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

Active substanceAnagrelideAnagrelide

Similar drugsTo uncover

Agrilin®

capsules inwards

Shayer Pharmaceuticals Ayerland Co., Ltd. Ireland

Thromboreductin®

capsules inwards

REGRADE, LTD. Russia

Dosage form: & nbspcapsules

Composition:

Active substance:

Anagrelide hydrochloride monohydrate 0.61 mg, calculated as anagrelide 0.5 mg.

Excipients:

Povidone (E1201) - 3.75 mg, anhydrous lactose - 65.76 mg, lactose monohydrate - 53.74 mg, microcrystalline cellulose (E460) - 22.50 mg, crospovidone 3.00 mg, magnesium stearate 0.75 mg.

Capsule composition (cap and body):

Gelatin - 37.87 mg, titanium dioxide (E171) 1.13 mg.

Composition of ink:

Shellac, ammonia solution concentrated, potassium hydroxide (E525), iron oxide black (E172).

Description:

Hard gelatin capsules No. 4, lid and body white, with an inscription in black ink "S063".

The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:Thrombocythemia is an essential treatment agent

ATX: & nbsp

L.01.X.X.35 Anagrelide

Pharmacodynamics:

The specific mechanism of action of anagrelide, leading to a decrease in platelet count is not fully understood. At the moment it is 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).

Effect on heart rate (heart rate) and QTc interval

In the course of a double-blind, randomized, placebo-and actively controlled, cross-sectional study of healthy men and women, the effect of two different doses of anagrelide (volunteers anagrelide in the form of doses of 0.5 mg or 2.5 mg) at heart rate and QTc interval.

A dose-dependent increase in heart rate was observed during the first 12 hours, the maximum increase in heart rate approximately corresponded to the time to reach the maximum concentration of anagrelide in blood plasma (CmOh). The maximum change in heart rate was observed two hours after admission and was +7.8 and +29.1 beats per minute for doses of 0.5 mg and 2.5 mg, respectively. A temporary visible increase in the QTc interval occurred with both doses taken simultaneously with an increase in heart rate, the maximum change in QTcF (Fridericia correction) was +5.0 msec two hours after taking 0.5 mg and +10.0 msec one hour after taking 2 , 5 mg of the preparation.The data indicate that an increase in QTc may be due to the physiological effect of increased heart rate and QT-RR hysteresis, rather than a direct effect on repolarization.

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 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.

An analysis of the pharmacokinetics of anagrelide in healthy volunteers showed that eating reduces the maximum concentration (C_Max) of anagrelide in blood plasma by 14%, but increases the area under the "concentration-time" curve (AUC) on 20%. Maximum concentration (FROM_Max) the active metabolite decreases more strongly - by 29%, but the area under the curve "concentration - time" (AUC) 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 when administered on an empty stomach by children and adolescents with essential thrombocythemia at the age of 7-14 years indicate that the values of maximum concentration (FROM_Max)anagrelide in the blood plasma and the area under the curve "concentration - time" (AUC), normalized by 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 fasting with elderly patients with essential thrombocythemia (65 to 75 years) compared with younger patients (22-50 years) indicate that the maximum concentration (C_Max) anagrelide in blood plasma and area under the curve "concentration - time" (AUC) they have 36% and 61%, respectively, and the maximum concentration (FROM_Max) in the blood plasma and the area under the curve "concentration - time" (AUC) of the active metabolite - 3-hydroxy-anagrelide - 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:

Agrilin® is designed to reduce the elevated platelet count in patients with essential high-risk group thrombocythemia who do not tolerate current therapy or reduce the elevated platelet count to an acceptable level.

Patients with essential high-risk group thrombocythemia are defined as having one or more of the following characteristics:

- age> 60 years;

- platelet count> 1000 x 10%;

- presence of thrombotic hemorrhagic complications in the anamnesis.

Contraindications:

- Hypersensitivity to anagrelide or any auxiliary component of the drug.

- Moderate or severe impairment of liver function.

- Moderate or severe renal dysfunction (creatinine clearance <50 ml / min).

- Due to the lack of clinical data on safety and effectiveness of the drug is not recommended in children under 7 years.

Carefully:

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.

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.

Agrilin® 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 have reliable means of contraception.

Lactation

It is not known whether anagrelide with 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®.

Dosing and Administration:

Treatment with Agrilin® should be initiated 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 1-3 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 Agrilin® in patients with impaired renal function, before using Agrilin®, such patients should compare the benefits and possible treatment risks.

Impaired liver function

At present, there is no data on the pharmacokinetics of Agrilin® in patients with impaired hepatic 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 It 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 effects:

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 adverse reactions was determined as follows: very frequent (> 1/10); frequent (from > 1/100 to <1/10); infrequent > 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 of 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.

Disturbances from the nervous system

very frequent: headache; frequent: dizziness;

infrequent: paresthesia, insomnia, depression, confusion, hypoesthesia, nervousness, dry mouth, amnesia;

rare: drowsiness, impaired coordination, dysarthria, migraine.

Vision disorders

rare: impaired vision, diplopia.

Hearing disorders and labyrinthine disorders

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, unknown: polymorphic ventricular pirouette tachycardia.

Disturbances from the respiratory system, chest and mediastinal organs

infrequent: shortness of breath, nosebleeds, 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.

Disturbances from the liver and bile ducts

infrequent: increased levels of hepatic enzymes;

unknown: hepatitis.

