Anagrelide zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANAGRELIDE ZENTIVA (ANAGRELIDE ZENTIVA)

Composition:

Active substance: anagrelide;

1 hard capsule contains 1.22 mg of anagrelide hydrochloride monohydrate equivalent to 1 mg of anagrelide;

Excipients: lactose monohydrate; sodium croscarmellose (E 466), povidone, anhydrous lactose, microcrystalline cellulose (E 460), magnesium stearate;

Capsule shell composition: gelatin, titanium dioxide (E 171), black iron oxide (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: capsule with grey body and cap. The contents of the capsules – white or almost white powder.

Pharmacotherapeutic group.

Antineoplastic agents. Anagrelide. ATC code L01X X35.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Anagrelide is a cyclic AMP phosphodiesterase III inhibitor. The mechanisms by which anagrelide reduces platelet count are still under investigation. Studies have shown that anagrelide suppresses the expression of transcription factors, including GATA‑1 and FOG‑1, which play a role in megakaryocytopoiesis, thereby reducing platelet formation.

In vitro studies of megakaryocyte development demonstrated that anagrelide-induced inhibition of platelet formation in humans is associated with delayed maturation of megakaryocytes, reduced size and density. Similar in vivo results were obtained from bone marrow biopsy samples of patients treated with anagrelide.

Clinical efficacy and safety

The safety and efficacy of anagrelide as a platelet-lowering agent were evaluated in studies involving over 4000 patients with myeloproliferative neoplasms. In patients with essential thrombocythemia (ET), complete remission was defined as a reduction in platelet count to ≤ 600 x 10⁹/L or by ≥ 50% from baseline, maintained for more than 4 weeks. During studies, the duration of complete remission ranged from 4 to 12 weeks. Given the clinical benefits, the risk of thrombohemorrhagic adverse effects is low.

Effect on heart rate and QT interval

The effect of two doses of anagrelide (0.5 mg and 2.5 mg, single doses) on heart rate (HR) and QT interval was evaluated in a double-blind, placebo- and active-controlled, crossover study in healthy adult male and female subjects.

Dose-dependent increases in HR were observed within the first 12 hours. Maximum increase in HR occurred at peak drug concentration (Cmax). The maximum change in mean HR was observed 2 hours after drug administration and was +7.8 beats/min for the 0.5 mg dose and +29.1 beats/min for the 2.5 mg dose.

Transient increases in mean QTc were observed with both doses, concurrent with increases in HR. The maximum change in mean QTcF was +5.0 ms at 2 hours for the 0.5 mg dose and +10 ms at 1 hour for the 2.5 mg dose.

Children

In a study involving 8 children and 10 adolescents (including both treatment-naïve patients and those previously treated with anagrelide for up to 5 years prior), mean platelet counts decreased to controlled levels within 12 weeks of treatment. The mean daily dose was higher in adolescents.

In a pediatric registry study, anagrelide treatment resulted in reduced mean platelet counts compared to baseline, with sustained control over 18 months in 14 children with ET (4 children and 10 adolescents). In prior open-label studies, reduced mean platelet counts were observed in 7 children and 9 adolescents, with treatment duration ranging from 3 months to 6.5 years.

The mean daily dose of anagrelide varied across all pediatric ET studies; however, data suggest that adolescents may be treated with adult dosing, and the lowest starting dose for children aged 6 years and older is 0.5 mg per day (see sections «Pharmacological properties», «Special instructions», «Administration and dosage», and «Adverse reactions»). Dose selection in pediatric patients should be done cautiously and on an individual basis.

Pharmacokinetics.

Absorption

Following oral administration, 70% of anagrelide is rapidly absorbed in the gastrointestinal tract. When administered on an empty stomach, Cmax in plasma is reached within 1 hour. Pharmacokinetic data from healthy volunteers indicate that food intake reduces the Cmax of anagrelide by 14%, but increases its mean urinary concentration by 20%. Concomitant food intake also reduces the Cmax of the active metabolite, 3-hydroxy-anagrelide, by 29%, but does not affect its mean urinary concentration.

Biotransformation

Anagrelide is metabolized by the CYP1A2 isoenzyme into 3-hydroxy-anagrelide, which is further metabolized by CYP1A2 into the inactive metabolite 2-amino-5,6-dichloro-3,4-dihydroquinazoline.

