Anagrelide-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANAGRELIDE-VISTA (ANAGRELIDE-VISTA)

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, povidone, anhydrous lactose, microcrystalline cellulose, magnesium stearate;

Capsule shell composition: gelatin, titanium dioxide (E 171); iron oxide black (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 megakaryopoiesis, thereby reducing platelet formation. In vitro studies on 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 neoplasm. In patients with essential thrombocythemia, complete remission was defined as a reduction in platelet count to ≤ 600x10⁹/L or by ≥ 50% from baseline, maintained for more than 4 weeks. During the studies, the duration of complete remission ranged from 4 to 12 weeks. Given the clinical benefits, the risk of thrombohemorrhagic adverse events 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, 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 peak anagrelide concentration. The maximum change in mean HR was observed 2 hours after anagrelide administration and was +7.8 bpm for the 0.5 mg dose and +29.1 bpm for the 2.5 mg dose. Transient increases in mean QTc were observed with both doses, concurrent with HR increases. 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), 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 reduced mean platelet counts from baseline and maintained control over 18 months in 14 children with essential thrombocythemia (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 pediatric studies; however, data suggest that adolescents may be treated with adult doses, and the lowest starting dose for children aged 6 years and older is 0.5 mg daily (see sections "Pharmacological properties", "Dosage and administration", "Administration and dosage", and "Adverse reactions"). Dose selection in children should be done cautiously and on an individual basis.

Pharmacokinetics.

Absorption.

Following oral administration, approximately 70% of anagrelide is rapidly absorbed in the gastrointestinal tract. When administered on an empty stomach, maximum plasma concentration (C_max) is reached within 1 hour. Pharmacokinetic data from healthy volunteers indicate that food intake reduces the C_max of anagrelide by 14%, but increases its mean urinary concentration by 20%. Concomitant food intake also reduces the C_max 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 elimination half-life of anagrelide is short, approximately 1.3 hours, and there is no evidence of accumulation in plasma. Less than 1% of anagrelide is excreted unchanged in urine. 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 (aged 7 to 16 years) with essential thrombocythemia receiving anagrelide on an empty stomach indicate that dose-normalized exposure, C_max, 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 C_max and peak urinary concentration of anagrelide were 36% and 61% higher, respectively, in the elderly group. In contrast, C_max 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 to reduce elevated platelet levels in patients at high risk of developing essential thrombocythemia who are intolerant to current therapy or for whom this therapy does not reduce platelet counts to the required level.

At-risk group.

Patients at 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 10⁹/L;
• History of thromboembolism or circulatory disorders.

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 medicinal products, including fluvoxamine and enoxacin, inhibit CYP1A2 enzyme activity; therefore, such 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 consequences of anagrelide in such cases are not established. Therefore, clinical monitoring is recommended for patients taking concomitant CYP1A2 inducers. Doses of anagrelide may be adjusted if necessary.

Effect of anagrelide on other medicinal products.

Anagrelide has properties of a weak inhibitor of the CYP1A2 isoenzyme and may theoretically interact with other medicinal products whose clearance is mediated via the same mechanism, 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 and digoxin.

At recommended doses, anagrelide may enhance the effect of other medicinal products that inhibit or modify platelet function, such as acetylsalicylic acid. Interaction studies conducted in healthy volunteers showed that concomitant 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, cases of massive bleeding have occurred. The potential risk of hemorrhage should be evaluated before initiating concomitant use of acetylsalicylic acid and anagrelide, especially 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 its 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.

Hepatic impairment.

The potential risks and benefits of using anagrelide in patients with hepatic impairment should be considered before initiating anagrelide therapy. The medicinal product is not recommended for 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").

Monitoring.

Careful monitoring of the patient's clinical condition is required during treatment, including blood tests (haemoglobin, 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.

Platelets.

Platelet counts begin to increase within 4 days after discontinuation of the drug and return to pre-treatment levels by days 10–14. Thrombotic complications have been reported in patients following abrupt discontinuation or interruption of treatment (including due to medical procedures), as well as in patients receiving maintenance doses but with platelet counts above 600,000/μL. Therefore, platelet counts should be monitored frequently. Abrupt discontinuation of treatment or significant dose reduction should be avoided due to the risk of sudden increase in platelet count, which may lead to potentially fatal thrombotic complications, such as stroke.

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 disorders or suspected cardiovascular disorders only if 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 known to prolong the QTc interval, and hypokalaemia.

Anagrelide should be administered with caution in patients who may have higher plasma concentrations 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.

Cardiological evaluation (electrocardiogram and echocardiogram) is recommended for patients with cardiovascular disorders 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. Hypokalaemia or hypomagnesaemia should be ruled out before initiating anagrelide and monitored during treatment.

