Abilifay - instructions for use, dose, side effects, contraindications

Excipients: tartaric acid granulated - 10.4 mg, P-cyclodextrin sulfobutyl ether (Captisol®) - 200.0 mg, sodium hydroxide - up to pH 4.3, water for injection - up to 1.33 ml.

* - Packing is done taking into account the over-recycling, which is necessary to ensure the extraction of 1.33 ml of a solution containing at least 10 mg of active substance. The total volume of the solution in the vial is 1.69 ml (the total amount of aripiprazole in the vial is 12.675 mg).

Description:

Transparent colorless solution without visible mechanical inclusions.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.X Other antipsychotics

N.05.A.X.12 Aripiprazole

Pharmacodynamics:

It is assumed that the therapeutic effect of aripiprazole in schizophrenia is due to partial agonism in relation to D2-dopamine and 5-HT1_a-cepothennin receptors and antagonism of 5-HT2-serotonin receptors.

Pharmacodynamics

Aripiprazole in conditions in vitro has a high affinity for D2- and D3- dopamine receptors, and 5-HT1_a- and 5-HT2_aserotonin receptors and moderate affinity for D₄dopamine, 5-HT_2c- and 5-HT₇-serotonin, alpha-1-adrenergic receptors and H1-histamine receptors. Aripiprazole is also characterized by a moderate affinity for the sites of serotonin reuptake and the lack of affinity for m-holinoretseptoram. Aripiprazole in animal experiments, inhibited dopamine-induced hyperactivity and increased dopamine-induced hypoactivity.

Pharmacokinetics:

With intramuscular injection aripiprazole absorbed quickly and completely. The pharmacokinetics of aripiprazole were studied with the participation of healthy volunteers who received aripiprazole in the form of tablets, intramuscular or intravenous injections. With intramuscular administration of aripiprazole at a dose of 5 mg, its absolute bioavailability was 100%.The mean time to reach the maximum concentration of aripiprazole in plasma (Cmah) for intramuscular injection was 2.8 hours (1.5 to 6.0 hours) compared to 3.0 hours (0.5 to 10.0 hours) for the same dose taken in the form of tablets. The average value of C_m_Oh after intramuscular injection was an average of 19% higher than after taking the tablets. In accordance with the higher Cmax, the area under the concentration-time curve (AUC) aripiprazole for the first 2 hours after intramuscular injection was 90% higher than AUC after taking the same dose in the form of tablets. In patients with schizophrenia or a low-performance disorder in a stable state the pharmacokinetics of aripiprazole was linear with intramuscular doses in the range of 1 mg to 45 mg. In this range, the average values of Cmah and AUC for each mg of administered aripiprazole for 24 hours were 3.7 ng / ml and 62.3 ng / h / ml, respectively. Aripiprazole is metabolized in the liver mainly by three mechanisms of biotransformation: dehydrogenation, hydroxylation and, N- dealkylation. Based on research in vitro it can be concluded that "isoenzymes CYP3A4 and CYP2D6 are responsible for dehydrogenation and hydroxylation of aripiprazole, whereas N-dealkylation is catalyzed by isoenzyme CYP3A4. The systemic blood flow prevails aripiprazole, and in a plasma in an equilibrium state, dehydroaripiprazole is 40% AUC. The average half-life of aripiprazole is about 75 hours in patients with a high degree of metabolism by isoenzyme CYP2D6 and about 146 hours for people with a low degree of metabolism with the participation of isoenzyme CYP2D6. The total clearance of aripiprazole is 0.7 ml / min / kg, mainly through the liver.

Indications:

The drug Abilifay® solution for intramuscular injection is used to quickly arrest the state of excitation and behavioral disorders in patients with schizophrenia and in patients with manic episodes in type I bipolar disorder with the inability to take the drug inside.

As soon as it becomes possible to take the drug inside, therapy in the form of intramuscular injections is canceled.

Contraindications:

- Hypersensitivity to aripiprazole or any other component of the drug;

- Age to 18 years;

- Lactation period.