Elimination

The half-life of anagrelide is short, approximately 1.3 hours, and there is no evidence of accumulation in plasma. Less than 1% of the drug is excreted in urine as unchanged anagrelide. The mean urinary excretion of 2-amino-5,6-dichloro-3,4-dihydroquinazoline accounts for 18–35% of the administered dose.

Additionally, there is no evidence of autoinduction of anagrelide clearance.

Linearity

Dose proportionality is observed within the range of 0.5–2 mg.

Children

Pharmacokinetic data obtained in children and adolescents with ET (aged 7 to 16 years) receiving anagrelide on an empty stomach indicate that dose-normalized exposure, Cmax, and peak urinary concentration were higher in this patient group compared to adults. A trend toward higher dosing was also observed to ensure adequate formation of active metabolites.

Elderly patients

Comparative pharmacokinetic analysis of data from elderly patients with ET (aged 65 to 75 years) and younger adults (aged 22 to 50 years), all receiving anagrelide on an empty stomach, showed that Cmax and peak urinary concentration of anagrelide were 36% and 61% higher, respectively, in elderly patients. In contrast, Cmax and peak urinary concentration of the active metabolite, 3-hydroxy-anagrelide, were 42% and 37% lower, respectively, in the elderly group. These differences are likely due to reduced presystemic metabolism of anagrelide to 3-hydroxy-anagrelide in elderly patients.

Clinical Characteristics.

Indications.

Anagrelide is indicated to reduce platelet counts in patients at high risk of essential thrombocythemia (ET) who are intolerant of or unresponsive to current therapy, or when such therapy fails to reduce platelet counts to the desired level.

High-risk group

Patients at high risk of developing essential thrombocythemia include those with one or more of the following characteristics:

• age over 60 years;
• platelet count exceeding 1000 x 10^9/L;
• history of thromboembolism or circulatory disturbances.

Contraindications.

Hypersensitivity to anagrelide or to any of the excipients.

Moderate or severe hepatic impairment.

Moderate or severe renal impairment (creatinine clearance < 50 mL/min).

Interaction with other medicinal products and other forms of interaction.

There are insufficient data on the pharmacokinetic or pharmacodynamic interaction of anagrelide with other medicinal products.

Effect of other medicinal products

In vivo drug interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic parameters of anagrelide.

CYP1A2 inhibitors

Anagrelide is primarily metabolized by the CYP1A2 isoenzyme. It is known that certain drugs, including fluvoxamine and enoxacin, inhibit CYP1A2 activity; therefore, these medicinal products may theoretically adversely affect anagrelide clearance.

CYP1A2 inducers

CYP1A2 inducers, such as omeprazole, may reduce the effect of anagrelide by increasing its major active metabolite. The safety and efficacy implications of this interaction have not been established. Therefore, clinical monitoring is recommended for patients receiving concomitant CYP1A2 inducers. Dose adjustments of anagrelide may be necessary if required.

Effect of anagrelide on other medicinal products

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

Anagrelide is a phosphodiesterase III inhibitor. Concomitant use of anagrelide with other phosphodiesterase III inhibitors such as milrinone, enoximone, amrinone, olprinone, and cilostazol is not recommended.

In vivo interaction studies in humans have shown that anagrelide does not affect the pharmacokinetics of warfarin or digoxin.

At recommended doses, the drug may potentiate the effects of other medicinal products that inhibit or modify platelet function, such as acetylsalicylic acid. Interaction studies conducted in healthy volunteers showed that co-administration of anagrelide at a repeated dose of 1 mg once daily and 75 mg acetylsalicylic acid once daily may enhance the antiplatelet aggregation effects of each active substance compared to acetylsalicylic acid alone.

In some patients with polycythemia vera treated concomitantly with acetylsalicylic acid and anagrelide, episodes of severe hemorrhage have occurred. Before initiating concomitant treatment with acetylsalicylic acid and anagrelide, the potential risk of hemorrhage should be evaluated, particularly in patients at high risk.

In some patients, anagrelide may cause gastrointestinal disturbances and may interfere with the absorption of oral hormonal contraceptives.

