Anagrelide zentiva

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

Composition:

Active substance: anagrelide;

One hard capsule contains 0.61 mg of anagrelide hydrochloride monohydrate equivalent to 0.5 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).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: capsule with an opaque white body and cap. The capsule contents are a 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 megakaryopoiesis, thereby reducing platelet production.

In vitro studies of megakaryocyte formation demonstrated that anagrelide-induced inhibition of platelet formation in humans is associated with delayed maturation of megakaryocytes, reduced size, and decreased density. Similar in vivo results were observed in bone marrow biopsy samples from 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 4,000 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 the studies, the complete remission period 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 effects of two doses of anagrelide (0.5 mg and 2.5 mg, single doses) on heart rate (HR) and QT interval were evaluated in a double-blind, randomized, 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. The maximum increase in HR occurred at the time of peak drug concentration (Cmax). The maximum change in mean HR was recorded 2 hours after 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 increased 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 to the study), 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). During prior open-label studies, reductions in 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 doses, while the lowest initial dose for children aged 6 years and older is 0.5 mg per day (see sections "Pharmacological properties", "Special instructions", "Method of administration and dosage", and "Adverse reactions"). Dose selection in pediatric patients should be done cautiously and individually.

Pharmacokinetics.

Absorption

Following oral administration, approximately 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 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 from 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 are higher in this patient group compared to adults. A trend toward higher dosing was also observed to ensure adequate formation of active metabolites.

Geriatric patients

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

Clinical characteristics.

Indications.

Anagrelide is indicated for reduction of platelet count in patients at high risk of essential thrombocythemia (ET) who are intolerant of, or have an inadequate response to, current therapy.

High-risk group

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

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

Contraindications.

Hypersensitivity to anagrelide or to any of the excipients.

Moderate or severe hepatic impairment.

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Special precautions for use.

Hepatic impairment

The potential risks and benefits of using anagrelide in patients with hepatic impairment should be carefully considered before prescribing anagrelide. The use of the drug 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

Abrupt discontinuation of treatment should be avoided due to the risk of sudden 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. In case of such symptoms, immediate medical attention is required.

Discontinuation of treatment

Following interruption or discontinuation of dosing, platelet recovery is variable, but platelet count begins to increase within 4 days after stopping anagrelide and returns to pre-treatment levels within 10–14 days, possibly rising above baseline values. Therefore, frequent monitoring of platelet levels is necessary (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 diseases 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 used in patients of any age with cardiovascular diseases or suspected cardiovascular disorders 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 drugs capable of causing 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 diseases should undergo a cardiological evaluation (electrocardiogram and echocardiogram) before starting anagrelide treatment and during therapy 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 initiating 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 treating patients of any age and in patients with possible heart disease. Moreover, serious cardiovascular adverse events have been reported in patients without pre-existing heart disease who underwent cardiological evaluation prior to starting treatment.

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 symptoms of cardiovascular disease should be evaluated before and during anagrelide treatment.

Children

Limited data are available 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").

Regular assessment of complete blood count, cardiovascular, liver, and kidney function is required in adult patients before and during treatment. 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 is higher in children than in adults.

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

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

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

One 0.5 mg capsule contains 28.0 mg of lactose monohydrate and 32.9 mg of lactose.

Therefore, this product must not be taken by patients with hereditary galactose intolerance, 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 drug. The potential risk to the fetus is unknown. The use of anagrelide during pregnancy is not recommended.

If a woman takes anagrelide during pregnancy or becomes pregnant while taking the drug, 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 into breast milk. Risk to the newborn or infant cannot be excluded; therefore, if treatment 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 after administration at doses exceeding the therapeutic dose.

Ability to affect reaction speed when driving or operating machinery.

Dizziness was frequently reported during clinical studies. Patients should refrain from driving or operating machinery while taking anagrelide if dizziness occurs.

Method of Administration and Dosage

For oral use. Capsules must 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; the dose should be titrated 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.

The dose increase should not exceed 0.5 mg per day per week. The maximum single dose of the drug should not exceed 2.5 mg (see section "Overdose"). The maximum daily dose used during clinical trials of the drug was 10 mg per day.

Regular monitoring of the effect of anagrelide is required (see section "Special Warnings and Precautions for Use"). Platelet counts should be measured every 2 days during the first week of treatment, and thereafter at least weekly until a stable dose is achieved. A reduction in platelet count is usually observed within 14 to 21 days after initiation of treatment, and 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 the event of missed doses 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") do not require adjustment of the initial dose or titration procedure to achieve the individual optimal maintenance dose. Clinical studies involving anagrelide, in which 50% of patients were aged 60 years or older, demonstrated that these patients did not require age-related dosage adjustments. However, in this age group, serious adverse reactions occurred twice as frequently, primarily affecting the cardiovascular system.

Renal Impairment

Data on the pharmacokinetic properties of the drug in this patient group are limited. The potential risks and benefits of anagrelide use in patients with renal insufficiency must be carefully considered before initiating therapy (see section "Contraindications").

Hepatic Impairment

Currently, there are no data on the pharmacokinetics of anagrelide in patients with hepatic impairment. Since hepatic metabolism is the primary route of drug clearance, impaired liver function is expected to affect this process. The use of anagrelide is not recommended in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment, the benefit-risk ratio of treatment should be carefully evaluated before initiating anagrelide (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 with anagrelide in this population, it should be used with caution. In the absence of specific pediatric recommendations, WHO diagnostic criteria for essential thrombocythemia in adults may be applied for diagnosing children. Diagnostic recommendations for ET should be strictly followed, and in doubtful cases, repeat evaluation should be performed 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 considered only when there are signs of disease progression or in patients suffering from thrombosis. If anagrelide is used, continuous monitoring of the benefit-risk balance is required, along with periodic reassessment of the need for continued treatment.

Target platelet counts should be determined by the physician based on individual patient characteristics.

If satisfactory response is not 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 provided in sections "Pharmacological Properties", "Special Warnings and Precautions for Use", and "Undesirable Effects", but dosage recommendations are lacking.

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 must be monitored. Anagrelide administration 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 lead to reduced blood pressure accompanied by dizziness (see section "Special Warnings and Precautions for Use").

Adverse reactions

Information on adverse effects during clinical trials, post-marketing surveillance, and from sporadic reports is presented below in the table. According to organ system classes, adverse effects are listed as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data). Within each column, adverse reactions are listed in order of decreasing severity.

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

Children

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions following marketing authorization is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare 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 light and moisture at a temperature not exceeding 30 °C.

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

Prescription status. Prescription only.

Manufacturer.

SYNTON HISPANIA, S.L.

Manufacturer's address and location of manufacturing operations.

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