Analidas (Capsules) Instructions for Use

Marketing Authorization Holder

Aspectus Pharma LLC (Russia)

Manufactured By

Synthon Hispania, S.L. (Spain)

ATC Code

L01XX35 (Anagrelide)

Active Substance

Anagrelide (Rec.INN registered by WHO)

Dosage Forms

	Analidas	Capsules 0.5 mg: 100 pcs.
		Capsules 1 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin No. 4, cap and body white, opaque; capsule contents – white or almost white powder.

Excipients : lactose monohydrate – 28.03 mg, anhydrous lactose – 32.9 mg, microcrystalline cellulose type 102 – 14.03 mg, croscarmellose sodium – 0.79 mg, povidone K30 – 1.8 mg, magnesium stearate – 0.35 mg.

Capsule shell composition : gelatin – 37.24 mg, titanium dioxide – 0.76 mg.

100 pcs. – bottles (1) – cardboard pack.
3000-33000 pcs. – bags – containers.

Capsules hard gelatin No. 4, with gray body and cap, opaque; capsule contents – white or almost white powder.

Excipients : lactose monohydrate – 56.05 mg, anhydrous lactose – 65.8 mg, microcrystalline cellulose type 102 – 28.06 mg, croscarmellose sodium – 1.57 mg, povidone K30 – 3.6 mg, magnesium stearate – 0.7 mg.

Capsule shell composition : gelatin – 37.13 mg, titanium dioxide – 0.76 mg, iron oxide black dye – 0.11 mg.

100 pcs. – bottles (1) – cardboard pack.
3000-33000 pcs. – bags – containers.

Clinical-Pharmacological Group

Drug for the treatment of thrombocythemia

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents

Pharmacological Action

A drug for the treatment of thrombocythemia, an inhibitor of cyclic adenosine monophosphate (AMP) PDE3. The specific mechanism of action of anagrelide leading to a reduction in platelet count is not fully understood. It is currently established that Anagrelide acts selectively on platelets in vitro and in vivo.

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

Pharmacokinetics

After oral administration of anagrelide, approximately 70% of the active substance is absorbed from the gastrointestinal tract. When taken on an empty stomach at a dose of 0.5 mg, C_max in plasma is reached after 1 h; T_1/2 is approximately 1.3 h. In the dose range of 0.5-2 mg, the pharmacokinetics of anagrelide are dose-proportional. Anagrelide is metabolized mainly by the isoenzyme CYP1A2. 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 anagrelide pharmacokinetics in healthy volunteers showed that food intake reduces the C_max of anagrelide in plasma by 14%, but increases AUC by 20%. A more pronounced reduction in C_max of the active metabolite by 29% is observed, while the AUC of the metabolite does not change.

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

Data on the pharmacokinetics of anagrelide when taken on an empty stomach by children and adolescents with essential thrombocythemia aged 7-14 years indicate that the C_max of anagrelide in plasma and AUC, normalized for dose and body weight, are lower in children/adolescents than in adult patients. A trend towards a lower degree of exposure to the active metabolite was also identified. These differences may reflect more efficient metabolic clearance of anagrelide in younger patients.

Data on the pharmacokinetics of anagrelide when taken on an empty stomach by elderly patients with essential thrombocythemia (65-75 years) compared to younger patients (22-50 years) indicate that their C_max of anagrelide in plasma and AUC are higher by 36% and 61% respectively, while the C_max in plasma and AUC of the active metabolite – 3-hydroxy-anagrelide – are lower by 42% and 37% respectively. These differences are likely due to less pronounced local (before 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.

ICD codes

Dosage Regimen

High-risk patients with essential thrombocythemia are defined as patients having one or more of the following characteristics: age >60 years; platelet count >1000×10⁹/L; history of thrombohemorrhagic complications.

Take orally. The recommended initial dose is 1 mg/day in 2 divided doses of 500 mcg. The initial dose should be taken for at least 1 week. After that, 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 600×10⁹/L, optimal level between 150×10⁹/L and 400×10⁹/L. The rate of dose increase should not exceed 500 mcg/day per week, maximum single dose is 2.5 mg.

The effect of anagrelide use should be regularly assessed. If the initial dose exceeds 1 mg/day, then in the first week the platelet count should be determined every 2 days, and then at least once a week until a stable maintenance dose is achieved. Usually, a drop in platelet count is observed on days 14-21 after the start of treatment, and in most patients, sufficient therapeutic effect is achieved and maintained at a dose of 1-3 mg/day.