Carefully:

Patients with cardiovascular diseases (coronary heart disease, suffered myocardial infarction, heart failure and conduction disturbance); in patients with cerebrovascular diseases and conditions predisposing to arterial hypotension (dehydration, hypovolemia and taking antihypertensive drugs) - in connection with the possibility of developing orthostatic hypotension; in patients with convulsive seizures or diseases in which cramps are possible; in patients with an increased risk of hyperthermia, for example, with intense physical exertion, overheating, with m-holinoblokatorov, with dehydration (due to the ability of neuroleptics to disrupt thermoregulation); in patients with an increased risk of aspiration pneumonia due to the risk of impaired motor function of the esophagus and aspiration; in patients with obesity and diabetes mellitus in a family history.

Pregnancy and lactation:

Adequate and well-controlled studies in pregnant women have not been conducted. There were cases of congenital anomalies of newborns, but their causal relationship with aripiprazole was not established. Studies in animals do not allow to exclude the potential negative effect on fetal development.The patient should be warned that it is necessary to inform the attending physician if she is pregnant or planning a pregnancy during treatment with aripiprazole.

Due to insufficient information on the safety of the drug during admission during pregnancy, and taking into account the results of animal studies, Abilifay® should be given during pregnancy only when the potential benefit to the mother exceeds the potential risk to the fetus.

Aripiprazole penetrates the milk of rats. There are no data on the penetration of aripiprazole into human breast milk. Breastfeeding when using the drug is not recommended.

Dosing and Administration:

It is used only for intramuscular injections.

The recommended initial dose is 10 mg (1 vial, 1.33 ml) as a single intramuscular injection. Effective doses are in the range of 5.25 to 15 mg in the form of a single injection. A reduced dose of 5.25 mg (0.7 ml) can be prescribed based on an assessment of the clinical state of the patient, which should already take into account prescribed to the patient preparations for maintenance treatment or for emergency therapy.The second injection can be made 2 hours after the first injection, depending on the individual clinical status of the patient. Do not prescribe more than three injections within 24 hours.

The maximum daily dose is 30 mg of aripiprazole, with doses introduced in the form of a solution for intramuscular injection and doses taken in the form of tablets.

If further treatment with Abilifay® is expected in the form of tablets, the instructions for the use of tablets should be carefully studied.

To improve absorption, the drug should be injected into the deltoid or deep into the large muscle of the buttocks, avoiding areas with pronounced subcutaneous fat. The drug is not intended for intravenous or subcutaneous administration.

The drug is used exclusively as a short course of therapy.

Use in special groups patients

Patients with renal insufficiency

Dose adjustments for prescribing patients with renal insufficiency are not required.

Patients with hepatic insufficiency

Dose adjustments for prescribing patients with mild or moderate liver failure are not required.In severe hepatic insufficiency, caution should be used, especially with a maximum daily dose of 30 mg.

Use in patients over 65 years of age

Given the increased risk of adverse reactions in this group of patients, consideration should be given to assigning them a reduced initial dose.

Effect of the patient's sex on the dosing regimen

Dosage regimen for patients of both sexes is the same.

Effect of smoking on the dosing regimen

Dosage regimen for smoking and non-smoking patients is the same.

Use in children

Safety and efficacy in patients younger than 18 years of age with psychomotor agitation in schizophrenia or bipolar mania have not been established.

Correction of dose due to interactions

With the simultaneous administration of aripiprazole and potent inhibitors of isoenzymes - CYP3A4 and CYP2D6 the dose of aripiprazole should be reduced. After the cancellation of potent inhibitors of isoenzymes CYP3A4 and CYP2D6 the dose of aripiprazole is increased.

With the simultaneous administration of aripiprazole and powerful isoenzyme inducers CYP3A4 the dose of aripiprazole should be increased. After the cancellation of the powerful isoenzyme inducer CYP3A4 the dose of aripiprazole is reduced.

