It is assumed that the therapeutic effect of aripiprazole in schizophrenia is caused by a combination of partial agonist activity toward D2-dopamine and serotonin 5HT1A receptors and antagonistic activity against serotonin-5HT2A receptors.
Aripiprazole possesses high affinity in vitro for D2- and D3-dopamine receptor-5NT1a- and 5HT2A serotonin receptors and moderate affinity for the D1-dopamine, and 5NT2s- 5NT7-serotonin, α1-adrenoceptors and histamine H1 receptors.
Aripiprazole is also characterized by a moderate affinity for serotonin reuptake sites and the lack of affinity for muscarinic. Aripiprazole in animal experiments showed antagonism of dopaminergic hyperactivity and agonism against dopaminergic hypoactivity. Some of the clinical effects of aripiprazole may be explained by interactions with other receptors in addition to dopamine and serotonin.
The average T1 / 2 aripiprazole is approximately 75 hours. Css dostigaetsyacherez 14 days. Drug accumulation after repeated admission predictable. Pharmacokinetics of aripiprazole in an equilibrium state
proportional to dose. There was no daily fluctuations of distribution of aripiprazole and its metabolite degidroaripiprazola. It is established that the main metabolite of the drug in human plasma, degidroaripiprazol has the same affinity for dopamine D2-like aripiprazole.
Aripiprazole is rapidly absorbed after oral administration, wherein the Cmax of aripiprazole plasma achieved in 3-5 hours.
Zilaksera drug bioavailability upon oral administration is 87%. Eating does not affect the bioavailability of aripiprazole.
Aripiprazole is widely distributed in tissues, and the apparent Vd is 4.9 L / kg, indicating that vigorous extravascular distribution. At therapeutic concentrations greater than 99% of aripiprazole binds to serum proteins, mainly albumin.
Aripiprazole does not affect the pharmacokinetics and pharmacodynamics of warfarin, that is, does not displace warfarin from binding with blood proteins.
Aripiprazole is subject to first-pass metabolism only minimally. Aripiprazole is metabolized in the liver in three ways: by the dehydrogenation, hydroxylation and N-dealkylation. According to in vitro data, dehydrogenation and hydroxylation of aripiprazole occurs under the action of isozymes CYP3A4 and CYP2D6, and N-dealkylation catalyzed isoenzyme CYP3A4.
When equilibrium AUC degidroaripiprazola state is about 40% of aripiprazole AUC in plasma.
After a single dose of 14C-labeled aripiprazole about 27% and 60% of the radioactivity is determined in urine and feces, respectively. Less than 1% of unchanged aripiprazole determined in urine and approximately 18% of the dose is displayed in unchanged form via the intestine in bile. Aripiprazole total clearance is 0.7 ml / min / kg, mainly due to excretion by the liver.
Krka dd AO Novo mesto, Slovenia
The active ingredient is:
Aripiprazole 10 mg
Schizophrenia: acute attacks and supportive therapy; bipolar disorder type 1: manic episodes and maintenance therapy to prevent recurrence in patients with bipolar disorder type I, recently undergone manic or mixed episode.
- hereditary galactosemia, lactase deficiency, glucose-galactose malabsorption;
- the age of 18 years (effectiveness and safety have not been established);
- hypersensitivity to aripiprazole or other ingredients.
Precautions: cardiovascular disease (ischemic heart disease or myocardial infarction, chronic heart failure or a history of conduction disorders); cerebrovascular diseases; conditions that predispose to the development of hypotension (dehydration, hypovolemia, antihypertensive drug therapy) due to the possibility of orthostatic hypotension or hypertension, including progressive or malignant; hereditary syndrome elongated QT interval on the ECG; epilepsy, seizures, or diseases in which the possible convulsions, diabetes, or the presence of risk factors for diabetes (obesity, diabetes mellitus, family history); Patients with an increased risk of aspiration pneumonia because of the risk of disturbances in motor function of the esophagus and aspiration; elderly patients; severe hepatic impairment; Patients with a high risk of suicide (psychotic disorders, bipolar disorders), among persons aged 18-24 years due to the risk of suicidal behavior, pregnancy, the risk of hyperthermia (intense exercise, overheating, taking anticholinergics medicines, dehydration).
