Composition, form of production and packaging
Capsules hard gelatinous в„–4, a lid and the case of white color, with an inscription in black ink "S063"; the contents of the capsules are white or almost white powder.
1 caps.
anagrelide hydrochloride monohydrate 610 Ојg,
which corresponds to the content of anagrelide 500 Ојg
Auxiliary substances: povidone (E1201) - 3.75 mg, anhydrous lactose - 65.76 mg, lactose monohydrate - 53.74 mg, microcrystalline cellulose (E460) - 22.5 mg, crospovidone - 3 mg, magnesium stearate - 0.75 mg.
The composition of the capsule (cap and body) : gelatin - 37.87 mg, titanium dioxide (E171) - 1.13 mg.
Ink composition : shellac, ammonia solution concentrated, potassium hydroxide (E525), iron oxide black (E172).
100 pieces. - bottles of high-density polyethylene (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
The specific mechanism of action of anagrelide, leading to a decrease in platelet count is not fully understood. It has now been established that anagrelide selectively acts on platelets in vitro and in vivo.
Studies of the formation of megakaryocytes in vitro have shown that in humans, the inhibition of platelet formation caused by anagrelide is associated with a delay in the maturation of megakaryocytes, a decrease in their size and ploidy. Similar in vivo effects were found in bone marrow biopsy specimens of patients receiving the drug.
Anagrelide is an inhibitor of phosphodiesterase III of cyclic adenosine monophosphate (AMP).
Children
It is possible to use anagrelide in children with caution because of the limited experience of its use in this age group due to the rarity of the disease (see "Contraindications").
PHARMACOKINETICS
After oral ingestion of anagrelide, about 70% of the substance is absorbed in the gastrointestinal tract. When taking an empty stomach at a dose of 0.5 mg, the maximum concentration in the blood plasma is reached after 1 hour; the half-life is approximately 1.3 hours. In the dose range of 0.5 -2 mg, the pharmacokinetics of the drug are proportional to the dose.
Anagrelide is metabolized mainly by the isoenzyme CYP1A2; less than 1% of the accepted dose of anagrelide is excreted in the urine unchanged. Two metabolites of anagrelide-2-amino-5,6-dichloro-3,4-dihydroquinazoline and 3-hydroxy-anagrelide were detected. The average content of 2-amino-5,6-dichloro-3,4-dihydroquinazoline in urine is 18-35% of the accepted dose of anagrelide.
Analysis of the pharmacokinetics of anagrelide in healthy volunteers showed that eating reduces the C max of anagrelide in blood plasma by 14%, but increases the area under the concentration-time curve (AUC) by 20%. C max of the active metabolite decreases more strongly - by 29%, but the area under the "concentration-time" curve (AUC) of the metabolite does not change.
No evidence of anagrelide accumulation in blood plasma was found. Also, the effect of anagrelide on its own clearance was not revealed.
Special patient groups
Children
Data on the pharmacokinetics of anagrelide in fasting with children and adolescents with essential thrombocythemia at the age of 7-14 years indicate that the C max values ​​of anagrelide in the blood plasma and the area under the concentration-time curve (AUC) normalized for the dose and body weight , in children / adolescents is less than in adult patients. There is also a trend towards a lower level of exposure to the active metabolite. These differences may reflect a more effective metabolic clearance of the drug at a young age.
Elderly patients
Data on the pharmacokinetics of anagrelide in patients with fasting with elderly patients with essential thrombocythemia (65 to 75 years) compared with younger patients (22-50 years) suggest that the C max values ​​of anagrelide in blood plasma and the area under the concentration-time curve (AUC), they have 36% and 61%, respectively, and Cmax in blood plasma and the area under the concentration-time curve (AUC) of the active metabolite - 3-hydroxy-anagrelide - is less by 42% and 37%, respectively . These differences are probably due to a smaller local (before entering the systemic circulation) metabolism of anagrelide to 3-hydroxy-anagrelide in elderly patients.
INDICATIONS
- increased platelet count in patients with essential thrombocythemia of the high-risk group, in whom current therapy is poorly tolerated or does not reduce elevated platelet count to an acceptable level.
