Aripiprazole-Teva (Tablets) Instructions for Use

ATC Code

N05AX12 (Aripiprazole)

Active Substance

Aripiprazole

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

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 affinity in vitro 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 within 3-5 hours. The absolute bioavailability is 87%. Food intake does not affect the bioavailability of aripiprazole.

C_ss is reached after 14 days. Accumulation of the drug upon 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 minimal presystemic metabolism. 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 the 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 the initial dose for schizophrenia and bipolar I disorder as 10 mg or 15 mg once daily.

Do not take with a high-fat meal, as it does not significantly affect absorption.

Increase the dose to a target of 15 mg daily after a minimum of two weeks, based on clinical response and tolerability.

Use a maximum daily dose of 30 mg.

Adjust the dose for known CYP2D6 poor metabolizers; reduce to half the standard dose.

Administer half the standard dose when used concomitantly with potent CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine).

Reduce the dose by at least half when used concomitantly with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole).

Double the dose when used concomitantly with potent CYP3A4 inducers (e.g., carbamazepine, rifampin).

Re-evaluate the dosage once the inducer is discontinued.

Swallow tablets whole with water; do not crush or chew.

Adverse Reactions

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

Digestive system: very often – nausea, loss of appetite; often – dyspepsia, vomiting, constipation; possibly – 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; rarely – esophagitis, gum bleeding, glossitis, hematemesis, intestinal bleeding, duodenal ulcer, cheilitis, hepatitis, hepatomegaly, pancreatitis, intestinal perforation; very rarely – increased ALT, AST, ALP activity.

Allergic reactions: very rarely – anaphylaxis, angioedema, itching and urticaria.

Musculoskeletal system: often – myalgia, convulsions; possibly – joint and bone pain, myasthenia, arthritis, arthrosis, muscle weakness, spasms, bursitis; very rarely – increased CPK activity, rhabdomyolysis, tendinitis, tenobursitis, rheumatoid arthritis, myopathy.

Central and peripheral nervous system: very often – insomnia, drowsiness, akathisia; often – dizziness, tremor, extrapyramidal syndrome, psychomotor agitation, depression, nervousness, hypersalivation, hostility, suicidal thoughts, manic thoughts, unsteady gait, confusion, cogwheel rigidity; possibly – 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; rarely – delirium, euphoria, buccoglossal syndrome, akinesia, depression of consciousness up to loss of consciousness, hyporeflexia, obsessive thoughts, NMS.

Respiratory system: often – dyspnea, pneumonia; possibly – asthma, epistaxis, hiccups, laryngitis; rarely – hemoptysis, aspiration pneumonia, increased sputum production, nasal dryness, pulmonary edema, pulmonary embolism, hypoxia, respiratory failure, apnea.

Dermatological reactions: often – dry skin, itching, increased sweating, skin ulceration; possibly – acne, vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea; rarely – maculopapular rash, exfoliative dermatitis, urticaria.

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

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

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

Metabolism: often – weight loss, increased CPK level; possibly – dehydration, edema, hypercholesterolemia, hyperglycemia, hypokalemia, diabetes mellitus, hyperlipidemia, hypoglycemia, thirst, increased blood urea, hyponatremia, iron deficiency anemia, increased creatinine, bilirubinemia, increased LDH level, obesity; rarely – 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 in cases where the potential therapeutic benefit to 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; when taking drugs with m-cholinolytic activity.

Susceptibility to suicidal thoughts and attempts is 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 treatment, its dose should be reduced or it should be discontinued. After discontinuation of therapy, these symptoms may temporarily worsen or even appear for the first time.

During treatment with neuroleptics, including aripiprazole, neuroleptic malignant syndrome (NMS) may develop, which is manifested by hyperpyrexia, muscle rigidity, mental disorders and instability of the autonomic nervous system (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 noted 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 the 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.