2010/06/23

Abilify



Composition, structure and packing
Tablets rectangular shape with rounded edges, blue, marked "A-007" and "5" on one side.

1 tab. Aripiprazole - 5 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, gidroksipropiltsellyuloza, magnesium stearate, aluminum paint blue.
Tablets rectangular shape with rounded edges, pink and marked "A-008" and "10" on one side.

1 tab. Aripiprazole - 10 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, gidroksipropiltsellyuloza, magnesium stearate, iron oxide red pigment.
Tablets are round, yellow, with a facet, labeled "A-009" and "15" on one side.

1 tab. Aripiprazole - 15 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, gidroksipropiltsellyuloza, magnesium stearate, iron oxide yellow.
Tablets are round, white or slightly yellow in color, with beveled, labeled "A-010" and "20" on one side.

1 tab. Aripiprazole - 20 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, gidroksipropiltsellyuloza, magnesium stearate.
Tablets are round, pink, with beveled, labeled "A-011" and "30" on one side.

1 tab. Aripiprazole 30 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, gidroksipropiltsellyuloza, magnesium stearate, iron oxide red.

Clinico-pharmacological group: antipsihotichesky drug (neuroleptic).

Pharmacological action

Antipsychotic (neuroleptic). It is assumed that the therapeutic effect of aripiprazole in schizophrenia due to a combination of partial agonistic activity on dopamine D2-and serotonin 5HT1a receptors and antagonistic activity against serotonin 5HT2-receptors. Aripiprazole has a high affinity in vitro for dopamine D2-and D3-receptors, serotonin 5HT1a-and 5HT2a-receptors and moderate affinity for dopamine D4-, serotonin 5HT2c-and 5HT7-, α1-adrenoreceptor and histamine H1-receptors. Aripiprazole is also characterized by a moderate affinity for serotonin reuptake sites and the lack of affinity for muscarinic receptors. In experimental animal studies Aripiprazole showed antagonism against the dopaminergic hyperactivity and dopaminergic agonism against gipoaktivnosti. Some clinical effects of aripiprazole may be explained by interaction with dopamine and serotonin receptors.

Pharmacokinetics

Absorption

Once inside Aripiprazole is rapidly absorbed from the gastrointestinal tract. Cmax in plasma achieved after 3-5 h. The absolute bioavailability - 87%. Eating does not affect the bioavailability of aripiprazole.

Distribution and Metabolism

Css achieved after 14 days. Cumulation of the drug after repeated admission predictable. Indicators of aripiprazole pharmacokinetics in an equilibrium state is proportional to dose. There was no daily fluctuations in the distribution of aripiprazole and its metabolite degidroaripiprazola. Aripiprazole extensively distributed in tissues, Vd is 4.9 L / kg. At therapeutic concentrations over 99% of aripiprazole binds to serum proteins, primarily albumin. Found that degidroaripiprazol, major metabolite in human plasma, has the same affinity for D2-receptor dopaminvym as Aripiprazole. Aripiprazole undergoes presistemnomu metabolism only minimally. Metabolised in the liver in three ways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro dehydrogenation and hydroxylation of aripiprazole occurs under isozymes CYP3A4 and CYP2D6, N-dealkylation - CYP3A4. Activity Abilifaya mainly due to the presence of unchanged aripiprazole. In equilibrium degidroaripiprazola AUC in plasma is about 39% of aripiprazole AUC.

Withdrawal

The average T1 / 2 aripiprazole - about 75 hours after single dose of 14C-labeled aripiprazole about 27% and 60% of radioactivity is determined in the urine and feces, respectively. Less than 1% of unchanged aripiprazole is determined in the urine and about 18% of applied dose in unchanged form excreted in the feces. The total clearance of aripiprazole is 0.7 ml / min / kg, mainly due to excretion by the liver. Aripiprazole does not affect the pharmacokinetics and pharmacodynamics of warfarin, ie, does not displace warfarin from its association with blood proteins.

Statement
treatment of acute attacks of schizophrenia, maintenance treatment of schizophrenia;
Treatment of acute manic episodes of bipolar disorder type I and for maintenance therapy of patients with bipolar disorder type I, has recently suffered from manic or mixed episode.

