infrequently. Aripiprazole should be used with caution in patients with a history of seizure disorders or the presence of conditions leading to the development of seizures.

Elderly patients with psychosis due to dementia

Increased mortality

Three placebo-controlled studies showed an increased risk of death in elderly patients (56–99 years, mean age 82.4 years) with psychosis due to Alzheimer’s disease when treated with aripiprazole compared with placebo.

Mortality rates in the aripiprazole-treated group compared with the placebo group were 3.5% and 1.7%, respectively. Although the causes of death varied, most were cardiovascular (eg, heart failure, sudden cardiac death) or infectious (eg, pneumonia).

Cerebrovascular adverse reactions

In the same studies, patients (mean age: 84 years; age range: 78-88 years) experienced cerebrovascular adverse events (eg, stroke, transient ischemic attack), including deaths. Overall, 1.3% of patients in the aripiprazole group experienced cerebrovascular adverse events compared with 0.6% in the placebo group. The differences did not reach statistical significance. However, one fixed-dose study reported a statistically significant dose-dependent incidence of cerebrovascular adverse reactions in patients receiving aripiprazole.

Zilaxera® is not indicated for the treatment of psychosis associated with dementia.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases severe and accompanied by ketoacidosis or hyperosmolar coma with a fatal outcome, has been noted in patients taking atypical antipsychotics. Risk factors such as obesity and a family history of diabetes mellitus could contribute to the development of severe complications. In clinical studies of aripiprazole, there were no significant differences in the incidence of hyperglycemic adverse reactions (including diabetes mellitus) or hyperglycemia compared with placebo. Based on the available data, it is not possible to directly compare the incidence of hyperglycemic adverse reactions with aripiprazole and other atypical antipsychotics. All patients taking atypical antipsychotics, including aripiprazole, should be closely monitored for symptoms of hyperglycemia (increased thirst, frequent urination, polyphagia, weakness). In patients with diabetes mellitus or risk factors for diabetes mellitus, plasma glucose concentrations should be regularly monitored.

Hypersensitivity

As with the use of other drugs, when treated with aripiprazole, the development of hypersensitivity reactions, manifested by allergic symptoms, is possible.

Weight gain

Patients with schizophrenia or bipolar mania often experience weight gain associated with comorbid disorders, use of weight-inducing antipsychotics, and lack of physical activity. Weight gain can lead to serious complications. In post-marketing studies of aripiprazole, an increase in patient weight was noted. However, it was usually observed against the background of significant risk factors, such as diabetes mellitus, thyroid disease or a history of pituitary adenoma in adult patients. In clinical studies in adolescent patients with bipolar mania, aripiprazole treatment showed an increase in body weight after 4 weeks. It is necessary to control body weight in adolescents with bipolar mania. If there is a significant increase in body weight, a dose reduction may be indicated.

Dysphagia

When using antipsychotics, cases of disturbances in esophageal peristalsis and aspiration have been reported.

Caution should be exercised when used in patients with risk factors for developing aspiration pneumonia.

Pathological gambling and other impulse control disorders

While taking aripiprazole, patients may experience increased urges, especially for gambling, and an inability to control these urges.

Increased sex drive, compulsive shopping, overeating or compulsive eating, and other impulsive and compulsive behavior disorders have also been reported. Patients and their caregivers should be informed of the development of previously unrecognized urges or increases in gambling, sexual desire, compulsive shopping, overeating or compulsive eating, or other urges during treatment with aripiprazole. It should be noted that symptoms of impulse control disorder may be related to the underlying disease, but there have been reports of symptoms resolving with dose reduction or drug discontinuation. Failure to promptly diagnose the development of impulse control disorders can cause harm to the patient and others. In cases of development of impulse control disorders, the issue of reducing the dose of the drug or its discontinuation should be considered.

Patients with attention deficit hyperactivity disorder (ADHD)

Despite the high incidence of comorbidity with bipolar I disorder and ADHD, there is limited data on the safety of the simultaneous use of aripiprazole and psychostimulants. Therefore, special care should be taken when using them simultaneously.

Falls

Aripiprazole may cause drowsiness, orthostatic hypotension, and motor and sensory disturbances, which may lead to falls. Caution should be exercised when treating high-risk patients (for example, elderly or debilitated patients) and consider the use of lower initial doses (see section “Dosage and Administration”).