With the cardiovascular system: often – orthostatic hypotension, tachycardia; infrequently – bradycardia, palpitations, myocardial infarction, lengthening the interval QT, heart failure, hemorrhage, atrial fibrillation, heart failure, AV-block, myocardial ischemia, deep vein thrombosis, phlebitis, arrythmia, decreased blood pressure; rarely – vasovagal syndrome, expansion of borders of the heart, atrial flutter, thrombophlebitis, intracranial hemorrhage, cerebral ischemia; very rarely – swoon.
From the digestive system: very often – nausea, anorexia; often – dryness of the nasal mucosa, indigestion, feeling of heaviness in the stomach, vomiting, constipation; Infrequent – increased appetite, gastroenteritis, difficulty swallowing, flatulence, gastritis, dental caries, gingivitis, hemorrhoids, gastroesophageal reflux disease, gastrointestinal bleeding, periodontal abscess, swollen tongue, faecal incontinence, colitis, rectal hemorrhage, stomatitis, ulceration of the mucous membrane oral, cholecystitis, fekaloma, candidiasis of the oral mucosa, cholelithiasis, belching, gastric ulcer; rarely – esophagitis, bleeding gums, glossitis, melena, gastrointestinal hemorrhage, ulcer 12 duodenal ulcer, cheilitis, hepatitis, increased liver size, pancreatitis, intestinal perforation, hematemesis; very rarely – increased activity of ALT and ACT, jaundice, dysphagia.
Immune system: very rare – allergic reactions: anaphylaxis, angioedema, laryngospasm, pruritus, urticaria.
On the part of the musculoskeletal system: often – muscle stiffness, myalgia, muscle cramps; infrequently – ossalgia, arthralgia, myasthenia gravis, arthritis, arthrosis, muscle weakness, muscle spasms, bursitis; very rarely – increasing the activity of creatine phosphokinase (CPK), rhabdomyolysis, tendonitis, tenobursit, rheumatoid arthritis, myopathy;
From the nervous system: very often – insomnia, somnolence, akathisia; often – dizziness, tremor, extrapyramidal syndrome, agitation, depression, nervousness, increased salivation, hostility, suicidal ideation, delusions, unsteady gait, confusion, resistance to passive movement execution (gear syndrome), sedation; infrequently – dystonia, muscle twitching, reduced concentration, paresthesia, tremor of limbs, impotence, bradykinesia, reduced / increased libido, panic reactions, apathy, dyskinesia, memory loss, stupor, amnesia, stroke, hyperactivity, depersonalization, myoclonus, depressed mood, hyperreflexia, slowing of mental function, increased sensitivity to stimuli, impaired oculomotor reaction; rarely – delirium, euphoria, bukkoglossalny syndrome, akinesia, depression of consciousness down to a loss of consciousness, hyporeflexia, intrusive thoughts, neuroleptic malignant syndrome; very rarely – a speech disorder.
From respiratory system: often – shortness of breath, pneumonia; rarely – bronchospasm, epistaxis, hiccup, laryngitis; rare – hemoptysis, aspiration pneumonia, increased sputum production, dryness of nasal mucosa, pulmonary edema, pulmonary embolism, hypoxia, respiratory insufficiency, apnea.
For the skin: often – dry skin, itching, increased sweating, skin ulceration; infrequently – acne, vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea; rarely – maculopapular rash, exfoliative dermatitis, urticaria.
From the senses: common – conjunctivitis, ear pain; Infrequent – dry eyes, eye pain, tinnitus, otitis media, cataracts, loss of taste, blepharitis; rarely – increased lacrimation, frequent blinking, otitis externa, amblyopia, deafness, diplopia, intraocular hemorrhage, photophobia.
With the genitourinary system: often – urinary incontinence; infrequently – cystitis, urinary frequency, Leucorrhœa, urinary retention, hematuria, dysuria, amenorrhea, premature ejaculation, vaginal bleeding, vaginal candidiasis, renal insufficiency, uterine bleeding, menorrhagia, albuminuria, nocturia, polyuria, frequent urination; rarely – pain in the breast, cervicitis, galactorrhea, anorgasmia, burning of the external genitalia, glycosuria, gynecomastia, nephrolithiasis, painful erection; very rarely – priapism.
