Zylaxera^® (Tablets) Instructions for Use

ATC Code

N05AX12 (Aripiprazole)

Active Substance

Aripiprazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotics; other antipsychotics

Pharmacological Action

Antipsychotic agent (neuroleptic). It is assumed that the therapeutic effect of aripiprazole in schizophrenia is due to a combination of partial agonist activity at dopamine D₂ and serotonin 5-HT_1a receptors and antagonist activity at serotonin 5-HT₂ receptors.

Aripiprazole has high in vitro affinity for dopamine D₂ and D₃ receptors, serotonin 5-HT_1a and 5-HT_2a receptors, and moderate affinity for dopamine D₄, serotonin 5-HT_2c and 5-HT₇, α₁-adrenergic receptors and histamine H₁ receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and no affinity for muscarinic receptors.

Pharmacokinetics

After oral administration, Aripiprazole is rapidly absorbed from the gastrointestinal tract. C_max in plasma is reached in 3-5 hours. Absolute bioavailability is 87%. Food intake does not affect the bioavailability of aripiprazole.

C_ss is reached in 14 days. Accumulation of the drug with repeated administration is predictable. The pharmacokinetic parameters of aripiprazole at steady state are dose-proportional. No diurnal fluctuations in the distribution of aripiprazole and its metabolite dehydroaripiprazole were noted.

Aripiprazole is extensively distributed in tissues, V_d is 4.9 L/kg. At therapeutic concentrations, more than 99% of aripiprazole is bound to serum proteins, mainly albumin.

Dehydroaripiprazole, the main metabolite in human plasma, has been found to have affinity for dopamine D₂ receptors similar to that of Aripiprazole.

Aripiprazole undergoes presystemic metabolism only to a minimal extent. Aripiprazole is metabolized in the liver by three pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro, dehydrogenation and hydroxylation of aripiprazole are mediated by the CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation is mediated by CYP3A4.

At steady state, the AUC of dehydroaripiprazole is about 39% of the AUC of aripiprazole in plasma.

The mean T_1/2 of aripiprazole is about 75 hours.

After a single dose of labeled ¹⁴C aripiprazole, approximately 27% and 60% of radioactivity is detected in urine and feces, respectively. Less than 1% of unchanged aripiprazole is detected in urine and approximately 18% of the administered dose is excreted unchanged in feces. The total clearance of aripiprazole is 0.7 ml/min/kg, mainly due to hepatic excretion.

Indications

Treatment of acute episodes of schizophrenia, maintenance therapy for schizophrenia.

Treatment of acute manic episodes of bipolar I disorder and for maintenance therapy in patients with bipolar I disorder who have recently experienced a manic or mixed episode.

ICD codes

Dosage Regimen

Administer Zylaxera^® tablets orally once daily, with or without food. The tablet must be swallowed whole; do not split, crush, or chew.

For schizophrenia in adults, initiate treatment at a starting dose of 10 mg or 15 mg once daily. The recommended target dose is 15 mg once daily. Titrate the dose at intervals of no less than two weeks. The maximum recommended daily dose is 30 mg.

For acute manic episodes in bipolar I disorder, initiate treatment at a starting dose of 15 mg once daily as monotherapy or as an adjunct to lithium or valproate. The recommended target dose is 15 mg once daily. Titrate the dose based on clinical response and tolerability. The maximum recommended daily dose is 30 mg.

For maintenance therapy in schizophrenia or bipolar I disorder, continue the patient at the same dose that was effective during stabilization. Regularly reassess the need for continued pharmacotherapy at the lowest effective dose.

Adjust the dosage when co-administered with potent CYP3A4 inhibitors (e.g., ketoconazole) or CYP2D6 inhibitors (e.g., quinidine); reduce the dose by half. When the CYP inhibitor is discontinued, return to the original dose.

If co-administered with potent CYP3A4 inducers (e.g., carbamazepine, rifampin), double the dose over 1-2 weeks. When the CYP inducer is discontinued, return to the original dose within two weeks.

In known CYP2D6 poor metabolizers, administer half the standard dose. Similarly, when a known CYP2D6 poor metabolizer is also receiving a potent CYP3A4 inhibitor, administer a quarter of the standard dose.

Perform dose adjustments based on clinical assessment and individual patient tolerability. Do not exceed the maximum daily dose of 30 mg.