Interaction with food

Food intake slows the absorption of anagrelide but does not result in a clinically significant effect on systemic exposure.

The effect of food on bioavailability is not considered clinically significant for anagrelide use.

Pediatric population: interaction studies have been conducted only in adults.

Special precautions for use.

Hepatic impairment

The potential risks and benefits of using anagrelide in patients with hepatic impairment should be considered before initiating anagrelide therapy. The use of the medicinal product is not recommended in patients with elevated transaminase levels (>5 times the upper limit of normal) (see sections "Contraindications" and "Dosage and administration").

Renal impairment

The potential risks and benefits of using anagrelide in patients with renal impairment should be considered before initiating anagrelide therapy (see sections "Contraindications" and "Dosage and administration").

Thrombosis risk

Sudden discontinuation of treatment should be avoided due to the risk of rapid increase in platelet count, which may lead to potentially fatal thrombotic complications such as stroke. Patients should be informed how to recognize early signs and symptoms indicating thrombotic complications, such as stroke. Medical attention must be sought immediately if such symptoms occur.

Discontinuation of treatment

Upon interruption or discontinuation of dosing, platelet recovery is variable, but platelet counts begin to increase within 4 days after stopping anagrelide and return to pre-treatment levels within 10–14 days, possibly rising above baseline values. Therefore, platelet counts should be monitored frequently (see section "Dosage and administration").

Monitoring

Careful monitoring of the patient's clinical condition is required during treatment, including blood tests (hemoglobin, leukocytes, and platelets), assessment of liver function (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels), kidney function (serum creatinine and urea concentrations), and electrolyte levels (potassium, magnesium, and calcium).

Treatment with anagrelide in patients with cardiovascular disorders or hepatic dysfunction should be conducted under continuous medical supervision.

Cardiovascular system

Cases of torsades de pointes ventricular tachycardia, ventricular tachycardia, cardiomyopathy, cardiomegaly, and chronic heart failure have been observed (see section "Adverse reactions").

Anagrelide should be administered to patients of any age with cardiovascular disease or suspected cardiovascular disease only when the expected benefit outweighs the potential risk.

Anagrelide should be used with caution in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, history of acquired QT prolongation, concomitant use of medicinal products capable of inducing QTc prolongation, and hypokalemia.

Anagrelide should be prescribed with caution to patients who may have higher plasma Cmax levels of anagrelide and its active metabolite, 3-hydroxy-anagrelide, e.g., in hepatic impairment or concomitant use of CYP1A2 isoenzyme inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Careful monitoring of the QTc interval is recommended.

Patients with cardiovascular disease should undergo a cardiological evaluation (electrocardiogram and echocardiogram) before initiating anagrelide therapy and during treatment due to the positive inotropic effect of anagrelide and possible cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure. Hypokalemia or hypomagnesemia should be ruled out before starting anagrelide and monitored during treatment.

Anagrelide inhibits cyclic AMP phosphodiesterase III; due to its positive inotropic and chronotropic effects, it should be used cautiously in the treatment of patients of any age and in patients with possible heart disease. Moreover, serious cardiovascular adverse effects have been reported in patients without pre-existing heart disease who underwent cardiological evaluation prior to treatment initiation.

Anagrelide should be used only when the expected benefit outweighs the potential risk.

Respiratory system

Cases of pulmonary hypertension have been reported in patients receiving anagrelide. The presence of cardiovascular disease symptoms should be evaluated before and during anagrelide treatment.

Paediatric population

There are limited data on the use of anagrelide in children; therefore, it should be used with caution in this patient group (see sections "Pharmacological properties", "Dosage and administration", and "Adverse reactions").

Before initiating treatment and during treatment in adults, regular monitoring of complete blood count, cardiovascular, liver, and kidney function is required. The disease may progress to myelofibrosis or acute myeloid leukemia. Since the likelihood of such progression is unknown and the duration of disease in children is longer, the risk of developing malignancies in children is higher than in adults.

Regular monitoring for disease progression in children, in accordance with standard clinical practice, including physical examination, assessment of relevant markers, and bone marrow biopsy, is required.

Any abnormalities should be promptly evaluated and appropriate measures taken, including dose reduction, or temporary or permanent discontinuation of the medicinal product.