Dosage regimen

In schizophrenia encouraged to nominate Abilifay in an initial dose of 10-15 mg 1 time per day, regardless of the meal. Maintenance dose is 15 mg / day. In clinical studies demonstrated the effectiveness of the drug in doses ranging from 10 to 30 mg / day.

In manic episodes in bipolar disorder Abilifay should take 1 time per day regardless of the meal, beginning with doses of 15 or 30 mg / day. Changing the dose, if necessary, should be conducted at intervals of not less than 24 hours

In clinical studies demonstrated the effectiveness of the drug in doses of 15-30 mg / day for manic episodes while taking over 3-12 weeks. Safety of the drug in doses of 30 mg / day in clinical studies was not evaluated. In the observation of patients with bipolar disorder type I and manic or mixed episodes who had no symptoms at intake of Abilifaya for 6 weeks at a dose of 15 mg / day or 30 mg / d at an initial dose of 30 mg / day, set a favorable effect a maintenance therapy. It should periodically examine the patient to determine the need for continued maintenance therapy.

Patients with renal insufficiency, hepatic insufficiency (classes A, B and C on the scale of Child-Pugh) do not want to change the dose of the drug. Although the experience of the drug in patients aged over 65 years is limited, dosage adjustment for this category of patients is required.

Side effect

Determining the frequency of side effects: very common - ≥ 10%, and often - from ≥ 1% to <10% rarely - from ≥ 0.1% to <1%, rare - of ≥ 0.01% to <0.1%, very rare - ≤ 0.01 %.

Since the cardiovascular system: often - orthostatic hypotension, tachycardia infrequently - bradycardia, palpitations, myocardial infarction, lengthening the interval QT, cardiac arrest, hemorrhage, atrial fibrillation, heart failure, AV-block, myocardial ischemia, deep vein thrombosis, phlebitis , beats, rarely - vasovagal syndrome, enlargement of the heart, atrial flutter, thrombophlebitis, intracranial hemorrhage, cerebral ischemia, very rarely - syncope.

On the part of the digestive system: very often - nausea, loss of appetite, often - indigestion, vomiting, constipation, rarely - increased appetite, gastroenteritis, difficulty swallowing, flatulence, gastritis, dental caries, gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal bleeding, periodontal abscess, tongue edema, urinary stool, colitis, rectal hemorrhage, stomatitis, mouth ulceration, cholecystitis, fekaloma, candidiasis of the mucous membranes of the mouth, gallstone disease, flatulence, gastric ulcer, rarely - esophagitis, bleeding gums, inflammation of the tongue, a bloody vomiting, intestinal bleeding, duodenal ulcer, cheilitis, hepatitis, liver enlargement, pancreatitis, perforation of the intestine, very rarely - increased activity of ALT, AST, alkaline phosphatase.

On the part of the musculoskeletal system: often - myalgia, convulsions, rarely - a pain in the joints and bones, myasthenia gravis, arthritis, arthrosis, muscle weakness, cramps, bursitis, very rarely - increased activity of CPK, rhabdomyolysis, tendenit, tenobursit, rheumatoid arthritis, myopathy.

From the side of the central nervous system and peripheral nervous system: very often - insomnia, somnolence, akathisia, often - dizziness, tremor, extrapyramidal syndrome, psychomotor agitation, depression, nervousness, increased salivation, hostility, suicidal thoughts, manic thoughts, staggering, confusion, resistance to the implementation of passive motion (cogwheel) infrequently - dystonia, muscle spasms, weakening of concentration, paresthesia, tremor of limbs, impotence, bradykinesia, decreased / increased libido, panic reaction, apathy, dyskinesia, weakening of memory, stupor, amnesia, stroke , hyperactivity, depersonalization, dyskinesia, a syndrome of "restless legs (akathisia), myoclonus, depressed mood, increased reflexes, slowing of mental function, increased sensitivity to stimuli, hypotension, a violation of oculomotor reaction rarely - delirium, euphoria, bukkoglossalny syndrome, akinesia, depression of consciousness and even the loss of consciousness, depressed reflexes, obsessive thoughts, CSN.

On the part of the respiratory system: often - shortness of breath, pneumonia, rarely - asthma, epistaxis, hiccup, laryngitis; rare - hemoptysis, aspiration pneumonia, increased sputum, dryness of the nasal mucosa, pulmonary edema, pulmonary embolism, hypoxia, respiratory failure, apnea .