Patients with essential high-risk group thrombocythemia are defined as patients who have one or more of the following characteristics:
- age> 60 years;
- Platelet content> 1000 x 10 9 / l;
- presence of thrombotic hemorrhagic complications in the anamnesis.
DOSING MODE
Treatment with Agrilin should be started by a physician with experience in the treatment of essential thrombocythemia.
The recommended initial dose of anagrelide is 1 mg / day orally in 2 divided doses of 0.5 mg.
The initial dose should be taken for at least one week. After that, the dose can be gradually increased individually, until the minimum effective dose that reduces and / or maintains platelets to / below 600 x 109 / L is reached, the optimum level is between 150 x 109 / l and 400 x 109 / l. The rate of increase of the dose should not exceed 0.5 mg / day during the week, and the maximum single dose should not exceed 2.5 mg.
It should be regularly evaluated the effect of anagrelide. If the initial dose exceeds 1 mg / day, then in the first week, the platelet count should be measured every 2 days, and then at least 1 time per week until a stable maintenance dose is reached. Usually, the drop in platelet count is observed on the 14th-21st day after the start of treatment, and in most patients, a sufficient therapeutic effect is achieved and maintained with a dose of 1 to 3 mg / day.
Special patient groups
Elderly patients
The observed difference in drug pharmacokinetics in elderly and younger patients does not require correction of the initial dose or correction of the dose titration procedure until an individual optimal maintenance dose is achieved. Nevertheless, in this group of patients, serious adverse events were observed twice as often (mainly cardiovascular disorders).
Impaired renal function
Since there is currently no data on the pharmacokinetics of the drug Agrilin in patients with impaired renal function, before using Agrilin in such patients, the benefit and the possible risk of treatment should be compared.
Impaired liver function
At present, there is no data on the pharmacokinetics of the drug Agrilin in patients with impaired liver function. Nevertheless, since hepatic metabolism is the main way of clearance of the drug, it can be expected that a violation of liver function will affect this process. Therefore, anagrelide is not recommended for patients with moderate or severe impairment of liver function. Before using anagrelide in patients with mild liver dysfunction, the possible benefits and possible treatment risks should be compared.
Children
The experience of using the drug in children is limited; Anagrelide should be used in children with caution.
SIDE EFFECT
The most frequent adverse reactions were headache (frequency 14%), palpitation (9%), fluid retention in the body (6%), nausea (6%), diarrhea (5%).
The frequency of undesirable side reactions was determined as follows: very frequent (? 1/10); Frequent (from? 1/100 to <1/10); infrequent (from? 1/1000 to <1/100); rare (from? 1/10 000 to <1/1000); very rare (<1/10 000), is unknown (frequency can not be determined based on available data).
Violations from the blood and lymphatic system: frequent: anemia; infrequent: thrombocytopenia, pancytopenia, ecchymosis, bleeding.
Disorders from the metabolism and nutrition: frequent: fluid retention; infrequent: edema, weight loss; rare: weight gain.
Impaired nervous system: very frequent: headache; frequent: dizziness; infrequent: paresthesia, insomnia, depression, confusion, hypoesthesia, nervousness, dry mouth, amnesia; rare: drowsiness, impaired coordination, dysarthria, migraine.
Impaired vision: rare: visual impairment, diplopia.
Hearing disorders and labyrinthine disturbances: rare: tinnitus.
Disorders from the cardiovascular system: frequent: palpitations, tachycardia; infrequent: congestive heart failure, increased blood pressure, arrhythmia, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, syncope; rare: angina pectoris, myocardial infarction, cardiomegaly, cardiomyopathy, pericardial effusion, vasodilation, orthostatic hypotension.
Disturbances from the respiratory system, chest and mediastinal organs: infrequent: dyspnea, epistaxis, pleural effusion, pneumonia; rare: hypertension of the pulmonary artery, infiltrates in the lungs; unknown: allergic alveolitis.
