Zylaxera, tablets 15 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.

Active ingredient

Composition

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

Active substance:

Aripiprazole fumarate semifinished pellets 74.25 mg/148.50 mg/222.75 mg/445.50 mg

[Active substance of semifinished pellets:

Aripiprazole fumarate (in the form of aripiprazole hemifumarate) 5.647 mg/11.293 mg/16.940 mg/33.880 mg, equivalent to 5 mg/10 mg/15 mg/30 mg aripiprazole

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

Excipients:magnesium stearate

How to take, the dosage

Schizophrenia

The recommended initial dose is 10 mg to 15 mg once daily, regardless of meal times. The maintenance dose is usually 15 mg per day. In clinical trials, the effectiveness of the drug in doses from 10 mg to 30 mg per day has been shown.

Manic episodes in bipolar disorder

Monotherapy

The recommended starting dose is 15 mg once daily, regardless of meal times. The dose is changed, if necessary, at intervals of at least 24 hours. In clinical studies in manic episodes, efficacy of the drug in doses of 15-30 mg/day when taken for 3-12 weeks has been demonstrated. The safety of doses higher than 30 mg/day has not been evaluated in clinical trials.

In observing patients with type I bipolar disorder who had a manic or mixed episode and who experienced stabilization of symptoms while taking Zylaxer® (15 mg/day or 30 mg/day at an initial dose of 30 mg/day) for 6 weeks, then 6 months and then 17 months, favorable effects of such maintenance therapy have been established. Patients should be evaluated periodically to determine whether continuation of maintenance therapy is necessary.

Addition to therapy with lithium or valproic acid for treatment of manic or mixed episodes within type I bipolar disorder

The recommended starting dose is 10 mg to 15 mg once daily, with a maintenance dose of 15 mg/day. The dose may be increased to 30 mg/day depending on clinical indications. When observing patients with bipolar disorder type I, favorable effect of aripiprazole maintenance therapy at a dose of 10 mg to 30 mg daily as an adjunct to therapy with lithium or valproic acid has been established. Patients should be periodically evaluated to determine whether continuation of maintenance therapy is necessary.

Additional therapy for major depressive disorder

As an adjunct to antidepressant treatment, Zylaxer® is recommended at an initial dose of 5 mg per day; if necessary and therapy is well tolerated, the daily dose of Zylaxer® can be increased weekly by 5 mg up to a maximum of 15 mg per day.

The duration of therapy with Zylaxer® for all the above indications has not been determined; the patient should be regularly evaluated to see if the therapy can be cancelled.

Patients with hepatic impairment should use the 30 mg dose with caution.

Application in special patient groups

Patients with renal insufficiency

Dose adjustment is not required when prescribing Zylaxer® to patients with renal impairment.

Patients with hepatic insufficiency

Dose adjustment is not required when prescribing Zylaxer® to patients with hepatic impairment.

Application in patients over 65 years

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

Influence of the patient’s gender on the dosing regimen

The dosing regimen of Zylaxer® for patients of either gender is the same.

Influence of smoking on dosing regimen

The dosing regimen of Zylaxer® for smoking and non-smoking patients is the same.

Dosing regimen for concomitant therapy

When Zylaxer® and potent CYP3A4 isoenzyme inhibitors (ketoconazole, clarithromycin) are used concomitantly, the dose of Zylaxer® should be reduced by half. When CYP3A4 isoenzyme inhibitors are cancelled, the dose of Zylaxer® should be increased.

When Zylaxer® and potent CYP2D6 isoenzyme inhibitors (quinidine, fluoxetine, paroxetine) are used concomitantly, the dose of Zylaxer® should be reduced by at least half. When CYP2D6 isoenzyme inhibitors are withdrawn, the dose of Zylaxer® should be increased.

Zylaxera® should be used without changing the dosing regimen if it is prescribed as adjunctive therapy in patients with major depressive disorder.

When Zylaxer® is used concomitantly and potent CYP2D6 isoenzyme inhibitors (quinidine, fluoxetine, paroxetine) and CYP3A4 (ketoconazole, clarithromycin), the dose of Zylaxer® should be decreased by ¾ (ie, to 25% of the usual dose). When CYP2D6 and/or CYP3A4 isoenzyme inhibitors are cancelled, the dose of Zylaxer® should be increased.