Adverse Reactions

Cardiovascular system frequent – orthostatic hypotension, tachycardia; possible – bradycardia, palpitations, myocardial infarction, QT interval prolongation, cardiac arrest, hemorrhage, atrial fibrillation, heart failure, AV block, myocardial ischemia, deep vein thrombosis, phlebitis, extrasystole; rare – vasovagal syndrome, cardiomegaly, atrial flutter, thrombophlebitis, intracranial hemorrhage, cerebral ischemia; very rare – syncope.

Digestive system very frequent – nausea, loss of appetite; frequent – dyspepsia, vomiting; constipation; possible – increased appetite, gastroenteritis, dysphagia, flatulence, gastritis, dental caries, gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal hemorrhage, periodontal abscess, tongue edema, fecal incontinence, colitis, rectal hemorrhage, stomatitis, mouth ulceration, cholecystitis, fecaloma, oral candidiasis, cholelithiasis, belching, gastric ulcer; rare – esophagitis, gingival bleeding, glossitis, hematemesis, intestinal hemorrhage, duodenal ulcer, cheilitis, hepatitis, hepatomegaly, pancreatitis, intestinal perforation; very rare – increased ALT, AST, ALP activity.

Allergic reactions very rare – anaphylaxis, angioedema, itching and urticaria.

Musculoskeletal system frequent – myalgia, muscle cramps; possible – joint and bone pain, myasthenia, arthritis, arthrosis, muscle weakness, muscle spasms, bursitis; very rare – increased CPK activity, rhabdomyolysis, tendinitis, tenobursitis, rheumatoid arthritis, myopathy.

Central and peripheral nervous system: very frequent – insomnia, somnolence, akathisia; frequent – dizziness, tremor, extrapyramidal syndrome, psychomotor agitation, depression, nervousness, hypersalivation, hostility, suicidal thoughts, manic thoughts, unsteady gait, confusion, cogwheel rigidity; possible – dystonia, muscle twitching, impaired concentration, paresthesia, limb tremor, impotence, bradykinesia, decreased/increased libido, panic reactions, apathy, memory impairment, stupor, amnesia, stroke, hyperactivity, depersonalization, dyskinesia, restless legs syndrome (akathisia), myoclonus, depressed mood, hyperreflexia, slowed thinking, hyperesthesia, hypotension, impaired oculomotor response; rare – delirium, euphoria, buccoglossal syndrome, akinesia, depression of consciousness up to loss of consciousness, hyporeflexia, obsessive thoughts, NMS.

Respiratory system frequent – dyspnea, pneumonia; possible – asthma, epistaxis, hiccups, laryngitis; rare – hemoptysis, aspiration pneumonia, increased sputum production, nasal dryness, pulmonary edema, pulmonary embolism, hypoxia, respiratory failure, apnea.

Dermatological reactions frequent – dry skin, pruritus, increased sweating, skin ulceration; possible – acne, vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea; rare – maculopapular rash, exfoliative dermatitis, urticaria.

Special senses: frequent – conjunctivitis, ear pain; possible – dry eyes, eye pain, tinnitus, otitis media, cataract, taste loss, blepharitis; rare – increased lacrimation, frequent blinking, external otitis, amblyopia, deafness, diplopia, eye hemorrhage, photophobia.

Urinary system: frequent – urinary incontinence; possible – cystitis, pollakiuria, leukorrhea, urinary retention, hematuria, dysuria, amenorrhea, premature ejaculation, vaginal bleeding, vaginal candidiasis, renal failure, uterine bleeding, menorrhagia, albuminuria, kidney stones, nocturia, polyuria, urinary urgency; rare – breast pain, cervicitis, galactorrhea, anorgasmia, burning sensation in the urogenital area, glycosuria, gynecomastia, urolithiasis, painful erection.

Body as a whole: frequent – flu-like syndrome, peripheral edema, chest pain, neck pain; possible – pelvic pain, facial edema, malaise, photosensitivity, jaw pain, chills, jaw stiffness, abdominal distension, chest tightness; rare – sore throat, back stiffness, head heaviness, candidiasis, throat tightness, Mendelson’s syndrome, heat stroke.