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

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

Respiratory system.

Cases of pulmonary hypertension have been reported in patients receiving anagrelide. Symptoms of cardiovascular disorders should be assessed before and during anagrelide treatment.

Paediatric population.

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").

Before 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 leukaemia. As the likelihood of such progression is unknown and the disease duration is longer in children, their risk of developing malignancies is higher than in adults. Regular monitoring for disease progression in children, in accordance with standard clinical practice—such as 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 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:

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

Therefore, this medicinal product must not be administered to patients with congenital galactosaemia, 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. The potential risk to the foetus is unknown. Use of anagrelide in pregnant women is not recommended.

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

Women of childbearing potential who are 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 milk. Risk to the newborn or infant cannot be excluded; therefore, if treatment with the medicinal product 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 administered doses exceeding the therapeutic range, anagrelide disrupted implantation.

Ability to affect driving and operating machinery.

Patients who experience dizziness or visual disturbances while taking the medicinal product should refrain from driving or operating machinery.

Method of Administration and Dosage

For oral use.

Capsules should be swallowed whole.

Do not break or dissolve the contents in liquid.

Treatment with the medicinal product Anagrelide-Vista should be initiated and managed by a physician experienced in the treatment of essential thrombocythemia.

Dosage.

The recommended initial dose of anagrelide is 1 mg per day. 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.

The dose increase should not exceed 0.5 mg per day per week. The maximum single dose of the medicinal product should not exceed 2.5 mg. The maximum daily dose used in clinical studies of anagrelide was 10 mg per day.

During the first week of treatment, platelet counts should be measured every 2 days, and thereafter at least weekly until a stable dose is achieved. Platelet reduction is usually observed within 14–21 days after initiation of treatment. In most patients, an adequate therapeutic 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.

If several doses are missed during long-term treatment, the patient should immediately contact the physician who prescribed anagrelide to monitor platelet levels.

Special Patient Groups.

Elderly patients.

Pharmacokinetic differences observed between elderly and younger patients with essential thrombocythemia did not require adjustment of the initial dose or titration procedure to reach the individual optimal maintenance dose. Clinical studies of anagrelide, in which 50% of participants were aged 60 years or older, showed that these patients did not require age-related dosage modifications. However, serious adverse reactions, primarily cardiovascular, were reported twice as frequently in this age group.

Renal impairment.

There are currently no data on the pharmacokinetics of anagrelide in patients with renal impairment. Therefore, the benefit and potential risk of treatment should be carefully considered before initiating therapy (see section "Contraindications").

Hepatic impairment.

There are currently 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 may affect this process. Anagrelide is not recommended for patients with moderate or severe hepatic impairment. For patients with mild hepatic impairment, the benefit and potential risk of treatment should be carefully weighed before initiating therapy (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, the medicinal product should be used with caution. In the absence of specific pediatric guidelines, the WHO diagnostic criteria for essential thrombocythemia in adults may be applied to children. Diagnostic recommendations for essential thrombocythemia should be strictly followed, and repeat evaluation should be performed in uncertain cases to differentiate between congenital and acquired thrombocytosis. Genetic testing and bone marrow biopsy may be required. In pediatric practice, cytoreductive therapy is generally reserved for patients at high risk. Anagrelide may be considered only in cases of disease progression or thrombotic events.

When anagrelide is used in children, 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 a satisfactory response has not been achieved after 3 months of treatment in children, discontinuation of therapy should be considered.

Current available data are presented in the sections "Pharmacological properties," "Special Warnings and Precautions for Use," and "Undesirable Effects," but dosage recommendations are lacking.

Overdose.

There is limited information on intentional anagrelide overdose. Symptoms. A small number of overdose cases have been reported, with symptoms including sinus tachycardia and vomiting, which resolved with symptomatic treatment. Treatment. 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 medicinal product should be discontinued until platelet counts return to normal. Anagrelide administered at doses higher than recommended has been associated with decreased blood pressure and periodic hypotension. A single 5 mg dose of anagrelide may cause a reduction in blood pressure accompanied by dizziness.

Adverse Reactions

The information currently available on adverse effects from clinical trials, post-marketing surveillance, and spontaneous reports is presented below in the table. According to organ system classes, adverse reactions are listed as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 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.

Children

Safety data are limited and do not allow a comparative analysis of results obtained in adult and pediatric patients (see section "Dosage and Administration").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of a medicinal product is an important procedure. It enables continuous monitoring of the benefit-risk balance for the respective medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original container to protect from moisture at a temperature not exceeding 25 °C. Keep out of reach of children.

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

Prescription category. Prescription only.

Manufacturer.

SintonyHispagna, S.L.

Manufacturer's address and place of business.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.