Clinically significant interactions

Anagrelide is a phosphodiesterase III inhibitor. Concomitant use of anagrelide with other phosphodiesterase III inhibitors such as milrinone, enoximone, amrinone, olprinone, and cilostazol is not recommended.

Concomitant use of anagrelide and acetylsalicylic acid is associated with extensive circulatory disorders (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

1 capsule of 1 mg contains 56 mg of lactose monohydrate and 65.80 mg of lactose.

Therefore, this medicinal product is contraindicated in patients with congenital galactosemia, glucose-galactose malabsorption syndrome, or lactase deficiency.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential who are taking anagrelide should use contraception.

Pregnancy

There are no adequate data on the use of anagrelide in pregnant women or women who are breastfeeding. Animal studies have shown reproductive toxicity of the medicinal product. The potential risk to the fetus is unknown. The use of anagrelide in pregnant women is not recommended.

If a woman becomes pregnant while taking anagrelide or takes anagrelide during pregnancy, she should be informed of the potential risk to the fetus.

Women of childbearing potential taking anagrelide should use contraception.

Breastfeeding

It is unknown whether anagrelide passes into breast milk. Animal studies have shown excretion of anagrelide and its metabolites in milk. Risk to the newborn or infant cannot be excluded; therefore, if treatment with anagrelide is necessary, breastfeeding should be discontinued.

Fertility

Data on the effect of anagrelide on fertility are lacking. In male animals, anagrelide had no effect on fertility or reproductive function. In female animals, anagrelide disrupted implantation at doses exceeding the therapeutic dose.

Ability to affect reaction speed when driving vehicles or operating machinery.

Dizziness was frequently reported during clinical studies. Patients are advised to refrain from driving vehicles or operating machinery while taking anagrelide if they experience dizziness.

Method of Administration and Dosage

For oral use. Capsules should be swallowed whole. Do not crush or dissolve the contents in liquid.

Treatment with the drug should be managed by a physician experienced in the treatment of essential thrombocythemia.

Dosage

The recommended initial dose of anagrelide is 1 mg per day, administered orally in two divided doses of 0.5 mg each. This dose should be maintained for 1 week. After 1 week, the dose may be individually adjusted, gradually increasing to the minimum effective dose sufficient to reduce/maintain platelet count below 600×10⁹/L, and ideally within the range of 150×10⁹/L to 400×10⁹/L.

Dose increases should not exceed 0.5 mg per day per week. The maximum single dose of the drug should not exceed 2.5 mg. The maximum daily dose used during clinical studies was 10 mg per day.

During the first week of treatment, platelet counts should be monitored every 2 days, and thereafter at least weekly until a stable dose is achieved. Platelet count reduction is usually observed within 14 to 21 days after initiation of treatment. In most patients, an adequate response is achieved and maintained with a daily dose of 1–3 mg (see section "Pharmacological Properties").

There are no specific dosage recommendations for elderly patients.

In case of missed dose or discontinuation of treatment, platelet levels should be closely monitored (see section "Special Warnings and Precautions for Use").

Special Patient Groups

Elderly Patients

Pharmacokinetic differences observed between elderly and younger patients with ET (see section "Pharmacological Properties") did not require adjustment of the initial dose or titration procedure to reach the individual optimal maintenance dose. Clinical studies involving 50% of patients aged 60 years and older demonstrated that these patients did not require age-related dosage adjustments. However, this age group experienced serious adverse reactions approximately twice as often, primarily related to the cardiovascular system.

Renal Impairment

Currently, there are no data available on the pharmacokinetics of anagrelide in patients with renal impairment. Therefore, the benefit-risk ratio of treatment should be carefully evaluated before administration (see section "Contraindications").

Hepatic Impairment

Currently, there are no data available on the pharmacokinetics of anagrelide in patients with hepatic impairment. Since hepatic metabolism is the primary route of drug clearance, hepatic dysfunction is expected to affect this process. Anagrelide is not recommended for use in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment, the benefit-risk ratio of treatment should be carefully assessed before administration (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Children

The safety and efficacy of anagrelide in children have not been established. Due to limited experience in this population, anagrelide should be used with caution. In the absence of specific pediatric recommendations, WHO diagnostic criteria for ET in adults may be applied for diagnosis in children. Diagnostic recommendations should be strictly followed, and repeat evaluations should be performed in uncertain cases to differentiate between inherited and acquired thrombocytosis. Genetic testing and bone marrow biopsy may be necessary.