When Zylaxer® and potent, moderate or weak CYP2D6 and CYP3A4 isoenzyme inhibitors are used concomitantly, the dose of Zylaxer® may initially be reduced by ¾ (i.e., to 25% of the usual dose) and then increased to achieve optimal clinical benefit.

When Zylaxer® is administered to patients with low CYP2D6 isoenzyme activity, the dose of Zylaxer® should be initially reduced by half and then increased to achieve optimal clinical benefit. If Zylaxer® and a potent CYP3A4 isoenzyme inhibitor are used concomitantly, the dose of Zylaxer® should be reduced by ¾ (ie, to 25% of the usual dose).

If Zylaxer® and potential CYP3A4 isoenzyme inducers (carbamazepine) are used concomitantly, the dose of Zylaxer® should be doubled. When CYP3A4 isoenzyme inducers are cancelled, the dose of Zylaxer® should be reduced to 10-15 mg.

Interaction

Due to the inherent antagonism of aripiprazole to alpha-1-adrenoceptors, the effect of some hypotensive drugs may be enhanced.

Since aripiprazole affects the central nervous system (CNS), concomitant administration of alcohol or other CNS-affecting drugs should be avoided because it may increase the side effects, such as sedation. Caution should be exercised when using aripiprazole with drugs that may cause prolongation of the QT interval or electrolyte imbalance.

Perhaps the effect of other drugs on aripiprazole

No clinically significant effect of the histamine H2-receptor blocker famotidine, which causes inhibition of gastric hydrochloric acid secretion, on aripiprazole was found, despite the decrease in aripiprazole absorption rate.

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

Hinidine and other CYP2D6 isoenzyme inhibitors

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

Ketoconazole and other CYP3A4 isoenzyme inhibitors

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

If a CYP2D6 or CYP3A4 isoenzyme inhibitor is discontinued, the dose of Zylaxer® should be increased to that used by the patient before concomitant therapy is indicated.

When using weak CYP3A4 isoenzyme inhibitors (e.g., diltiazem or escitalopram) or CYP2D6 in combination with Zylaxera®, slightly increased aripiprazole concentrations should be expected.

Carbamazepine and other CYP3A4 isoenzyme inducers

When carbamazepine, a potent inducer of the CYP3A4 isoenzyme, was combined, the geometric mean Cmah and AUC of aripiprazole were 68% and 73% lower, respectively, compared with aripiprazole monotherapy at 30 mg dose. The geometric mean values of Cmah and AUC of dehydroapiprazole when combined with carbamazepine were 69% and 71% lower, respectively, compared with aripiprazole monotherapy. The dose of Zylaxer® should be doubled when combined with carbamazepine. Other potent inducers of CYP3A4 isoenzyme (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St John’s Wort preparations) are expected to have similar effects; therefore, exactly the same dose increase is recommended. If a potent inducer of CYP3A4 isoenzyme is stopped, the dose of Zylaxer® should be reduced to the recommended level.

Valproate and lithium

No clinically significant changes in aripiprazole concentrations have been found with the combined use of valproate or lithium.

Serotonin syndrome

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

Perhaps the effects of aripiprazole on other medications

In clinical trials of aripiprazole at a dose of 10-30 mg/day, no significant effect on the metabolism of CYP2D6 (dextromethorphan/3-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP3A4 (dextromethorphan) isoenzyme substrates was noted. In addition, aripiprazole and dehydroapiprazole have not been shown to affect CYP1A2-mediated metabolism under in vitro conditions. Thus, it is unlikely that aripiprazole has a clinically significant effect on drugs metabolized by this isoenzyme.

Simultaneous administration of lithium, lamotrigine or valproate with aripiprazole does not result in clinically significant changes in lithium, lamotrigine or valproate concentrations.

Special Instructions

Cardiovascular diseases (coronary heart disease [CHD] or myocardial infarction, chronic heart failure [CHF] or conduction disorders), cerebrovascular disease, conditions predisposing to the development of arterial hypotension (dehydration, hypovolemia, use of hypotensive drugs) due to the possibility of orthostatic hypotension, seizures or diseases in which seizures are possible, increased risk of hyperthermia (e.g., intense physical activity, overheating, use of m-cholinoblockers, dehydration, because neuroleptics can impair the development of arterial hypotension). as neuroleptics can impair thermoregulation), in patients at increased risk of aspiration pneumonia because of the risk of esophageal motor dysfunction and aspiration, obesity or diabetes in a family history, in patients at high risk of suicide (psychotic illness, bipolar disorder, major depressive disorder), in persons aged 18-24 years due to the risk of suicidal behavior.