Side effects:

The most frequent adverse reactions noted in clinical studies of aripiprazole injection solution (in more than 3% of patients) were nausea, dizziness and drowsiness.

The following adverse reactions, noted in clinical studies of aripiprazole injection for injection at a frequency of >1/100 or evaluated as clinically relevant, are marked with an asterisk (*).

The incidence of the following side effects is shown in accordance with the following scale:

frequent > 1/100<1/10

infrequent > 1/1000 <1/100.

From the central nervous system

Often: Drowsiness, dizziness, headache, akathisia

From the side of the cardiovascular system

Infrequently: tachycardia *, orthostatic hypotension *, increased diastolic blood pressure *

From the digestive system

Often: nausea, vomiting

Infrequently: dryness of the oral mucosa *

General reactions

Infrequently: fatigue*

The following adverse reactions noted in clinical studies of aripiprazole for oral administration at a frequency >1/100 or evaluated as clinically relevant, are marked with an asterisk (*).

From the side of the psyche:

Often: anxiety, insomnia, anxiety

Infrequently: depression*

From the central nervous system

Often: extrapyramidal disorders, akathisia, tremor, dizziness, drowsiness, sedation, headache,

From the side of the organ of vision

Often: blurred vision

From the side of the cardiovascular system

Infrequently: tachycardia *, orthostatic hypotension *

From the digestive system

Often: dyspepsia, nausea, vomiting, constipation, hypersecretion of the salivary glands

General reactions

Infrequently: fatigue*

Influence on indicators of laboratory research

In 3.5% of patients who took aripiprazole, there was an increase in the activity of creatine phosphokinase (usually transient and asymptomatic).

Adverse reactions characteristic of all neuroleptics

Dystonia: symptoms of dystonia (prolonged pathological contractions of muscle groups) may occur in some patients during the first days of treatment. Symptoms of dystonia are spasms of the musculature of the neck, sometimes up to the feeling of squeezing the throat, difficulty in swallowing, shortness of breath, protrusion of the tongue. These symptoms are more frequent and more pronounced when high doses of typical neuroleptics are used. Risk groups are men and young patients.

NSA, tardive dyskinesia, seizures, reaction from the cardiovascular system, and increased mortality in patients with senile dementia, hyperglycemia and diabetes occur in the application of all antipsychotics, including aripiprazole.

In the course of postmarketing use, the following adverse reactions were noted, the frequency of which was not established:

On the part of the circulatory system and lymph circulation - Lakopenia, neutropenia, thrombocytopenia;

From the immune system - allergic reactions (anaphylaxis, vascular edema, including swelling of the tongue, face edema, pruritus, urticaria);

From the endocrine system - hyperglycemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma;

Disorders of nutrition and metabolism - weight gain, weight loss, anorexia, hyponatremia;

Disorders from the psyche - Excitation, nervousness, suicidal thoughts and attempts;

From the nervous system - Speech disorders, CNS, convulsions (grand mal);

From the side of the cardiovascular system - lengthening the interval Q-T, ventricular arrhythmia, sudden death, cardiac arrest, torsades de points, bradycardia, syncope, hypertension, venous thrombosis (including pulmonary embolism and deep vein thrombosis);

On the part of the respiratory system, the organs of the thorax and the mediastinum - Spasm of the oropharynx, laryngospasm, aspiration pneumonia;

From the digestive system - pancreatitis, dysphagia, discomfort in the stomach, discomfort in the abdominal cavity, diarrhea; jaundice, hepatitis;

From the skin and skin appendages - rash, photosensitivity reactions, alopecia, hyperhidrosis;

From the side of the musculoskeletal system - rhabdomyolysis, myalgia, stiffness;

From the genitourinary system - urinary incontinence, urinary retention, priapism;

General reactions - violation of thermoregulation (hypothermia, pyrexia), chest pain, peripheral edema;

Change in laboratory indicators - increased activity of alanine aminotransferase, aspartate aminotransferase, gamma glutamyl aminotransferase, alkaline phosphatase, creatine phosphokinase, an increase in the concentration of glycosylated hemoglobin.