Disturbances from the skin and subcutaneous tissues

frequent: rash;

infrequent: alopecia, discoloration, itching;

rare: dry skin.

Disturbances from musculoskeletal and connective tissue

infrequent: myalgia, arthralgia, back pain.

Disorders from the genitourinary system

infrequent: impotence; rare: bedwetting, renal failure;

unknown: tubulointerstitial nephritis.

General disorders and disorders at the site of administration

frequent: fatigue;

infrequent: chest pain, weakness, chills, general malaise, fever;

rare: asthenia, pain, flu-like syndrome.

Impact on laboratory results and instrumental research

rare: increased levels of creatinine in the blood.

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. AT depending on the situation, the drug should be withdrawn or the dose should be reduced to restore normal platelet count.

In doses exceeding the recommended levels, the Agrilin® preparation 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.

Interaction:

At the moment, there is insufficient information on the pharmacokinetic or pharmacodynamic interaction of anagrelide with other drugs.

The effect of other drugs on anagrelide

Anagrelide is metabolized mainly by the isoenzyme CYP1A2. It is known that some drugs, including fluvoxamine and omeprazole, suppress the activity of the isoenzyme CYP1A2, therefore such drugs can theoretically 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 of the isoenzyme CYP1A2 and can theoretically interact with other drugs, the clearance of which is carried out by the same mechanism, for example, with theophylline.

Anagrelide is an inhibitor of phosphodiesterase III (PDE III). It can enhance the effects of drugs that have the same effect, including inotropes of milrinone, amrinone, enoximone, olprinone, cilostazol.

Human interaction studies in vivo have shown that anagrelide does not affect the pharmacokinetics of warfarin and digoxin.

In the doses recommended for the treatment of essential thrombocythemia, anagrelide can enhance the effects of other drugs that depress or modify platelets, such as acetylsalicylic acid.

The study of clinical interaction in healthy volunteers showed,that repeated reception of anagrelide in a dose of 1 mg 1 time a day together with acetylsalicylic acid 75 mg once a day can strengthen the inhibition caused by these preparations aggregation of thrombocytes in comparison with the reception of acetylsalicylic acid.

There are reports of the development of severe bleeding with the simultaneous use of anagrelide and acetylsalicylic acid. Therefore, due to the lack of appropriate data for patients with essential thrombocythemia, before starting the joint use of these drugs, possible risk should be assessed, especially for patients with a high risk of bleeding.

In some patients anagrelide can disrupt the bowel function and can disrupt the absorption of oral hormonal of contraceptives.

Interaction with food

Eating slows the absorption of anagrelide, but does not significantly affect the level of its systemic effect. The effect of food intake on the bioavailability of anagrelide is not considered clinically significant.

Special instructions:

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 with an increase in the level of transaminases 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 necessary, including a complete clinical blood test (hemoglobin, leukocytes, platelets), liver function (ALT) and aspartate aminotransferase (ACT) level, kidney function (creatinine and urea concentration in blood serum) and the content of electrolytes (potassium, magnesium and calcium).

Platelets

Platelet content 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. Patients of any age with confirmed heart disease or suspected of heart disease anagrelide should be used with caution, and only if the possible benefits of treatment exceed the possible risk. Anagrelide is an inhibitor of phosphodiesterase III of cyclic adenosine monophosphate (AMP) and has a positive inotropic and chronotropic action, so it is recommended that all patients undergo a cardiovascular examination, including echo- and electrocardiography if necessary. During treatment, the occurrence of cardiovascular events should be monitored, which may require additional examination.

Studies have shown that anagrelide increases the heart rate, resulting in a visible increase in the QTc interval on the electrocardiogram of healthy volunteers. The clinical significance of this effect is unknown (see Pharmacodynamics).

Caution should be applied anagrelide in patients who have risk factors for prolonging the QT interval, such as congenital QT prolongation syndrome, acquired QTc prolongation in history, taking medications that can induce prolongation of the QTc interval and hypokalemia.

Caution should be given anagrelide patients who may have an elevated maximum concentration of anagrelide and its active metabolite, 3-hydroxyanagrelide, in plasma, particularly in liver failure or in taking CYP1A2 isoenzyme inhibitors (see Table 1).Interaction with other drugs).

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 apply anagrelide simultaneously with other phosphodiesterase III inhibitors, including milrinone, amrinone, enoximone, olprinone and cilostazol.

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

Studies on the effect of the drug on the ability to manage car and moving mechanisms were not carried out.

It is recommended to refrain from driving and other potentially dangerous activities, requiring increased concentration and speed psychomotor reactions, since the drug can cause dizziness and other side effects that may affect these abilities.

Form release / dosage:

Capsules 0.5 mg.

Packaging:

For 100 capsules in a bottle of high-density polyethylene with a dehumidifier and a system of protection from opening by children.

1 bottle with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:4 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001824

Date of registration:07.09.2012/13.07.2015

Expiration Date:07.09.2017

The owner of the registration certificate:Shayer Pharmaceuticals Ayerland Co., Ltd.Shayer Pharmaceuticals Ayerland Co., Ltd. Ireland

Manufacturer: & nbsp

DSM Pharmaceuticals, Inc. USA

Representation: & nbspSchayer Pharmaceutical Contracts LimitedSchayer Pharmaceutical Contracts LimitedRussia

Information update date: & nbsp23.01.2017

Illustrated instructions

Instructions

Agrilin® (Agrylin®)