Adverse Reactions

From the hematopoietic system common – anemia; uncommon – thrombocytopenia, pancytopenia, ecchymosis, bleeding.

From metabolism common – fluid retention; uncommon – edema, weight loss; rare – weight gain.

From the nervous system: very common – headache; common – dizziness; uncommon – paresthesia, insomnia, depression, confusion, hypoesthesia, nervousness, dry mouth, amnesia; rare – drowsiness, impaired coordination, dysarthria, migraine.

From the sensory organs: rare – visual impairment, diplopia, tinnitus.

From the cardiovascular system common – palpitations, tachycardia; uncommon – 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.

From the respiratory system: uncommon – dyspnea, epistaxis, pleural effusion, pneumonia; rare – pulmonary artery hypertension, lung infiltrates; unknown – allergic alveolitis.

From the digestive system common – nausea, diarrhea, abdominal pain, flatulence, vomiting; uncommon – dyspepsia, anorexia, pancreatitis, constipation, gastrointestinal bleeding, gastrointestinal disorder; rare – colitis, gastritis, gum bleeding.

From the liver and biliary tract uncommon – increased activity of liver enzymes; unknown – hepatitis.

From the skin and subcutaneous tissues common – rash; uncommon – alopecia, skin discoloration, pruritus; rare – dry skin.

From the musculoskeletal system uncommon – myalgia, arthralgia, back pain.

From the genitourinary system uncommon – impotence; rare – nocturnal enuresis, renal failure; unknown – tubulointerstitial nephritis.

General disorders common – fatigue; uncommon – chest pain, weakness, chills, general malaise, fever; rare – asthenia, pain, flu-like syndrome.

From laboratory parameters rare – increased blood creatinine concentration.

Contraindications

Moderate or severe hepatic impairment; moderate or severe renal impairment (CrCl <50 ml/min); children under 7 years of age; hypersensitivity to anagrelide.

Use in Pregnancy and Lactation

Data on the use of anagrelide in pregnant women are insufficient. Anagrelide should not be used during pregnancy. If use during pregnancy is necessary or if pregnancy occurs during treatment, the patient should be warned about the possible risk to the fetus.

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

It is not known whether Anagrelide is excreted in breast milk. If it is necessary to use anagrelide during lactation, breastfeeding should be discontinued.

In experimental studies on animals, anagrelide has been shown to have reproductive toxicity.

Special Precautions

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

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

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

The platelet count usually increases 4 days after discontinuation of anagrelide and returns to the baseline level after 10-14 days.

Cases of cardiomegaly and congestive heart failure have been described. In patients of any age with confirmed heart disease or suspected heart disease, Anagrelide should be used with caution, and only if the expected benefit of treatment outweighs the possible risk. Anagrelide is an inhibitor of cyclic AMP PDE3 and has a positive inotropic effect, therefore, before starting treatment, it is recommended to examine the cardiovascular system, including, if necessary, echocardiography and ECG. During treatment, the occurrence of cardiovascular phenomena should be monitored, which may require additional examination.

It is not recommended to use Anagrelide concomitantly with other PDE3 inhibitors, including milrinone, amrinone, enoximone, olprinone and cilostazol.

Use in pediatrics

Experience with the use of anagrelide in children is limited. Anagrelide should be used with caution in children over 7 years of age.

Effect on ability to drive vehicles and operate machinery

During treatment, patients are advised to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, because Anagrelide may cause dizziness and other side effects.

Drug Interactions

Anagrelide is metabolized mainly by the isoenzyme CYP1A2. It is known that some drugs, including fluvoxamine and omeprazole, inhibit the activity of the CYP1A2 isoenzyme, so such drugs may theoretically adversely affect the clearance of anagrelide.

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

Anagrelide is a PDE3 inhibitor. It may enhance the effects of drugs with the same action, including the inotropic drugs milrinone, amrinone, enoximone, olprinone and cilostazol.

At doses recommended for the treatment of essential thrombocythemia, Anagrelide may theoretically enhance the effects of other drugs that inhibit or alter platelet functions, for example, acetylsalicylic acid.

A clinical interaction study in healthy volunteers showed that multiple administration of anagrelide at a dose of 1 mg once/day together with acetylsalicylic acid 75 mg once/day 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 intake slows the absorption of anagrelide but does not significantly affect its systemic exposure.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.