Overdose:

In clinical studies, a random or deliberate overdose of aripiprazole with a single dose of up to 1260 mg, not accompanied by a fatal outcome, has been described. Symptoms of an overdose: lethargy, increased blood pressure, drowsiness, tachycardia, loss of consciousness.Hospitalized patients showed no clinically significant changes in the basic physiological parameters, laboratory parameters and ECG.

Cases of overdose of aripiprazole in children (intake up to 195 mg) are described. Potentially dangerous symptoms of overdose include extrapyramidal disorders and transient loss of consciousness.

Treatment: monitoring of vital functions, continuous ECG, maintenance therapy, airway patency, oxygenation, effective ventilation, Activated carbon, symptomatic treatment, careful medical observation until all symptoms disappear. Consider the possible impact of concomitant therapy. Activated carbon, taken 1 hour after aripiprazole, reduces the maximum concentration FROM_Max- by 41% and the area under the concentration / time curve (AUC) by approximately 51%, which may indicate the benefit of prescribing activated charcoal in an overdose of aripiprazole.

Data on the use of hemodialysis in case of an overdose of aripiprazole are absent; The favorable effect of this method is unlikely, since aripiprazole is not excreted by the kidneys in an unchanged form and is largely associated with plasma proteins.

Interaction:

The effect of other drugs on the pharmacokinetics of Abilifay®

Aripiprazole displays antagonism to α1-adrenergic receptors, and in this connection it can be expected that it will enhance the action of antihypertensive agents when used simultaneously.

Aripiprazole primarily affects the central nervous system, in this regard, to avoid excessive sedation and suppression of respiratory and cardiovascular systems should be particularly careful when using other drugs that affect the central nervous system. When combined, therapy with parenteral aripiprazole and benzodiazepines (lorazepam) increases the risk of increased sedation and the development of orthostatic hypotension.

Caution should be exercised while using aripiprazole and drugs that can lengthen the interval Q-T or disturb the electrolyte balance.

The H2-histamine receptor blocker famotidine reduces the rate of absorption of aripiprazole, but the clinical significance of this effect is not clear.

Various routes of metabolism of aripiprazole are known, including with the participation of isoenzymes CYP2D6 and CYP3A4, but not isoenzyme CYP1 A. In this regard, dose adjustment for smokers is not required.

In studies in healthy people, a potent inhibitor of isoenzyme CYP2D6 quinidine increased AUC aripiprazole by 107%, whereas the value FROM_Max did not change. Values AUC and FROM_Maxdehydroaripiprazole (active metabolite) decreased by 32% and 47%, respectively. In this regard, the dose of Abilafaj® with quinidine should be reduced by about half. It is expected that a similar effect can also have powerful inhibitors of the isoenzyme CYP2D6 fluoxetine and paroxetine.

In studies in healthy people, a powerful isoenzyme inhibitor CYP3A4 ketoconazole increased values AUC and FROM_Max aripiprazole by 63% and 37%, respectively. Values AUC and FROM_Maxdehydroaripiprazole (active metabolite) increased by 77% and 47%, respectively. In patients with low metabolic activity by isoenzyme CYP2D6 simultaneous use of powerful inhibitors CYP3A4 can lead to an increase in the concentration of aripiprazole, in plasma compared to patients in whom metabolism by CYP2D6 passes more actively.The use of ketoconazole or other potent inhibitors of isoenzyme CYP3A4 and the drug Abilifay® is justified only in cases where the potential The benefit of therapy exceeds the possible risk from its use. The dose of Abilifai® when applied with ketoconazole should be reduced approximately half. It is expected that a similar effect can also have other potent inhibitors of the isoenzyme of Abilifay®, for example, itraconazole and inhibitors protease of HIV, therefore, the necessary correction of the dose of Abilifay® should be carried out. After discontinuation of therapy with isozyme inhibitors CYP3A4 and CYP2D6 the dose of Abilifay® is increased.