From the senses: common - conjunctivitis, pain in the ears; infrequently - dry eyes, eye pain, tinnitus, otitis media, cataracts, loss of taste, blepharitis; rarely - increased tearing, frequent blinking, external otitis, amblyopia, deafness, diplopia, eye hemorrhage, photophobia.

On the part of the urogenital system: often - urinary incontinence, infrequent - cystitis, frequent urination, leykoreya, urinary retention, hematuria, dysuria, renal failure, albuminuria, kidney stones, nocturia, polyuria, urination, amenorrhea, premature ejaculation, vaginal bleeding , vaginal candidiasis, uterine bleeding, menorrhagia, rarely - stinging in the urethra, glycosuria, painful erection, pain in the breast, cervicitis, galactorrhoea, anorgasmia, gynaecomastia (an increase of mammary glands in men).

On the part of metabolism: often - weight loss, increased CPK; infrequently - Dehydration, edema, high cholesterol, hyperglycemia, hypokalemia, diabetes mellitus, hyperlipidemia, hypoglycemia, thirst, increased level of blood urea, hyponatremia, iron deficiency anemia, increased creatinine, bilirubinemia, elevated levels of LDH, obesity, rare - hyperkalaemia, gout, hypernatremia, cyanosis, acidification of urine, hypoglycemic reaction. Dermatological reactions: often - dry skin, itching, excessive sweating, skin ulcer; infrequently - acne, vezikulobuleznaya (bubbly), rash, eczema, alopecia, psoriasis, seborrhea, rarely - Makulo-papular rash, exfoliative dermatitis.

On the part of the immune system: a very rare - allergic reactions (anaphylaxis, angioedema, pruritus and urticaria).

On the part of the body in general: often - flu-like syndrome, peripheral edema, chest pain, neck; infrequently - pelvic pain, face edema, malaise, photosensitivity, oral pain, chills, stiff jaw, bloating, tension in the chest; rarely - sore throat, stiffness in the back, heavy-headedness, candidiasis, stiffness in the neck, Mendelson syndrome, heat stroke.

Contraindications
age 18;
hypersensitivity to aripiprazole and other components of the drug.

With caution to patients with cardiovascular diseases (coronary heart disease or myocardial infarction with heart failure and conduction disorders), cerebrovascular diseases and conditions, predisposing to arterial hypotension (dehydration, hypovolemia, and antihypertensive drugs) in connection with the possibility of orthostatic hypotension, in patients with convulsive seizures, or suffer from diseases that may be convulsions, patients with increased risk of hyperthermia (eg, physical exercise, overheating, taking anticholinergic drugs during dehydration because of the ability of neuroleptics disrupt thermoregulation) in patients with increased risk of aspiration pneumonia because of the risk of disturbances in motor function of the esophagus and aspiration, in patients suffering from obesity and diabetes in the family history.

Pregnancy and lactation

There are no adequate and strictly controlled clinical studies of safety during pregnancy has not been. Aripirazol can be used in pregnancy when the potential benefits of therapy for the mother exceeds potential risk to the fetus. It is not known whether allocated aripirazol with breast milk in humans. We do not recommend the use of aripiprazole in the period of lactation (breastfeeding). In experimental studies showed that Aripiprazole is excreted in milk in lactating rats.

Patients with hepatic insufficiency (classes A, B and C on the scale of Child-Pugh) do not want to change the dose of the drug.

Patients with renal failure may need to adjust dose.

Cautions

The tendency to suicidal thoughts and attempts are characteristic of psychosis, so during drug therapy requires careful medical supervision. The risk of developing tardive dyskinesia increases with duration of neuroleptic therapy, so if you appear on the intake of aripiprazole symptoms of tardive dyskinesia should reduce the dose or cancel the drug. After the abolition of therapy, these symptoms may temporarily worsen or even appear for the first time.

