Agrylin^® (Capsules) Instructions for Use

ATC Code

L01XX35 (Anagrelide)

Active Substance

Anagrelide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug for the treatment of thrombocythemia

Pharmacotherapeutic Group

Other antineoplastic drugs

Pharmacological Action

The specific mechanism of action of anagrelide leading to a reduction in platelet count has not been fully elucidated. It is currently established that Anagrelide acts selectively on platelets in vitro and in vivo.

Studies of megakaryocyte formation in vitro have shown that in humans, the inhibition of platelet formation caused by anagrelide is associated with delayed maturation of megakaryocytes, a reduction in their size and ploidy. Similar effects in vivo have been found in bone marrow biopsy samples from patients treated with the drug.

Anagrelide is an inhibitor of cyclic adenosine monophosphate (AMP) phosphodiesterase III.

Children

Anagrelide may be used in children with caution due to limited experience with its use in this age group because of the rarity of the disease (see “Contraindications”).

Pharmacokinetics

After oral administration of anagrelide, approximately 70% of the substance is absorbed in the gastrointestinal tract. When a 0.5 mg dose is taken on an empty stomach, the maximum plasma concentration 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 dose-proportional.

Anagrelide is metabolized mainly by the CYP1A2 isoenzyme; less than 1% of the administered anagrelide dose is excreted unchanged in the urine. Two metabolites of anagrelide have been identified: 2-amino-5,6-dichloro-3,4-dihydroquinazoline and 3-hydroxy-Anagrelide. The mean urinary content of 2-amino-5,6-dichloro-3,4-dihydroquinazoline is 18 – 35% of the administered anagrelide dose.

Analysis of the pharmacokinetics of anagrelide in healthy volunteers showed that food intake reduces the C_max of anagrelide in plasma by 14%, but increases the area under the concentration-time curve (AUC) by 20%. The C_max of the active metabolite is reduced more strongly – by 29%, but the area under the concentration-time curve (AUC) of the metabolite does not change.

No signs of accumulation of anagrelide in plasma were found. No effect of anagrelide on its own clearance was identified.

Special patient groups

Children

Data on the pharmacokinetics of anagrelide taken on an empty stomach by children and adolescents with essential thrombocythemia aged 7-14 years indicate that the dose- and body weight-normalized values of anagrelide C_max in plasma and the area under the concentration-time curve (AUC) are lower in children/adolescents than in adult patients. A trend towards lower exposure to the active metabolite was also identified. These differences may reflect more efficient metabolic clearance of the drug at a young age.

Elderly patients

Data on the pharmacokinetics of anagrelide taken on an empty stomach by elderly patients with essential thrombocythemia (65 – 75 years) compared to younger patients (22 – 50 years) indicate that their anagrelide plasma C_max and area under the concentration-time curve (AUC) values are higher by 36% and 61%, respectively, while the plasma C_max and area under the concentration-time curve (AUC) of the active metabolite, 3-hydroxy-anagrelide, are lower by 42% and 37%, respectively. These differences are likely due to reduced local (prior to entering the systemic circulation) metabolism of anagrelide to 3-hydroxy-anagrelide in elderly patients.

Indications

• Elevated platelet count in high-risk patients with essential thrombocythemia in whom current therapy is poorly tolerated or does not reduce the elevated platelet count to an acceptable level.

High-risk patients with essential thrombocythemia are defined as patients having one or more of the following characteristics:

• Age > 60 years;
• Platelet count > 1000 x 10⁹/L;
• History of thrombohemorrhagic complications.

ICD codes

Dosage Regimen

Capsules

Treatment with Agrylin^® should be initiated by a physician experienced in the treatment of essential thrombocythemia.

The recommended initial dose of anagrelide is 1 mg/day orally in two divided doses of 0.5 mg each.

The initial dose should be taken for at least one week. After this, the dose can be gradually increased individually to achieve the minimum effective dose that reduces and/or maintains the platelet count to/at a level below 600 x 10⁹/L, with the optimal level being between 150 x 10⁹/L and 400 x 10⁹/L. The rate of dose increase should not exceed 0.5 mg/day per week, and the maximum single dose should not exceed 2.5 mg.

The effect of anagrelide should be regularly assessed. If the initial dose exceeds 1 mg/day, the platelet count should be measured every 2 days during the first week, and then at least once a week until a stable maintenance dose is achieved. A decrease in platelet count is usually observed on days 14 – 21 after the start of treatment, and in most patients, an adequate therapeutic effect is achieved and maintained at a drug dose of 1 – 3 mg/day.