With the simultaneous use of Abilifay® and weak isozyme inhibitors CYP3A4 (e.g., diltiazem and escitalopram) and CYP2D6 one can expect a small increase in the concentrations of aripiprazole in the blood plasma.

The use of aripiprazole (30 mg) together with carbamazepine, a powerful isoenzyme inducer CYP3A4, was accompanied by a decrease of 68% and 73% C_m_Oh and AUC aripiprazole, respectively, and a decrease of 69% and 71% Cmah and AUC its active metabolite dehydroaripiprazole, respectively. The dose of Abilafaj® should be doubled in such cases.It is possible to expect a similar effect on other powerful inductors of isoenzymes CYP3A4 (rifampicin, rifabutin, phenytoin, phenobarbital, primidon, efavirenz, nevirapine, preparations of St. John's wort perfumed), therefore, it is necessary to correct the dose of Abilifay®. After discontinuing therapy with powerful inducers CYP3A4 the dose of Abilifay® is reduced. Simultaneous use of lithium or valproic acid and aripiprazole did not have a clinically significant effect on the pharmacokinetics of aripiprazole.

Effect of Abilifay® on the pharmacokinetics of other drugs

With the simultaneous use of a solution of aripiprazole for injection and lorazepam for injection, the pharmacokinetics of lorazepam does not change. However, with a single intramuscular administration of aripiprazole at a dose of 15 mg to healthy volunteers concomitantly with intramuscular administration of lorazepam at a dose of 2 mg, the incidence of orthostatic hypotension was higher than with the administration of a single lorazepam.

In clinical studies, it was shown that aripiprazole in doses of 10-30 mg did not significantly affect the metabolism of substrates of isoenzymes CYP2D6 (the ratio of dextromethorphan / 3-methoxymorphinan), 2C9 (warfarin), 2C19 (omeprazole) and ZA4 (dextromethorphan). Besides, aripiprazole and dehydro-aripiprazole under in vitro conditions do not change the isoenzyme function CYP1A2, so it is unlikely that aripiprazole can have a clinically significant effect on the pharmacokinetics of drugs whose metabolism is mediated by this isoenzyme.

With simultaneous use with valproic acid, lithium or lamotrigine, no clinically significant changes in the concentrations of these preparations in the blood.

Special instructions:

Suicide attempts - the propensity to suicidal thoughts and attempts is characteristic for patients with psychotic diseases and bipolar disorder, so drug therapy must be combined with careful medical supervision. There were cases of suicidal behavior at the beginning of therapy with neuroleptics; as well as with the change of neuroleptic, including aripiprazole.

Late dyskinesia - the risk of developing tardive dyskinesia increases with the duration of therapy with neuroleptics, so when symptoms of tardive dyskinesia appear against the background of taking Abilifay®, the dose of the drug should be reduced or canceled.After the withdrawal of therapy, these symptoms may temporarily increase or even appear for the first time.

Malignant neuroleptic syndrome - In the treatment of neuroleptics, including aripiprazole, a life-threatening symptom complex known as "malignant neuroleptic syndrome" (CNS) is described. This syndrome is manifested by hyperpyrexia, muscle, rigidity, mental disorders and instability of the autonomic nervous system (irregular pulse and arterial pressure, tachycardia, sweating and cardiac arrhythmias). In addition, sometimes there is an increase in the activity of creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. In case of symptoms of NSA or unexplained fever, all antipsychotics, including Abilifay®, should be discontinued.

Convulsions

Like other antipsychotics, aripiprazole should be used with caution in patients with a history of seizures and the risk of their development.