Disorders from the gastrointestinal tract: often: nausea, diarrhea, abdominal pain, flatulence, vomiting; infrequently: dyspepsia, anorexia, pancreatitis, constipation, gastrointestinal bleeding, gastrointestinal upset; rarely: colitis, gastritis, bleeding gums.
Disorders from the liver and bile ducts: infrequent: increased activity of liver enzymes; unknown: hepatitis.
Disturbances from the skin and subcutaneous tissues: frequent: rash; infrequent: alopecia, discoloration, itching; rare: dry skin.
Disorders from the musculoskeletal and connective tissue: infrequent: myalgia, arthralgia, back pain.
Disorders from the genitourinary system: infrequent: impotence; rare: bedwetting, kidney failure; unknown: tubulointerstitial nephritis.
General disorders and disorders at the injection site: frequent: fatigue; infrequent: chest pain, weakness, chills, general malaise, fever; rare: asthenia, pain, flu-like syndrome.
Influence on laboratory results and instrumental studies: rare: increased concentration of creatinine in the blood.
CONTRAINDICATIONS
- Moderately severe or severe liver dysfunction;
- Moderately severe or severe renal dysfunction (creatinine clearance <50 mL / min);
- in view of the lack of clinical data on safety and efficacy, it is not recommended to use the drug in children under 7 years of age;
- hypersensitivity to anagrelide or any auxiliary component of the drug.
PREGNANCY AND LACTATION
Pregnancy
Data on the use of anagrelide in pregnant women is not enough. Studies in animals showed the presence of the drug reproductive toxicity.
Agriline is not recommended for use during pregnancy. When used during pregnancy or with the development of pregnancy during treatment with the drug, the patient should be warned about the possible risk to the fetus.
During the treatment with anagrelide, women who are capable of childbearing should use reliable means of contraception.
Lactation
It is not known whether anagrelide is excreted in breast milk. Since many drugs are excreted in breast milk, and because of the possibility of developing adverse reactions in infants, breastfeeding should be stopped during the treatment with Agrilin.
APPLICATION FOR FUNCTIONS OF THE LIVER
Since there is currently no data on the pharmacokinetics of the drug Agrilin in patients with impaired renal function, before using Agrilin in such patients, the benefit and the possible risk of treatment should be compared.
Contraindicated in moderately severe or severe renal impairment (creatinine clearance <50 mL / min).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
At present, there is no data on the pharmacokinetics of the drug Agrilin in patients with impaired liver function. Nevertheless, since hepatic metabolism is the main way of clearance of the drug, it can be expected that a violation of liver function will affect this process. Therefore, anagrelide is not recommended for patients with moderate or severe impairment of liver function. Before using anagrelide in patients with mild liver dysfunction, the possible benefits and possible treatment risks should be compared.
APPLICATION FOR CHILDREN
The experience of using the drug in children is limited; Anagrelide should be used in children with caution. Due to the lack of clinical data on safety and efficacy, it is not recommended to use the drug in children under 7 years of age.
APPLICATION IN ELDERLY PATIENTS
The observed difference in drug pharmacokinetics in elderly and younger patients does not require correction of the initial dose or correction of the dose titration procedure until an individual optimal maintenance dose is achieved. Nevertheless, in this group of patients, serious adverse events were observed twice as often (mainly cardiovascular disorders).
SPECIAL INSTRUCTIONS
Agrilin contains 53.7 mg lactose monohydrate and 65.8 mg lactose anhydrous in each capsule; this should be taken into account when prescribing the drug to patients with lactose intolerance, glucose-galactose malabsorption, congenital insufficiency of lactase.
Impaired liver function
Before using anagrelide in patients with mild liver dysfunction, the benefit and possible risk of use should be compared. The drug is not recommended for use when the activity of transaminases is increased more than 5 times higher than the upper limit of the norm.
Impaired renal function
Before using anagrelide in patients with impaired renal function, the benefit and possible risk of use should be compared.
Monitoring the clinical state of the patient
In the course of treatment, careful monitoring of the patient's clinical condition is needed, including a complete clinical blood test (hemoglobin, leukocytes, platelets), measuring the level of hepatic enzymes: alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), as well as renal function (determination of creatinine and urea concentration in the blood serum).