Special patient groups

Elderly patients

The observed difference in the pharmacokinetics of the drug between elderly and younger patients does not require adjustment of the initial dose or adjustment of the dose titration procedure to achieve an individual optimal maintenance dose. However, serious adverse events were observed twice as often in this patient group (mainly cardiovascular disorders occurred).

Renal impairment

Since there are currently no data on the pharmacokinetics of Agrylin^® in patients with renal impairment, the benefit and possible risk of treatment should be weighed before using Agrylin^® in such patients.

Hepatic impairment

There are currently no data on the pharmacokinetics of Agrylin^® in patients with hepatic impairment. However, since hepatic metabolism is the main route of clearance of the drug, it can be expected that hepatic impairment will affect this process. Therefore, Anagrelide is not recommended for patients with moderate or severe hepatic impairment. Before using anagrelide in patients with mild hepatic impairment, the potential benefit and possible risk of treatment should be weighed.

Children

Experience with the drug in children is limited; Anagrelide should be used in children with caution.

Adverse Reactions

The most common undesirable side reactions were: headache (frequency 14%), palpitations (9%), fluid retention (6%), nausea (6%), diarrhea (5%).

The frequency of undesirable side reactions was defined as follows: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10,000 to < 1/1000); very rare (< 1/10,000), unknown (frequency cannot be estimated from the available data).

Blood and lymphatic system disorders common: anemia; uncommon: thrombocytopenia, pancytopenia, ecchymosis, bleeding.

Metabolism and nutrition disorders common: fluid retention; uncommon: edema, weight decreased; rare: weight increased.

Nervous system disorders: very common: headache; common: dizziness; uncommon: paresthesia, insomnia, depression, confusion, hypoesthesia, nervousness, dry mouth, amnesia; rare: somnolence, coordination abnormal, dysarthria, migraine.

Eye disorders rare: vision blurred, diplopia.

Ear and labyrinth disorders rare: tinnitus.

Cardiac disorders common: palpitations, tachycardia; uncommon: congestive heart failure, hypertension, arrhythmia, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, syncope; rare: angina pectoris, myocardial infarction, cardiomegaly, cardiomyopathy, pericardial effusion, vasodilation, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon: dyspnea, epistaxis, pleural effusion, pneumonia; rare: pulmonary artery hypertension, pulmonary infiltrates; unknown: allergic alveolitis.

Gastrointestinal disorders common: nausea, diarrhea, abdominal pain, flatulence, vomiting; uncommon: dyspepsia, anorexia, pancreatitis, constipation, gastrointestinal hemorrhage, gastrointestinal disorder; rare: colitis, gastritis, gingival bleeding.

Hepatobiliary disorders uncommon: increased hepatic enzyme levels; unknown: hepatitis.

Skin and subcutaneous tissue disorders common: rash; uncommon: alopecia, skin discoloration, pruritus; rare: dry skin.

Musculoskeletal and connective tissue disorders uncommon: myalgia, arthralgia, back pain.

Renal and urinary disorders uncommon: impotence; rare: enuresis, renal failure; unknown: tubulointerstitial nephritis.

General disorders and administration site conditions common: fatigue; uncommon: chest pain, asthenia, chills, malaise, pyrexia; rare: asthenia, pain, influenza-like illness.

Investigations rare: blood creatinine increased.

Contraindications

• Moderate or severe hepatic impairment;
• Moderate or severe renal impairment (creatinine clearance < 50 ml/min);
• Due to insufficient clinical data on safety and efficacy, the use of the drug in children under 7 years of age is not recommended;
• Hypersensitivity to anagrelide or any excipient of the drug.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of anagrelide in pregnant women are insufficient. Animal studies have shown reproductive toxicity of the drug.

Agrylin^® is not recommended for use during pregnancy. If used during pregnancy or if pregnancy occurs during treatment with the drug, the patient should be warned of the potential risk to the fetus.

Women of childbearing potential should use reliable contraception during treatment with anagrelide.

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 adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with Agrylin^®.

Use in Hepatic Impairment

There are currently no data on the pharmacokinetics of Agrylin^® in patients with hepatic impairment. However, since hepatic metabolism is the main route of clearance of the drug, it can be expected that hepatic impairment will affect this process. Therefore, Anagrelide is not recommended for patients with moderate or severe hepatic impairment. Before using anagrelide in patients with mild hepatic impairment, the potential benefit and possible risk of treatment should be weighed.

Use in Renal Impairment

Since there are currently no data on the pharmacokinetics of Agrylin^® in patients with renal impairment, the benefit and possible risk of treatment should be weighed before using Agrylin^® in such patients.

Contraindicated in moderate or severe renal impairment (creatinine clearance < 50 ml/min).