Psychoses associated with senile dementia and Alzheimer's disease

In patients with psychoses due to senile dementia, the risk of a lethal outcome increases with treatment with atypical antipsychotics.In psychoses, patients with 56-99 years of age with Alzheimer's disease in three placebo-controlled studies on the background of aripiprazole increased the frequency of deaths (twice compared with placebo). The causes of death were different, however, in most cases they were associated with cardiovascular (cardiac failure, sudden death) and infections (for example, pneumonia). AT the same studies in patients 79-88 years more often than in patients of younger age, there were adverse reactions to the cardiovascular system: a heart attack, attacks of ischemia, including fatal. The use of the drug, Abilfai® for psychoses due to senile dementia, and in elderly patients with Alzheimer's disease is not recommended.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases expressed and accompanied by ketoacidosis or hyperosmolar coma with a fatal outcome, was noted in patients taking atypical antipsychotics. Although the relationship between the administration of atypical antipsychotics and hyperglycemic disorders is unclear, patients with diabetes mellitus,should regularly determine the concentration of glucose in the blood when taking atypical antipsychotics. Patients who have risk factors for diabetes (obesity, history of diabetes in the family history), with the appointment of atypical antipsychotics, should determine the blood glucose concentration at the beginning of the course and periodically during the treatment. Patients taking atypical antipsychotics need constant monitoring of symptoms of hyperglycemia, including increased thirst, frequent urination, polyphagia, weakness; special attention should be given to patients with diabetes mellitus and risk factors for its development.

Cardiovascular diseases

In connection with the risk of developing orthostatic hypotension aripiprazole should be used with caution in patients with cardiovascular diseases (myocardial infarction, ischemia attacks, heart failure, cardiac conduction abnormalities in the anamnesis), disorders of cerebral circulation or conditions predisposing to arterial hypotension (dehydration, hypovolemia, antihypertensive therapy).In the treatment with neuroleptics, there have been cases of venous thromboembolism, therefore, patients at risk for developing venous thromboembolism should be identified before treatment with Abilifay® and preventive measures are taken. In clinical studies of the drug Abilifay ® there were cases of lengthening the interval Q-T. Like other antipsychotics, Abilifay® should be administered with caution to patients with lengthening of the interval Q-T in a family history.

Dysphagia

With the appointment of neuroleptics, cases of peristalsis of the esophagus and, as a consequence, aspiration pneumonia were noted. Caution should be exercised when prescribing to patients with risk factors for the development of aspiration pneumonia.

Effect on body weight

In patients with schizophrenia and bipolar disorder, excessive body weight is often noted due to concomitant diseases, the administration of neuroleptics and poor diet. The increase in body weight was noted against the background of therapy with Abilifay®, more often in patients at risk (having diabetes, thyroid dysfunction, pituitary adenoma). In clinical studies, there was no significant effect of the drug on body weight.

Effect on the ability to thermoregulation

It is known that antipsychotics, including aripiprazole, can disrupt the ability to thermoregulation. Caution should be exercised when administering aripiprazole to patients who are likely to have fever (eg, increased physical exertion, increased ambient temperature, simultaneous administration of anticholinergic drugs, and dehydration of the body).

Reception of alcohol

The efficacy and safety of aripiprazole in the form of intramuscular injections during intoxication with alcohol or drugs has not been studied. Avoid alcohol during treatment with aripiprazole.

Effect on the ability to drive transp. cf. and fur:

As with the appointment of other neuroleptics, when treating aripiprazole, the patient should be warned of the dangers of working with moving mechanisms and driving.

Form release / dosage:Solution for intramuscular injection 7.5 mg / ml.

Packaging:

For 1.69 ml of the preparation into a colorless glass type I bottle, sealed with a rubber stopper and an aluminum cap under running in and a protective plastic cover (flip- off).

1 bottle with instructions for use in a cardboard box.

Storage conditions:

At a temperature of 15-25 ° C in the dark place.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000977

Date of registration:18.10.2011

Expiration Date:18.10.2016

The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA

Manufacturer: & nbsp

BRISTOL-MYERS SQUIBB HOLDINGS PHARMA, Ltd. Puerto Rico

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp17.01.2017

Illustrated instructions

Instructions

Abilifay® (Abilify®)