It is contraindicated in persons under the age of 18 years (effectiveness and safety have not been established).

Patients with renal insufficiency

Dose adjustment is not required when prescribing Zylaxer® to patients with renal impairment.

Patients with hepatic insufficiency

Dose adjustment is not required when prescribing Zylaxer® to patients with hepatic impairment.

Application in patients over 65 years

Dose adjustment is usually not required. However, due to hypersensitivity 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 the patient’s condition should be monitored.

Suicidal behavior

Suicidal behavior is often seen in psychotic disorders and mood disorders. In some cases, suicidal behavior occurs at the beginning of treatment or when changing antipsychotic medication, including when using aripiprazole. Treatment with neuroleptics in high-risk patients should be closely monitored. Epidemiologic studies have shown no increased risk of suicidal behavior with aripiprazole compared with other antipsychotics in adult patients with schizophrenia or bipolar disorder. There is insufficient data to assess the risk in younger patients (under 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 disease

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

Venous thrombosis may develop with the use of antipsychotics. Because patients receiving such medications may have predisposing factors to venous thromboembolism, patients should be carefully evaluated before treatment with aripiprazole to identify all possible risk factors, and preventive measures should be taken during treatment.

Longer interval QT

In clinical trials, the incidence of QT interval prolongation in patients when using 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 interval prolongation.

Late dyskinesia

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

Malignant neuroleptic syndrome

MNS is a potentially fatal set of symptoms that develops in the background of antipsychotic use. In clinical trials of aripiprazole, cases of MNS have been rare. MNS is manifested by increased body temperature, muscle rigidity, mental disturbances and instability of autonomic nervous system (unstable pulse and blood pressure, tachycardia, sweating and arrhythmias). In addition, increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis) and acute renal failure may be noted. However, the increase of phosphokinase and rhabdomyolysis does not necessarily indicate the development of MNS.

If symptoms of MNS or unexplained fever occur without additional clinical manifestations of MNS, all neuroleptics, including Zylaxer®, should be discontinued.

Convulsions

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

Elderly patients with psychosis with dementia

increased mortality

In three placebo-controlled studies in elderly patients (56-99 years, mean age 82.4 years) with psychosis due to Alzheimer’s disease, an increased risk of death was noted with aripiprazole therapy compared to the placebo group.

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

Cerebrovascular adverse reactions

In the same studies, patients (mean age: 84 years; age range: 78-88 years), the development of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including those with fatal outcomes, was reported. Overall, 1.3% of patients in the aripiprazole group had cerebrovascular adverse reactions compared to 0.6% in the placebo group. The differences did not reach statistical significance. However, in one fixed-dose study a statistically significant dose-dependence of the incidence of cerebrovascular adverse reactions in patients in the aripiprazole group was noted.

The drug Zylaxer® is not indicated for the treatment of dementia psychosis.

Hyperglycemia and diabetes

Hyperglycemia, occasionally severe and accompanied by ketoacidosis or a lethal hyperosmolar coma, has been reported in patients taking atypical neuroleptics. Risk factors such as obesity and hereditary burden of diabetes mellitus may have contributed to the development of severe complications. No significant differences in the incidence of hyperglycemic adverse reactions (including diabetes mellitus) or hyperglycemia compared with placebo were observed in clinical trials of aripiprazole. Based on the available data, a direct comparison of the incidence of hyperglycemic adverse reactions against aripiprazole and other atypical antipsychotics cannot be made. All patients taking atypical neuroleptics, including aripiprazole, should be carefully controlled for symptoms of hyperglycemia (increased thirst, frequent urination, polyphagia, weakness). In patients with diabetes mellitus or risk factors for diabetes mellitus, plasma glucose concentration should be monitored regularly.

Hypersensitivity

As with other drugs, hypersensitivity reactions manifested by allergic symptoms may develop during treatment with aripiprazole.

Body weight gain

In patients with schizophrenia or bipolar mania, weight gain is often associated with comorbid disorders, taking antipsychotics that cause weight gain, and lack of motor activity. Weight gain can lead to severe complications. In post-marketing studies of aripiprazole, an increase in body weight was noted in patients. 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 involving adolescent patients with bipolar mania, an increase in body weight after 4 weeks was shown during treatment with aripiprazole. It is necessary to monitor body weight in adolescents with bipolar mania. In case of a significant increase of body weight a dose reduction may be indicated.

