Abilify (Tablets, Solution) Instructions for Use

ATC Code

N05AX12 (Aripiprazole)

Active Substance

Aripiprazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Antipsychotic drug (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 5HT1_a receptors and antagonist activity at serotonin 5HT₂ receptors.

Aripiprazole has high affinity in vitro for dopamine D₂ and D₃ receptors, serotonin 5HT1_a and 5HT2_a receptors and moderate affinity for dopamine D₄, serotonin 5HT2_c and 5HT7, α₁-adrenergic receptors and histamine H₁ receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and no affinity for muscarinic receptors. In experimental animal studies, Aripiprazole exhibited antagonism to dopaminergic hyperactivity and agonism to dopaminergic hypoactivity. Some clinical effects of aripiprazole can be explained by interaction with dopamine and serotonin receptors.

Pharmacokinetics

Absorption

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.

Distribution and Metabolism

C_ss is reached in 14 days. Drug accumulation 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 the same affinity for dopamine D₂ receptors as Aripiprazole.

Aripiprazole undergoes minimal presystemic metabolism. It is metabolized in the liver by three pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro, dehydrogenation and hydroxylation of aripiprazole occur under the action of CYP3A4 and CYP2D6 isoenzymes, N-dealkylation – by CYP3A4.

The activity of Abilify is mainly due to the presence of unchanged aripiprazole.

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

Elimination

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.

Aripiprazole does not affect the pharmacokinetics and pharmacodynamics of warfarin, i.e., it does not displace warfarin from protein binding.

Indications

• Schizophrenia: acute episodes and maintenance therapy;
• Bipolar I disorder: manic episodes and maintenance therapy to prevent relapse in patients with bipolar I disorder who have recently experienced a manic or mixed episode;
• As an adjunct to therapy with lithium or valproic acid preparations for the treatment of manic or mixed episodes with or without psychotic symptoms;
• As an adjunct to antidepressant therapy for major depressive disorder.

ICD codes

Dosage Regimen

Solution

Individual, depending on the indications, course of the disease, tolerability of therapy. The dose is 10-30 mg once a day.

Tablets

For schizophrenia, it is recommended to prescribe Abilify at an initial dose of 10-15 mg once a day, regardless of food intake. The maintenance dose is 15 mg/day. Clinical studies have shown the efficacy of the drug at doses from 10 to 30 mg/day.

For manic episodes in bipolar disorder as monotherapy, the recommended initial dose is 15 mg once a day, regardless of food intake. Dose adjustment, if necessary, should be carried out at intervals of at least 24 hours. Clinical studies have demonstrated the efficacy of the drug at doses of 15-30 mg/day when taken for 3-12 weeks. The safety of the drug at doses above 30 mg/day has not been evaluated in clinical studies.

In patients with bipolar I disorder and manic or mixed episodes who showed symptom stabilization while taking Abilify for 6 weeks at a dose of 15 mg/day or 30 mg/day with an initial dose of 30 mg/day, then for 6 months and further for 17 months, a favorable effect of such maintenance therapy was established. Patients should be periodically examined to determine the need for continuation of maintenance therapy.

As an adjunct to therapy with lithium or valproic acid preparations, the recommended initial dose of Abilify is 15 mg once a day, regardless of food intake. Depending on clinical indications, the dose may be increased to 30 mg/day.

For major depressive disorder as an adjunct to antidepressant treatment, Abilify is recommended to be prescribed at an initial dose of 5 mg/day. If necessary and with good tolerability of therapy, the daily dose of Abilify can be increased weekly by 5 mg to a maximum of no more than 15 mg/day.

Patients with renal impairment, hepatic impairment, patients over 65 years of age do not require dose adjustment of the drug.

The dosage regimen of the drug is the same for patients of both sexes.

The dosage regimen of the drug is the same for smoking and non-smoking patients.

Dosage regimen for concomitant therapy

When Abilify and potent inhibitors of CYP2D6 or CYP3A4 isoenzymes are co-administered, the dose of Abilify should be reduced by half. When inhibitors of CYP2D6 or CYP3A4 isoenzymes are discontinued, the dose of Abilify should be increased. Abilify should be used without dose adjustment if it is prescribed as an adjunctive therapy for major depressive disorder.

When Abilify and inducers of the CYP3A4 isoenzyme are used concomitantly, the dose of Abilify should be doubled. Further increase in the dose of Abilify should be carried out taking into account clinical indications. When inducers of the CYP3A4 isoenzyme are discontinued, the dose of Abilify should be reduced.

When several drugs that inhibit CYP3A4 and CYP2D6 isoenzymes are prescribed, consideration should be given to reducing the daily dose of Abilify.

Adverse Reactions

Definition of frequency of adverse effects: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥ 0.01% and < 0.1%), very rare (≤ 0.01%).

Cardiovascular system common – orthostatic hypotension, tachycardia; uncommon – 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, atrial flutter, thrombophlebitis, intracranial hemorrhage, cerebral ischemia; very rare – syncope, increased blood pressure.