When using Zilaxera®, caution should be exercised until patients are sure that aripiprazole does not have a negative effect on them.

Active ingredient

Aripiprazole

Composition

1 tablet 5 mg/10 mg/15 mg/30 mg contains:

Active ingredient:

Aripiprazole fumarate semi-finished granules 74.25 mg/148.50 mg/222.75 mg/445.50 mg

[Active ingredient of the semi-finished granule product:

Aripiprazole fumarate (as aripiprazole hemifumarate) 5.647 mg/11.293 mg/16.940 mg/33.880 mg, equivalent to aripiprazole 5 mg/10 mg/15 mg/30 mg

Excipients of the semi-finished granule product: lactose monohydrate, corn starch, microcrystalline cellulose, hyprolose, blue dye [proprietary blue dye (E131), brilliant black dye (E151)] (for 5 mg tablets), yellow iron oxide dye (E172) (for 15 mg tablets), red iron oxide dye (E172) (for 10 mg and 30 mg tablets)]

Excipients: magnesium stearate

Pregnancy

Pregnancy

There are no adequate and well-controlled studies in pregnant women. It is not known whether the use of aripiprazole in a pregnant woman can cause harm to the fetus or cause reproductive harm. It is known that newborns whose mothers took antipsychotics during the third trimester of pregnancy are at risk of developing extrapyramidal disorders and/or withdrawal syndrome in the postpartum period. In newborns, agitation, muscle hypertension or hypotension, tremor, drowsiness, respiratory distress syndrome, and feeding disturbances were observed. These symptoms varied in severity and sometimes resolved without treatment, while in other cases the newborns required intensive care and prolonged hospitalization. When using aripiprazole, the development of such symptoms in newborns was very rare.

Patients should be warned that they should immediately inform the doctor if pregnancy occurs during treatment, and the doctor should also be informed of the planned pregnancy.

Zilaxera® can be taken during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Aripiprazole passes into breast milk. When using Zilaxera®, breastfeeding should be discontinued.

Contraindications

· Hypersensitivity to aripiprazole or other components of the drug.

· Age under 18 years (efficacy and safety have not been established).

· Breastfeeding period.

· Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome (since Zilaxera® contains lactose).

Interaction

Due to the inherent antagonism of aripiprazole to alpha-1 adrenergic receptors, there is a possibility of enhancing the effect of some antihypertensive drugs.

Because aripiprazole has central nervous system (CNS) effects, concomitant use of alcohol or other drugs with CNS effects should be avoided as this may result in increased side effects such as sedation. Caution should be exercised when aripiprazole is used with drugs that may cause QT prolongation or electrolyte imbalance.

Possibility of influence of other drugs on aripiprazole

There was no clinically significant effect of the histamine H2 receptor blocker famotidine, which causes inhibition of hydrochloric acid secretion in the stomach, on aripiprazole, despite a decrease in the rate of absorption of aripiprazole.

Various pathways of metabolism of aripiprazole are known, including those involving the CYP2D6 and CYP3A4 isoenzymes, with the exception of the CYP1A isoenzyme. Therefore, no dose adjustment is required for smokers.

Quinidine and other CYP2D6 inhibitors

In studies in healthy volunteers, a potent inhibitor of the CYP2D6 isoenzyme (quinidine) increased the AUC of aripiprazole by 107%, while Cmax remained unchanged. The AUC and Cmax of dehydroaripiprazole, the active metabolite, were decreased by 32% and 47%, respectively. In this regard, it is necessary to reduce the dose of Zilaxer® by approximately 2 times when used simultaneously with quinidine. Other strong CYP2D6 inhibitors, such as fluoxetine and paroxetine, may have similar effects and therefore require similar dose reductions.

Ketoconazole and other CYP3A4 inhibitors

In clinical studies in healthy volunteers, a potent inhibitor of the CYP3A4 isoenzyme (ketoconazole) increased the AUC and Cmax of aripiprazole by 63% and 37%, respectively. The AUC and Cmax of dehydroaripiprazole increased by 77% and 43%, respectively. In slow metabolizers of the CYP2D6 isoenzyme, the combined use of potent inhibitors of the CYP3A4 isoenzyme may lead to increased plasma concentrations of aripiprazole compared to “fast” metabolizers of the CYP2D6 isoenzyme. If it is necessary to combine the use of ketoconazole and other potent inhibitors of the CYP3A4 isoenzyme and the drug Zilaxer®, it is necessary to assess whether the risk of use outweighs the possible benefits. When used in combination with ketoconazole, the prescribed dose of Zilaxer® should be approximately halved. It is expected that other strong CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, may have similar effects and therefore a dose reduction is also recommended in this case.