Pediatric Use

Experience with the drug in children is limited; Anagrelide should be used in children with caution. Due to insufficient clinical data on safety and efficacy, the use of the drug in children under 7 years of age is not recommended.

Geriatric Use

The observed difference in the pharmacokinetics of the drug between elderly and younger patients does not require adjustment of the initial dose or adjustment of the dose titration procedure to achieve an individual optimal maintenance dose. However, serious adverse events were observed twice as often in this patient group (mainly cardiovascular disorders occurred).

Special Precautions

Agrylin^® contains 53.7 mg of lactose monohydrate and 65.8 mg of anhydrous lactose in each capsule; this should be taken into account when prescribing the drug to patients with lactose intolerance, glucose-galactose malabsorption, or congenital lactase deficiency.

Hepatic impairment

Before using anagrelide in patients with mild hepatic impairment, the benefit and possible risk of use should be weighed. The drug is not recommended for use when transaminase activity is more than 5 times the upper limit of normal.

Renal impairment

Before using anagrelide in patients with renal impairment, the benefit and possible risk of use should be weighed.

Patient monitoring

During treatment, careful monitoring of the patient’s clinical condition is necessary, including a complete blood count (hemoglobin, leukocytes, platelets), measurement of liver enzyme levels: ALT and AST, as well as assessment of renal function (determination of serum creatinine and urea concentrations).

Platelets

The platelet count usually increases 4 days after discontinuation of Agrylin^® and returns to the baseline level within 10 – 14 days.

Cardiovascular system

Cases of cardiomegaly and congestive heart failure have been reported. In patients of any age with confirmed heart disease or suspected heart disease, Anagrelide should be used with caution, and only if the potential benefit of treatment outweighs the possible risk. Anagrelide is an inhibitor of cyclic adenosine monophosphate (AMP) phosphodiesterase III and has a positive inotropic effect; therefore, it is recommended to conduct a cardiovascular examination before starting treatment, including, if necessary, echocardiography and electrocardiography. During treatment, the occurrence of cardiovascular events should be monitored, which may require additional examination.

Children

Experience with the drug in children is limited; Anagrelide should be used in children with caution.

Clinically significant interactions

Anagrelide is an inhibitor of cyclic adenosine monophosphate phosphodiesterase III (PDE III). The use of Anagrelide concurrently with other phosphodiesterase III inhibitors, including milrinone, amrinone, enoximone, olprinone, and cilostazol, is not recommended.

Effect on ability to drive and use machines

Studies on the effect of the drug on the ability to drive a car and operate machinery have not been conducted. It is recommended to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as the drug may cause dizziness and other side effects that may affect these abilities.

Overdose

There are a small number of reports of intentional anagrelide overdose. Symptoms included sinus tachycardia and vomiting and resolved with symptomatic therapy.

A specific antidote is unknown. In case of overdose, the patient’s clinical condition should be carefully monitored, including measurement of platelet count to detect thrombocytopenia. Depending on the situation, the drug should be discontinued or the dose should be reduced until normal platelet counts are restored.

At doses exceeding the recommended ones, Agrylin^® has sometimes caused a decrease in blood pressure. A single dose of 5 mg may lead to a decrease in blood pressure, usually accompanied by dizziness.

Drug Interactions

There is currently insufficient information regarding the pharmacokinetic or pharmacodynamic interaction of anagrelide with other medicinal products.

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 CYP1A2 isoenzyme, so such drugs could theoretically adversely affect the clearance of anagrelide.

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

Effect of anagrelide on other drugs

• Anagrelide exhibits properties of a weak inhibitor of the CYP1A2 isoenzyme and could theoretically interact with other drugs whose clearance is mediated by the same mechanism, for example, theophylline.

• Anagrelide is an inhibitor of phosphodiesterase III (PDE III). It may enhance the effects of drugs with the same action, including the inotropic drugs milrinone, amrinone, enoximone, olprinone, and cilostazol.

• Human in vivo interaction studies have shown 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 that inhibit or alter platelet function, for example, acetylsalicylic acid.

• A clinical interaction study in healthy volunteers showed that multiple doses of anagrelide 1 mg once daily together with acetylsalicylic acid 75 mg once daily may enhance the inhibition of platelet aggregation caused by these drugs compared to taking acetylsalicylic acid alone. Therefore, due to the lack of relevant data for patients with essential thrombocythemia, the possible risk should be assessed before starting concomitant use of these drugs, especially for patients at high risk of bleeding.

• In some patients, Anagrelide may cause intestinal dysfunction and may impair the absorption of oral hormonal contraceptives.

Food Interaction

• Food intake slows the absorption of anagrelide but does not significantly affect its systemic exposure level.

• The effect of food on the bioavailability of anagrelide is not considered clinically significant.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 4 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.