From a metabolism: often – weight loss; infrequently – dehydration, edema, hypercholesterolemia, hyperlipidemia, hyperglycemia, hypokalemia, diabetes, thirst, increased blood urea, hyponatremia, iron deficiency anemia, hypercreatininemia, hyperbilirubinemia, increasing activity of lactate dehydrogenase (LDH), obesity, elevated alkaline phosphatase (ALP); rarely – hyperkalemia, gout, hypernatremia, cyanosis, acidification of urine, hypoglycemia;
Other: often – flu-like symptoms, peripheral edema, pain in the chest, in the neck; rare – swelling of the face, malaise, photosensitivity, pain in the jaw, fever, stiffness of the jaw, the tension in the chest; seldom – a sore throat, stiffness, back pain, heaviness in the head, candidiasis, stiffness in the neck, Mendelson’s syndrome, heat stroke.
How to accept, acceptance rate and dosage
Inside, 1 times a day, regardless of the meal.
The starting dose of 10-15 mg 1 time per day. Maintenance dose – 15 mg / day.
In clinical studies demonstrated the efficacy of the drug in doses of 10 to 30 mg / day.
The maximum daily dose – 30 mg / day.
Manic episodes in bipolar disorder
The starting dose of 15-30 mg / day.
If necessary, correction is performed with a dose of at least 24 hours. The drug efficacy demonstrated in clinical studies at doses of 15-30 mg / day with manic episodes, when administered within 3-12 weeks. Safety doses above 30 mg / day in clinical trials have not been evaluated. When observed for 6 months and more, for 17 months for patients with bipolar disorder type 1 borne manic or mixed episode, who observed stabilization symptoms aripiprazole (15 mg / day or 30 mg / day) – favorable set the effect of such maintenance therapy. patients should be examined periodically to determine whether to continue the maintenance therapy.
Renal failure and hepatic failure (class A and B according to the classification Child-Pugh) – drug dose adjustment is required. Severe hepatic failure (class C Child-Pugh classification) – it is recommended to choose carefully the dose used with caution and the maximum daily dose of 30 mg.
Experience with the drug in patients older than 65 years is limited. Given the great sensitivity of this patient population and the presence of disturbing clinical factors, treatment should be started with lower doses.
At a temperature of not higher than 30 ° C, in the original package
Pregnancy and lactation
There are no adequate and well-controlled studies of aripiprazole in pregnant women have been conducted. It is recommended to inform the doctor about becoming pregnant or planning.
Zilaksera drug may be taken during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.
During drug treatment Zilaksera breastfeeding should be discontinued.
Symptoms: inhibition of consciousness of varying severity, up to coma, nausea, vomiting, fatigue, diarrhea, drowsiness. In hospitalized patients found no clinically significant changes in vital signs, laboratory parameters and indicators on the electrocardiogram (ECG). Post-marketing experience in adult patients receiving a single 450 mg aripiprazole suggests the possible development tachycardia. Moreover, cases are described random aripiprazole in children (reception to 195 mg). Potentially dangerous symptoms of overdose include extrapyramidal, convulsive, dystonic, cardiovascular (QT prolongation on the ECG, atrial fibrillation) disorders and transient loss of consciousness.
Treatment: supportive care, ensuring adequate airway patency, oxygen therapy, an effective ventilation and symptomatic treatment. It will be appreciated drug reactions. Immediately should be started monitoring indicators of the heart with the registration of ECG to detect arrhythmias. After confirmed or suspected overdose of aripiprazole requires careful medical supervision until the disappearance of all symptoms.
Activated charcoal (50 g) inputted after 1 h after administration of aripiprazole reduced AUC and Cmax aripiprazole 51 and 41%, respectively, which allows to recommend its use in overdose.
Although accurate data on the use of dialysis in overdose aripiprazole no beneficial effect of this method is unlikely, since aripiprazole hardly excreted by the kidneys in unchanged form and largely bound to plasma proteins.