In pediatric practice, cytoreductive therapy is generally reserved for patients at high risk.

Anagrelide may be used only when there are signs of disease progression or in patients suffering from thrombosis. When used, continuous monitoring of the benefit-risk ratio is required, along with periodic reassessment of the need for continued treatment.

Target platelet counts should be determined by the physician according to individual patient characteristics.

If a satisfactory response has not been achieved in children after 3 months of treatment, discontinuation of therapy should be considered (see section "Special Warnings and Precautions for Use").

Current available data are presented in sections "Pharmacological Properties", "Special Warnings and Precautions for Use", and "Undesirable Effects", but dosage recommendations are not available.

Overdose

Post-marketing data on intentional anagrelide overdose are available. A small number of overdose cases have been reported, with symptoms including sinus tachycardia and vomiting, which resolved with symptomatic treatment.

Treatment in Case of Overdose

There is no specific antidote for anagrelide. In case of overdose, the patient should be under close medical supervision. Platelet counts should be monitored. Administration of the drug should be discontinued until platelet counts return to normal.

Anagrelide administered at doses higher than recommended has been associated with decreased arterial pressure and periodic hypotension. A single dose of 5 mg anagrelide may cause a reduction in blood pressure accompanied by dizziness (see section "Special Warnings and Precautions for Use").

Adverse reactions

Information on adverse effects observed during clinical trials, post-marketing surveillance, and spontaneous reporting is presented in the table below, grouped by system organ class. The frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each column, adverse reactions are listed in order of decreasing severity.

MedDRA Organ systems	Frequency of adverse reactions
	very common	common	uncommon	rare	frequency unknown
Blood and lymphatic system disorders		anemia	pancytopenia, thrombocytopenia, hemorrhage, subcutaneous hematoma
Nutritional and metabolism disorders		fluid retention	edema, weight loss	weight gain
Nervous system disorders	headache	memory impairment	depression, amnesia, confusion, insomnia, paresthesia, hypoesthesia, restlessness, dry mouth	migraine, dysarthria, drowsiness, coordination disorder	cerebral infarction*
Eye disorders				double vision, visual disturbance
Ear and labyrinth disorders				tinnitus
Cardiac disorders		tachycardia, palpitations	ventricular tachycardia, congestive heart failure, atrial fibrillation, supraventricular tachycardia, arrhythmia, hypertension, loss of consciousness	myocardial infarction, cardiomyopathy, cardiomegaly, pericardial effusion, angina pectoris, postural hypotension, vasodilation, Prinzmetal's angina	bidirectional tachycardia
Respiratory, thoracic and mediastinal disorders			pulmonary hypertension, pneumonia, pleural effusion, dyspnea, epistaxis	pulmonary infiltrate	interstitial lung disease, including pneumonitis and allergic alveolitis
Gastrointestinal disorders		diarrhea, vomiting and abdominal pain, nausea, flatulence	gastrointestinal hemorrhage, pancreatitis, anorexia, digestive disorder, constipation	colitis, gastritis, gingival bleeding
Hepatobiliary disorders			elevated liver enzymes		hepatitis
Skin and subcutaneous tissue disorders		rash	alopecia, pruritus, skin discoloration	dry skin
Musculoskeletal and connective tissue disorders			arthralgia, myalgia, back pain
Renal and urinary disorders			impotence	renal failure, nocturia	tubulo-interstitial nephritis
General disorders and administration site conditions		fatigue	chest pain, fever, chills, anxiety, weakness	influenza-like syndrome, pain, asthenia
Investigations				elevated blood creatinine

* Cerebral infarction (see section "Special precautions": "Thromboembolic risk").

Children

Safety data are limited and do not allow a comparative analysis of results obtained in adult patients and children (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit/risk balance of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from moisture at a temperature not exceeding 30 °C.

Packaging. 100 capsules in a bottle. 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

SYNTON HISPANIA, S.L.

Manufacturer's address and location of operations.

C/Castello, n.1, Sant Boi de Llobregat, Barcelona, 08830, Spain.