Dysphagia

In cases of esophageal peristalsis and aspiration have been reported with neuroleptics.

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

Pathological cravings for gambling and other impaired impulse control

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

Increased sex drive, irresistible cravings for shopping, overeating or compulsive eating, and other impulsive and compulsive behavioral disorders have also been reported. Patients and caregivers should be informed of the development of previously unobserved urges or increased gambling cravings, sexual urges, irresistible shopping urges, overeating or compulsive eating or other urges during treatment with aripiprazole. It should be noted that symptoms of impaired urge control may be related to the underlying disease, but cases have been reported of cessation of symptoms when the dose is reduced or the drug is withdrawn. Failure to diagnose the development of impulse control disorders in a timely manner may be detrimental to the patient and others. In cases of the development of urge control disorders, a decision should be made to reduce the dose of the drug or to discontinue it.

Patients with attention deficit hyperactivity disorder (ADHD)

Despite the high incidence of concomitant bipolar disorder type I and ADHD, there are limited data on the safety of concomitant use of aripiprazole and psychostimulants. Therefore, special caution should be exercised when using them concomitantly.

Falls

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

When using Zylaxer®, caution should be exercised until patients are satisfied that aripiprazole has no adverse effects on them.

Synopsis

5 mg tablets: capsule-shaped, slightly biconvex tablets, light blue in color with marbling and possible dark spots.

Tablets 10 mg: capsule-shaped, slightly biconvex tablets, pale pink with marbling and dark spots.

Tablets 15 mg: round, slightly biconvex, beveled tablets, pale yellow with marbling and possible dark blotches.

Tablets 30 mg: round, slightly biconvex, beveled tablets, pale pink with marbling and dark flecks.

Contraindications

– High sensitivity to aripiprazole or other drug components.

– Age under 18 years (effectiveness and safety not established).

– Breastfeeding period.

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome (because Zylaxer® contains lactose).

Overdose

Symptoms

In clinical trials and postmarketing observations, accidental or intentional overdoses of aripiprazole in adult patients with a single dose of up to 1,260 mg have been described that were not fatal. Potentially clinically significant symptoms include lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea. Cases of aripiprazole overdose in children (ingestion up to 195 mg) without fatal outcome have been described. Potentially clinically significant symptoms included: somnolence, temporary loss of consciousness, and extrapyramidal symptoms.

Treatment

Supportive and symptomatic therapy, airway patency, ventilation, and oxygenation. Consideration should be given to prescribing multiple medications. Cardiovascular monitoring, including continuous ECG monitoring, should be initiated immediately to detect arrhythmias. In case of confirmed or suspected aripiprazole overdose, close monitoring is indicated until all symptoms disappear.

Activated charcoal at a dose of 50 g, administered 1 h after aripiprazole administration, resulted in 51% and 41% reduction in AUC and Cmah of aripiprazole, respectively, indicating that activated charcoal may be effective in treating overdose.

Hemodialysis

While there is no information on the effectiveness of hemodialysis in treating aripiprazole overdose, the effectiveness of hemodialysis is unlikely because aripiprazole is largely bound to blood plasma proteins.

Pregnancy use

Pregnancy

No adequate and well-controlled studies have been performed in pregnant women. It is not known whether the use of aripiprazole in a pregnant woman may have harmful effects on the fetus or cause reproductive dysfunction. Neonates whose mothers took neuroleptics during the third trimester of pregnancy are known to be at risk of developing extrapyramidal disorders and/or withdrawal syndrome in the postpartum period. Excitation, muscle hypertension or hypotension, tremor, somnolence, respiratory distress syndrome, and feeding disturbances have been reported in neonates. These symptoms had varying degrees of severity, sometimes they passed without treatment, while in other cases the newborns needed intensive therapy and prolonged hospitalization. When aripiprazole was used, the development of such symptoms in newborns was very rare.

Patients should be warned that they should immediately inform their physician if they become pregnant during treatment, they should also inform their physician of a planned pregnancy.

Zylaxera® may be taken during pregnancy only if the potential benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding

Aripiprazole penetrates into breast milk. Breastfeeding should be discontinued when using Zylaxer®.

Similarities