Digestive system very common – nausea, loss of appetite; common – increased appetite (when treating depression in combination with antidepressants), dyspepsia, vomiting, constipation, hypersalivation, dry mouth, abdominal heaviness, diarrhea; uncommon – gastroenteritis, difficulty swallowing, flatulence, gastritis, dental caries, gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal hemorrhage, periodontal abscess, tongue edema, fecal incontinence, colitis, rectal hemorrhage, stomatitis, oral mucosa ulceration, cholecystitis, fecaloma, oral candidiasis, belching, gastric ulcer; rare – esophagitis, gum bleeding, tongue inflammation, hematemesis, intestinal bleeding, duodenal ulcer, cheilitis, liver enlargement, intestinal perforation; very rare – increased ALT, AST and ALP activity, hepatitis, jaundice, pancreatitis, dysphagia.

Musculoskeletal system common – arthralgia, muscle rigidity; uncommon – myasthenia, arthritis, arthrosis, muscle weakness, muscle spasms, bursitis; very rare – increased CPK activity, rhabdomyolysis, tendinitis, tenobursitis, myalgia.

Central and peripheral nervous system: very common – insomnia, headache, akathisia (in patients with bipolar disorder and when treating depression in combination with antidepressants); common – drowsiness, dizziness, tremor, extrapyramidal syndrome, psychomotor agitation, depression, nervousness, hostility, suicidal thoughts, manic thoughts, confusion, resistance to passive movements (cogwheel rigidity), lethargy, impaired concentration, sedative effect; uncommon – dystonia, muscle twitching, paresthesia, limb tremor, impotence, bradykinesia, decreased/increased libido, panic reactions, apathy, memory impairment, stupor, amnesia, stroke, hyperactivity, depersonalization, dyskinesia, restless legs syndrome, myoclonus, depressed mood, hyperreflexia, slowed thinking, increased sensitivity to stimuli, impaired oculomotor response; rare – delirium, euphoria, buccoglossal syndrome, akinesia, depression of consciousness up to loss of consciousness, decreased reflexes, obsessive thoughts, NMS; very rare – speech disorder, seizures.

Respiratory system common – dyspnea, pneumonia; uncommon – epistaxis, hiccups, laryngitis; rare – hemoptysis, increased sputum production, dry nasal mucosa, pulmonary edema, pulmonary embolism, hypoxia, respiratory failure, apnea.

Sensory organs: common – blurred vision, photophobia, ear pain; uncommon – dry eyes, eye pain, tinnitus, otitis media, cataract, loss of taste, blepharitis; rare – increased lacrimation, frequent blinking, otitis externa, amblyopia, deafness, diplopia, intraocular hemorrhage.

Urinary system: uncommon – cystitis, frequent urination, leukorrhea, hematuria, dysuria, renal failure, albuminuria, kidney stones, nocturia, polyuria, urinary urgency; rare – burning in the urethra; very rare – urinary incontinence, urinary retention.

Reproductive system: uncommon – amenorrhea, premature ejaculation, vaginal bleeding, vaginal candidiasis, uterine bleeding, menorrhagia; rare – breast pain, cervicitis, galactorrhea, anorgasmia, burning in the external genital area, gynecomastia (breast enlargement in men), painful erection; very rare – priapism.

Metabolism: common – weight loss; uncommon – dehydration, edema, hypercholesterolemia, hypokalemia, hyperlipidemia, hypoglycemia, thirst, increased blood urea, iron deficiency anemia, increased LDH level, obesity; rare – hyperkalemia, gout, hypernatremia, glucosuria, cyanosis, urine acidification; very rare – hyponatremia, hyperglycemia, diabetic ketoacidosis, diabetic hyperosmolar coma.

Dermatological reactions common – dry skin, itching, skin ulceration; uncommon – acne, vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea; rare – maculopapular rash, exfoliative dermatitis, hyperhidrosis.

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

General disorders: common – asthenia, fatigue, flu-like syndrome, feeling of body tremors; uncommon – peripheral edema, facial edema, malaise, photosensitivity, jaw pain, chills, jaw stiffness, chest tightness; rare – sore throat, back stiffness, head heaviness, candidiasis, throat stiffness, Mendelson’s syndrome, heat stroke; very rare – temperature regulation disorders, pyrexia, chest pain, neck pain.

Contraindications

• Age under 18 years;
• Hypersensitivity to aripiprazole and other components of the drug.

Use with caution in patients with cardiovascular diseases (with coronary artery disease or history of myocardial infarction, with heart failure and conduction disorders), cerebrovascular diseases and conditions predisposing to arterial hypotension (dehydration, hypovolemia and taking antihypertensive drugs) due to the possibility of developing orthostatic hypotension; in patients 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 suffering from obesity and with a family history of diabetes.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of use during pregnancy have not been conducted. Abilify can be used during pregnancy in cases where the potential therapeutic benefit 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 the drug during lactation (breastfeeding) is not recommended.

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

Use in Hepatic Impairment

Patients with hepatic impairment do not require dose adjustment of the drug.

Use in Renal Impairment

Patients with renal impairment do not require dose adjustment of the drug.

Pediatric Use

Contraindication: age under 18 years.

Geriatric Use

Patients over 65 years of age do not require dose adjustment of the drug.