Platelets
The content of platelets usually rises 4 days after the abolition of Agrilin and returns to baseline after 10-14 days.
The cardiovascular system
Cases of cardiomegaly and congestive heart failure are described. In patients of any age with confirmed heart disease or suspected heart disease, anagrelide should be used with caution, and only if the possible benefit of the treatment exceeds the possible risk. Anagrelide is an inhibitor of phosphodiesterase III of cyclic adenosine monophosphate (AMP) and has a positive inotropic effect, so it is recommended that a cardiovascular examination be carried out before the start of treatment, including, if necessary, echo- and electrocardiography. During treatment, the occurrence of cardiovascular events should be monitored, which may require additional examination.
Children
The experience of using the drug in children is limited; Anagrelide should be used in children with caution.
Clinically Significant Interactions
Anagrelide is an inhibitor of phosphodiesterase III cyclic adenosine monophosphate phosphodiesterase (PDE III). It is not recommended to use anagrelide simultaneously with other phosphodiesterase III inhibitors, including milrinone, amrinone, enoximone, olprinone and cilostazol.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effect of the drug on the ability to drive and move vehicles have not been carried out. It is recommended to refrain from driving and other potentially hazardous activities requiring increased attention and speed of psychomotor reactions, as the drug may cause dizziness and other side effects that may affect these abilities.
OVERDOSE
There are few reports of cases of intentional overagain- tation of anagrelide. Symptoms included sinus tachycardia and vomiting and disappeared with symptomatic therapy.
Specific antidote is unknown. In case of overdose, the patient's clinical condition should be carefully monitored, including the measurement of platelet count for the detection of thrombocytopenia. Depending on the situation, the drug should be withdrawn or the dose should be reduced to restore normal platelet count.
In doses exceeding recommended, the drug Agrilin sometimes caused a drop in blood pressure. A single dose of 5 mg can lead to a reduction in blood pressure, usually accompanied by dizziness.
DRUG INTERACTION
At the moment, there is insufficient information on the pharmacokinetic or pharmacodynamic interaction of anagrilide with other drugs.
The effect of other drugs on anagrelide
• Anagrelide is metabolized mainly by the CYP1A2 isoenzyme. It is known that some drugs, including fluvoxamine and omeprazole, inhibit the activity of the isoenzyme CYP1A2, so such drugs theoretically can adversely affect the clearance of anagrelide.
• Human interaction studies in vivo have shown that warfarin and digoxin do not affect the pharmacokinetics of anagrelide.
Effect of anagrelide on other drugs
• Anagrelide exhibits the properties of a weak inhibitor and the CYP1A2 isoenzyme may theoretically interact with other drugs, a clearance which is carried on the same mechanism, for example, with theophylline.
• Anagrelide is an inhibitor of phosphodiesterase III (PDE III). It can enhance the effects of the drugs having the same action, including inotropes milrinone, amrinone, enoximone, and olprinona cilostazol.
• interaction studies in humans invivopokazali that anagrelide does not affect the pharmacokinetics of warfarin and digoxin.
• At doses recommended for the treatment of essential thrombocythemia, anagrelide could theoretically enhance the effects of other drugs which depress platelet function or altering, e.g., acetylsalicylic acid.
• clinical study interactions in healthy volunteers showed that multiple dose anagrelide 1 mg 1 time per day together with acetylsalicylic acid, 75 mg 1 time per day may enhance these drugs caused by platelet aggregation inhibition in comparison with reception of only acetylsalicylic acid. Therefore, due to the lack of relevant data for patients with essential thrombocythemia, before the start of the joint use of these drugs should assess the potential risks, especially for patients with high risk of bleeding.
• In some patients, anagrelide may cause disorder of bowel function and can interfere with the absorption of oral hormonal contraceptives.
Interaction with food
• Eating slows down the absorption of anagrelide but does not significantly affect the level of systemic exposure.
• The impact of receiving food on the bioavailability of anagrelide is not considered clinically significant.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
At temperatures above 25 В° C. Keep out of the reach of children. Shelf life - 4 years.