Metabolism: frequent – weight loss, increased CPK level; possible – dehydration, edema, hypercholesterolemia, hyperglycemia, hypokalemia, diabetes mellitus, hyperlipidemia, hypoglycemia, thirst, increased blood urea, hyponatremia, iron deficiency anemia, increased creatinine, bilirubinemia, increased LDH level, obesity; rare – hyperkalemia, gout, hypernatremia, cyanosis, urine acidification, hypoglycemic reaction.

Contraindications

Senile dementia, lactation period, children and adolescents under 18 years of age, hypersensitivity to aripiprazole.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of use during pregnancy have not been conducted. Aripiprazole can be used during pregnancy only if the potential benefit of therapy for the mother outweighs the possible risk to the fetus.

It is not known whether Aripiprazole is excreted in human breast milk. The use of aripiprazole during lactation (breastfeeding) is contraindicated.

In experimental studies, it was shown that Aripiprazole is excreted in the milk of lactating rats.

Pediatric Use

Contraindication: children and adolescents under 18 years of age.

Special Precautions

Use with caution in patients with cardiovascular diseases (coronary artery disease, including history of myocardial infarction, chronic heart failure, conduction disorders), conditions predisposing to arterial hypotension (dehydration, hypovolemia and taking antihypertensive drugs) due to the possibility of orthostatic hypotension; in patients with cerebrovascular diseases, with seizures or suffering from diseases in which seizures are possible; in patients with an increased risk of hyperthermia (e.g., during intense physical exertion, overheating, taking anticholinergic drugs, dehydration due to the ability of neuroleptics to impair thermoregulation); in patients with an increased risk of aspiration pneumonia due to the risk of impaired esophageal motor function and aspiration; in patients with obesity, with a history of diabetes mellitus; taking drugs with m-cholinolytic activity.

Suicidal thoughts and attempts are characteristic of psychoses, therefore, careful medical supervision is necessary during drug therapy.

The risk of developing tardive dyskinesia increases with the duration of neuroleptic therapy, so if symptoms of tardive dyskinesia appear during aripiprazole administration, its dose should be reduced or discontinued. After discontinuation of therapy, these symptoms may temporarily worsen or even appear for the first time.

Treatment with neuroleptics, including aripiprazole, may lead to the development of NMS, which is manifested by hyperpyrexia, muscle rigidity, mental disorders and autonomic nervous system instability (irregular pulse and blood pressure, tachycardia, sweating and cardiac arrhythmias). In addition, increased CPK activity, myoglobinuria (rhabdomyolysis) and acute renal failure sometimes occur. If symptoms of NMS or unexplained fever occur, all neuroleptics, including Aripiprazole, must be discontinued.

Hyperglycemia, in some cases severe and associated with ketoacidosis, which can lead to hyperosmolar coma and even death, has been observed in patients taking atypical antipsychotics. Although the relationship between the use of atypical antipsychotics and hyperglycemic disorders remains unclear, patients diagnosed with diabetes should regularly monitor blood glucose levels when taking atypical antipsychotics. Patients with risk factors for diabetes (obesity, family history of diabetes) should have their blood glucose levels measured at the beginning of the course and periodically during the drug administration. Any patients taking atypical antipsychotics require constant monitoring for symptoms of hyperglycemia, including increased thirst, frequent urination, polyphagia, and weakness.

Effect on ability to drive vehicles and operate machinery

As with the prescription of other neuroleptics, when prescribing aripiprazole, the patient should be warned about the dangers of working with moving mechanisms and driving a car.

Drug Interactions

There are various pathways of aripiprazole metabolism, including those involving CYP2D6 and CYP3A4 enzymes. In studies in healthy people, potent inhibitors of CYP2D6 (quinidine) and CYP3A4 (ketoconazole) reduced the oral clearance of aripiprazole by 52% and 38%, respectively (the dose of aripiprazole should be reduced when used concomitantly with CYP3A4 and CYP2D6 inhibitors).

Administration of aripiprazole at a dose of 30 mg simultaneously with carbamazepine, a potent inducer of CYP3A4, was accompanied by a decrease in C_max and AUC of aripiprazole by 68% and 73%, respectively, and a decrease in C_max and AUC of its active metabolite dehydroaripiprazole by 69% and 71%, respectively. A similar effect can be expected from other potent inducers of CYP3A4 and CYP2D6.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.