Special Precautions

Suicidal thoughts and attempts are characteristic of patients with psychosis, bipolar disorder and major depressive disorder, so drug therapy should be combined with careful medical supervision. Abilify should be prescribed at the minimum effective dose; this will reduce the risk of overdose.

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

When treated 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, arrhythmia). In addition, increased CPK activity, myoglobinuria (rhabdomyolysis) and acute renal failure sometimes occur. If symptoms of NMS or unexplained fever occur, all neuroleptics, including Abilify, should be discontinued.

Like other neuroleptics, Abilify should be used with caution in patients with a history of seizures and at risk of their development.

In patients with psychosis due to senile dementia, treatment with atypical neuroleptics increases the risk of fatal outcome. In psychosis in patients over 65 years of age with Alzheimer’s disease, cardiovascular disorders were observed: myocardial infarction, transient ischemic cerebrovascular accident, including fatal. The use of Abilify is not recommended for psychosis due to senile dementia and in elderly patients with Alzheimer’s disease.

Hyperglycemia, in some cases severe and accompanied by ketoacidosis, which can lead to hyperosmolar coma with fatal outcome, has been noted in patients taking atypical neuroleptics. Although the relationship between the use of atypical neuroleptics and hyperglycemic disorders remains unclear, patients diagnosed with diabetes should regularly monitor blood glucose levels when taking atypical neuroleptics. 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 use of atypical neuroleptics. In patients taking atypical neuroleptics, constant monitoring of symptoms of hyperglycemia (increased thirst, frequent urination, polyphagia, weakness) is necessary. Particular attention should be paid to patients with diabetes and risk factors for its development.

Due to the risk of developing orthostatic hypotension, Abilify should be used with caution in patients with cardiovascular diseases (myocardial infarction, coronary artery disease, heart failure, history of cardiac conduction disorders), cerebrovascular disorders, or conditions predisposing to arterial hypotension (dehydration, hypovolemia, therapy with antihypertensive agents).

Cases of impaired esophageal peristalsis and, as a consequence, aspiration pneumonia have been reported with the use of antipsychotics. The drug should be prescribed with caution to patients with risk factors for developing aspiration pneumonia.

Effect on the Ability to Drive Vehicles and Operate Machinery

As with the use of other antipsychotics, when prescribing Abilify, the patient should be warned about the dangers of working with moving mechanisms and driving a car.

Overdose

Clinical studies have described accidental or intentional overdoses of aripiprazole with a single dose of up to 1260 mg, which were not fatal. Symptoms: lethargy, increased blood pressure, drowsiness, tachycardia, loss of consciousness. In hospitalized patients, no clinically significant changes in key physiological parameters, laboratory parameters, or ECG were detected.

Cases of aripiprazole overdose in children (ingestion of up to 195 mg) have been reported. Potentially dangerous symptoms of overdose are extrapyramidal disorders and transient loss of consciousness.

Treatment: monitoring of vital functions, ECG, supportive therapy, ensuring airway patency, oxygenation, effective lung ventilation, activated charcoal, symptomatic treatment, careful medical observation until all symptoms resolve. There are no data on the use of hemodialysis for aripiprazole overdose; a favorable effect of this method is unlikely because Aripiprazole is not excreted by the kidneys unchanged and is largely bound to plasma proteins.

Drug Interactions

No significant effect of the histamine H₂-receptor blocker famotidine, which causes potent inhibition of hydrochloric acid secretion in the stomach, on the pharmacokinetics of aripiprazole was identified.

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

Administration of aripiprazole at a dose of 30 mg simultaneously with carbamazepine, a potent inducer of CYP3A4, was accompanied by a decrease in the C_max and AUC of aripiprazole by 68% and 73%, respectively, and a decrease in the 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.

The in vitro metabolism of aripiprazole does not involve the isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1, therefore, its interaction with drugs and other factors (for example, smoking) capable of inhibiting or activating these enzymes is unlikely.

Concomitant administration of lithium or valproate with aripiprazole at a dose of 30 mg once daily did not have a clinically significant effect on the pharmacokinetics of aripiprazole.

In clinical studies, Aripiprazole at doses of 10-30 mg/day did not have a significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan). Furthermore, Aripiprazole and its main metabolite, dehydroaripiprazole, did not alter metabolism involving the CYP1A2 enzyme in vitro. A clinically significant effect of aripiprazole on drugs metabolized by these isoenzymes is unlikely.

With the simultaneous use of aripiprazole (10-30 mg/day) and lamotrigine (100-400 mg/day) in patients with bipolar disorder, there were no changes in the pharmacokinetics of lamotrigine, so no dose adjustment of the latter is required.

Aripiprazole did not affect the pharmacokinetics of escitalopram and venlafaxine in healthy volunteers, so no dose adjustment of these drugs is required when co-administered with aripiprazole.

When using aripiprazole in patients with major depressive disorder simultaneously with fluoxetine (20-40 mg/day), paroxetine (37.5 -50 mg/day), and sertraline (2-20 mg/day), no significant changes in plasma concentrations of the antidepressants were detected.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature from 15°C (59°F) to 30°C (86°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.