In the treatment of neuroleptic drugs, including Aripiprazole may develop CSN, which is manifested hyperpyrexia, muscle rigidity, mental disturbances and instability of the autonomic nervous system (irregular pulse and blood pressure, tachycardia, sweating, arrhythmia). In addition, sometimes there is an increase in activity of CK, mioglobinuriya (rhabdomyolysis) and acute renal failure. In the case of symptoms or unexplained fever ZNS all antipsychotics, including Aripiprazole should be abolished. Hyperglycemia, in some cases expressed and associated with ketoacidosis, which can lead to hyperosmolar coma and even death, was observed in patients receiving atypical antipsychotics. Although the relationship between the intake of atypical neuroleptics and violations of hyperglycemic type remains unclear, patients diagnosed with diabetes must regularly determine the level of glucose in the blood while taking atypical neuroleptics.

Patients who present risk factors for diabetes (obesity, diabetes, a family history), when receiving atypical neuroleptics should be the determination of glucose in the blood early in the course and periodically during treatment. In all patients taking atypical antipsychotics, need constant monitoring of symptoms of hyperglycemia (enhanced thirst, frequent urination, polyphagia, weakness). Effects on ability to drive motor vehicles, and management mechanisms like the use of other neuroleptics, with the appointment of Abilifaya patient should be warned about the dangers of working with moving machinery and driving.

Overdose

In clinical studies described cases of accidental or intentional overdose with aripiprazole single dose to 1080 mg, not accompanied by death.

Symptoms: nausea, vomiting, asthenia, diarrhea, and drowsiness. In hospitalized patients revealed no clinically significant changes in basic physiological parameters, laboratory parameters and ECG. Postmarketing experience single dose of adult patients to 450 mg of aripiprazole suggests the possible development of arrhythmias. Furthermore, the described cases of overdose of aripiprazole in children (reception to 195 mg). To potentially dangerous symptoms of overdose include extrapyramidal disorder, and transient loss of consciousness.

Treatment: supportive care, ensuring adequate airway, oxygenation, effective ventilation of the lungs and symptomatic treatment. It should be drug reactions. Immediately be initiated monitoring the performance of the heart with ECG to detect arrhythmias. Once confirmed or suspected overdose of aripiprazole should be careful medical supervision until the disappearance of all symptoms. Activated carbon (50 g), introduced by one hour after administration of aripiprazole, decreased the AUC and Cmax of aripiprazole by 51% and 41% respectively, which allows to recommend its use in overdose. Although reliable data on the use of dialysis in overdose aripiprazole no beneficial effect of this method is unlikely, because Aripiprazole does not appear kidneys unchanged and largely bound to plasma proteins.

Drug Interactions

There were no significant effects blocker histamine H2-receptor famotidine, causing strong inhibition of secretion of hydrochloric acid in the stomach, on the pharmacokinetics of aripiprazole. There are different ways of metabolism of aripiprazole, including with the participation of enzymes CYP2D6 and CYP3A4. In studies in healthy potent inhibitors of CYP2D6 (quinidine) and CYP3A4 (ketoconazole) decreases the clearance of aripiprazole when administered at 52% and 38% respectively (with simultaneous application of inhibitors of CYP3A4 and CYP2D6 should decrease the dose of aripiprazole).

Acceptance of aripiprazole 30 mg simultaneously with carbamazepine, a potent inducer of CYP3A4, was accompanied by a decrease in Cmax and AUC of aripiprazole by 68% and 73% respectively, and a decrease in Cmax and AUC of its active metabolite degidroaripiprazola by 69% and 71% respectively. We can expect similar effects and other powerful inducers of CYP3A4 and CYP2D6. In the metabolism of aripiprazole in vitro is not involved enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1, and therefore unlikely to interact with medications and other factors (eg smoking), able to inhibit or activate these enzymes.

Simultaneous reception with lithium or valproate aripiprazole at a dose of 30 mg 1 time / day had no clinically significant effect on the pharmacokinetics of aripiprazole.

In clinical studies Aripiprazole at doses of 10-30 mg / day did not affect the metabolism of substrates of CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan). Furthermore, the Aripiprazole and its major metabolite degidroaripiprazol did not alter the metabolism involving the enzyme CYP1A2 in vitro. It is not likely clinically significant effect of aripiprazole on drugs metabolized with the participation of these enzymes.

Terms and Conditions of storage

The drug should be stored out of reach of children, dry place at temperatures from 15 ° to 30 ° C.

Shelf life - 3 years.