When discontinuing an inhibitor of CYP2D6 or CYP3A4 isoenzymes, it is necessary to increase the dose of Zilaxer® to that used by the patient before prescribing concomitant therapy.

When weak inhibitors of CYP3A4 isoenzymes (for example, diltiazem or escitalopram) or CYP2D6 are used in combination with Zilaxera®, a slight increase in aripiprazole concentrations should be expected.

Carbamazepine and other inducers of the CYP3A4 isoenzyme

With the combined use of carbamazepine, a potent inducer of the CYP3A4 isoenzyme, the geometric mean Cmax and AUC values ​​of aripiprazole were 68% and 73% lower, respectively, compared with aripiprazole monotherapy at a dose of 30 mg. Geometric mean Cmax and AUC values ​​of dehydroaripiprazole when combined with carbamazepine were reduced by 69% and 71%, respectively, compared with aripiprazole monotherapy. The dose of Zilaxer® should be doubled when used in combination with carbamazepine. Other strong CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John’s wort) can be expected to have similar effects, and therefore the same dose increases are recommended. When discontinuing a powerful inducer of the CYP3A4 isoenzyme, it is necessary to reduce the dose of Zilaxer® to the recommended level.

Valproate and lithium

With the combined use of valproate or lithium, no clinically significant changes in aripiprazole concentrations were found.

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking aripiprazole. Possible manifestations of this condition occur particularly frequently when used concomitantly with other serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs), or drugs that may increase concentrations of aripiprazole (see section “Side effects”).

Possibility of influence of aripiprazole on other drugs

In clinical studies of aripiprazole at a dose of 10-30 mg/day, there was no significant effect on the metabolism of substrates of the isoenzymes CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP3A4 (dextromethorphan). In addition, aripiprazole and dehydroaripiprazole have not been shown to affect CYP1A2-mediated metabolism in vitro. Therefore, aripiprazole is unlikely to have a clinically significant effect on drugs metabolized by this isoenzyme.

Concomitant use of lithium, lamotrigine or valproate with aripiprazole does not lead to a clinically significant change in the concentrations of lithium, lamotrigine or valproate.

Overdose

Symptoms

Clinical studies and post-marketing observations have described accidental or intentional overdoses of aripiprazole in adult patients with a single dose of up to 1260 mg, which were not accompanied by death. Potentially clinically significant symptoms: lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhea. Cases of aripiprazole overdose in children (taking up to 195 mg), which were not accompanied by death, have been described. Potentially clinically significant symptoms included somnolence, temporary loss of consciousness, and extrapyramidal symptoms.

Treatment

Supportive and symptomatic therapy, ensuring airway patency, ventilation and oxygenation. The need to prescribe multiple medications should be taken into account. To identify arrhythmias, monitoring of the state of the cardiovascular system, including continuous ECG monitoring, should be started immediately. In cases of confirmed or suspected aripiprazole overdose, careful monitoring is indicated until all symptoms disappear.

Activated charcoal 50 g administered 1 hour after aripiprazole administration reduced the AUC and Cmax of aripiprazole by 51% and 41%, respectively, suggesting that activated charcoal may be effective in the treatment of overdose.

Hemodialysis

Although there is no information on the effectiveness of hemodialysis in the treatment of aripiprazole overdose, the effectiveness of hemodialysis is unlikely because aripiprazole is highly bound to plasma proteins.

Clinical pharmacology

It is believed that the therapeutic effect of aripiprazole in schizophrenia and bipolar I disorder is due to a combination of partial agonist activity at D2-dopamine and 5HT1a-serotonin receptors and antagonistic activity at 5HT2a-serotonin receptors.

Pharmacodynamics

Aripiprazole has high in vitro affinity for D2 and D3 dopamine receptors, 5HT1a and 5HT2a serotonin receptors and moderate affinity for D4 dopamine, 5HT2c and 5HT7 serotonin, alpha1 adrenergic receptors and H1 histamine receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and lack of affinity for muscarinic cholinergic receptors. Aripiprazole in animal experiments exhibited antagonism in relation to dopaminergic hyperactivity and agonism in relation to dopaminergic hypoactivity. Some of the clinical effects of aripiprazole may be explained by interactions with receptors other than dopamine and serotonin.

The use of aripiprazole orally in doses from 0.5 mg to 30 mg 1 time per day in healthy volunteers for 2 weeks leads to a dose-dependent decrease in the binding of 11C-raclopride, a ligand of D2/D3 dopamine receptors, to the caudate nucleus and the cervix (according to positron emission tomography).

Pharmacokinetics

The activity of Zilaxera® is mainly due to the presence of aripiprazole. The average half-life (T1/2) of aripiprazole is approximately 75 hours. Equilibrium concentration is achieved after 14 days. The accumulation of aripiprazole with repeated doses is predictable. The pharmacokinetics of aripiprazole at steady state are proportional to the dose. There were no daily fluctuations in the distribution of aripiprazole and its metabolite, dehydroaripiprazole. It has been established that the main metabolite of the drug in human plasma, dehydroaripiprazole, has the same affinity for D2-dopamine receptors as aripiprazole.

Suction

Aripiprazole is rapidly absorbed after oral administration of Zilaxera® tablets, with the maximum concentration (Cmax) of aripiprazole in the blood plasma being achieved after 3-5 hours. The bioavailability of Zilaxer® tablets when taken orally is 87%. Food intake does not affect the bioavailability of aripiprazole.

Distribution

Aripiprazole is well distributed into tissues, with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations of more than 99% of aripiprazole is bound to serum proteins, mainly albumin.

Metabolism

Aripiprazole undergoes only minimal first-pass metabolism. Aripiprazole is metabolized in the liver in three ways: dehydrogenation, hydroxylation and N-dealkylation. According to an in vitro study, dehydrogenation and hydroxylation of aripiprazole occurs under the action of the CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation is catalyzed by the CYP3A4 isoenzyme. Aripiprazole is the main component of the drug in blood plasma. At steady state, the area under the concentration-time curve (AUC) of dehydroaripiprazole, the active metabolite, is approximately 40% of the plasma AUC of aripiprazole.

Removal

The average T1/2 of aripiprazole is about 75 hours in patients with high activity of the CYP2D6 isoenzyme and 146 hours in patients with low activity. Following a single oral dose of [14C]-labeled aripiprazole, approximately 27% and 60% of the radioactivity is detected in urine and feces, respectively. Less than 1% of unchanged aripiprazole is determined in the urine and approximately 18% of the dose taken is excreted unchanged through the intestines with bile. The total clearance of aripiprazole is 0.7 ml/min/kg, mainly due to hepatic excretion.

Pharmacokinetics in special groups of patients

Patients of the older age group

No age-related differences in the pharmacokinetic parameters of aripiprazole were detected in adult patients with schizophrenia, as well as in healthy volunteers.

Gender feature

No gender-related differences in the pharmacokinetic parameters of aripiprazole were found in adult patients with schizophrenia, as well as in healthy volunteers.

Race

There were no clinically significant differences in the pharmacokinetics of aripiprazole depending on race.

Smoking

Smoking does not affect the pharmacokinetics of aripiprazole.

Renal dysfunction

The pharmacokinetic parameters of aripiprazole and dehydroaripiprazole in patients with severe kidney disease do not differ from those in healthy volunteers.

Liver dysfunction

After a single dose of aripiprazole in patients with varying degrees of severity of liver cirrhosis, there was no significant effect of liver dysfunction on the pharmacokinetics of aripiprazole and dehydroaripiprazole. However, the study included only 3 patients with decompensated liver cirrhosis (Child-Pugh class C), and therefore it is impossible to draw definitive conclusions about the metabolic activity of the liver in patients with decompensated liver cirrhosis.

Storage conditions

At a temperature not exceeding 25 ºС, in the original packaging.

Keep out of the reach of children.

Shelf life

For tablets 10 mg, 15 mg, 30 mg: 5 years.

For 5 mg tablets: 2 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA-RUS, Russia