Eltrombopag (Eltrombopagum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Stimulators of hematopoiesis

Included in the formulation
  • Revolide®
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    Novartis Pharma AG     Switzerland
    • АТХ:

    B.02.B.X.05   Eltrombopag

    Pharmacodynamics:

    Thrombopoietin receptor agonist for oral administration. Interacts with the site of the human thrombopoietin receptor, which causes the proliferation and differentiation of megakaryocytes from the precursor cells of bone marrow hematopoiesis and leads to an increase in platelet formation.

    The number of platelets in the blood usually rises within 1-2 weeks after initiation of treatment with eltrombopag and decreases within 1-2 weeks after its withdrawal.

    Eltrombopag in a dose of up to 150 mg per day for 5 days does not prolong the interval QT / QTc.

    Pharmacokinetics:

    The pharmacokinetics of eltrombopag are described by a two-component model.

    After oral administration, the maximum concentration is reached in 2-6 hours. Absorption at ingestion is at least 52%. At a dose of 50 mg once a day, the system exposure is 91.9 μg x h / ml, with a dose of 75 mg - 146 μg h / ml. When taken during a standard breakfast with a high fat content, the system exposure is reduced by approximately 59%, the maximum concentration at 65%, the time of maximum concentration increases by 1 h. The calcium content of the food also plays a role in reducing bioavailability.

    Binding to plasma proteins is more than 99%. The concentration of eltrombopag in blood cells is approximately 50-79% of the plasma concentration.

    Eltrombopag is not a substrate of P-glycoprotein or OATP1B1. It is subjected to intensive metabolism, mainly by cleavage, oxidation and conjugation with glucuronic acid, glutathione, cysteine. Oxidative metabolism of eltrombopag is carried out with the participation of isoenzymes CYP1A2 and CYP2C8. Glucuronization of eltrombopag occurs with the participation of glucuronosyltransferases UGT1A1 and UGT1A3.

    Excretion with feces is 59%, with urine - 31%. Unchanged elthrombopag in feces is about 20%, in urine is not determined.

    Half-life from plasma is about 21-32 hours in healthy volunteers, in patients with idiopathic thrombocytopenic purpura - 26-35 hours.

    In patients with moderate hepatic insufficiency, the systemic exposure of eltrombopag increases by 41%, in patients with moderate to severe hepatic insufficiency - by 80-93%, in comparison with healthy volunteers.

    Indications:Thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura when corticosteroids are ineffective,immunoglobulins or splenectomy (used only in cases where the degree of thrombocytopenia and clinical condition increase the risk of bleeding).
    ICD-10

    III.D60-D64.D63.0 *   Anemia in neoplasm (C00-D48 +)

    III.D65-D69.D69.3   Idiopathic thrombocytopenic purpura

    III.D65-D69.D69.6   Thrombocytopenia, unspecified

    XVIII.R50-R69.R58   Bleeding, not elsewhere classified

    Contraindications:

    Hypersensitivity to eltrombopagu.

    Not intended for use only to normalize the number of platelets.

    Carefully:

    Eltrombopag has a hepatotoxic effect, so caution is required when used in patients with liver disease. With moderate and severe liver disease elthrombopag should be used in a minimal effective initial dose and under careful control of functional liver tests. Determination of ALT, AST, bilirubin content is carried out before the start of treatment, every 2 weeks during the period of dose adjustment and monthly after the determination of the constant dose. When increasing the bilirubin content, fractionation should be carried out. The examination of liver tests should be carried out with an interval of 3-5 days.In the case of persistent deviations, monitoring should be carried out weekly until they disappear, stabilize and return to the baseline values.

    Eltrombopag should be abolished if ALT exceeds the upper limit of the norm by 3 times and progresses, or persists for 4 weeks or more, or is accompanied by an increase in the content of direct bilirubin, or is accompanied by clinical symptoms of liver disease, or decompensated liver function. The resumption of therapy with elethrombopag is not recommended. If the potential benefit of restarting therapy exceeds the risk, caution should be started with the use of eltrombopag under the control of liver function during the dose selection period. With persistent impairment of functional liver tests elthrombopag should be abolished definitively.

    The safety and efficacy of eltrombopag in patients with impaired renal function of various degrees have not been established. During the treatment period, the kidney function should be carefully monitored.

    The safety and efficacy of elthrombopag in children and adolescents have not been established.

    Be wary of choosing a dose in elderly patients.

    Pregnancy and lactation:

    Category FDA not determined. Adequate and strictly controlled studies of the safety of the use of eltrombopag during pregnancy have not been conducted. The application is only possible in cases where the expected benefit of therapy for the mother exceeds the potential risk to the fetus.

    It is not known whether elthrombopag with human breast milk. If it is necessary to use eltrombopag during lactation, breastfeeding should be discontinued.

    In experimental studies on animals, data were obtained on embryo-lability and a decrease in the body weight of the offspring with the administration of eltrombopag in doses toxic to the maternal organism.

    Dosing and Administration:

    Take inside 1 hour before meals or 2 hours after meals.

    The initial dose is 50 mg once a day.

    For patients with impaired liver function from moderate to severe degree or for patients of East Asian origin, the initial dose is 25 mg once a day.

    After the start of treatment, the dose should be adjusted before reaching and maintaining a platelet count of ≥ 50 x 109/ l to avoid the risk of bleeding. Do not exceed a dose of 75 mg per day.

    When the number of platelets reaches ≥ 200 x 109/ l to ≤ 400 x 109/ l daily dose should be reduced by 25 mg and apply this reduced dose within 2 weeks before the development of the effect.

    When the number of platelets reaches more than 400 x 109/ l should stop taking eltrombopaga, control the number of platelets 2 times a week. When the platelet count is <150 x 109/ l should resume therapy in a dose reduced by 25 mg.

    When the number of platelets reaches more than 400 x 109/ l after 2 weeks of therapy with eltrombopagom in the minimum effective dose should be canceled elthrombopag.

    In order to avoid an excessive increase in the number of platelets during therapy with eltrombopag, the dosage regimen of concomitant medications should be adjusted to treat idiopathic thrombocytopenic purpura.

    The interval between doses of eltrombopag should be at least 24 h.

    To achieve and maintain a platelet count in the blood ≥ 50 x 109/ l elthrombopag should be used at the lowest effective dose to avoid the risk of bleeding.

    During treatment, hematological indicators and liver tests should be monitored regularly (ALT, AST,bilirubin) and adjust the dosing regimen of eltrombopag according to the change in the number of platelets.

    Between intervals of eltrombopag and other drugs, products containing calcium, vitamins containing polyvalent cations (iron, calcium, aluminum, magnesium, selenium, zinc), the interval should be at least 4 hours.

    Side effects:

    From the side digestive system: nausea, vomiting, dyspepsia, increased ALT, AST.

    From the side organ of vision: cataract, hemorrhage in the conjunctiva.

    From the side blood coagulation system: hemorrhagic complications after the abolition of eltrombopag - menorrhagia, ecchymosis, thrombocytopenia.

    Other: myalgia, paresthesia.

    Overdose:

    Symptoms: In clinical trials, one case of an overdose was recorded when the patient ingested 500 mg of eltrombopag, while the following symptoms were noted: an uncommon rash, a transient bradycardia, fatigue, and an increase in transaminase levels. These changes were reversible.

    In the case of an overdose, a significant increase in the number of platelets is possible, which can lead to thrombotic / thromboembolic complications.

    Treatment: In case of overdose, consideration should be given to the ingestion of preparations containing metal cations, for example calcium, aluminum or magnesium, to reduce the absorption of eltrombopag. Thrombocyte count should be carefully monitored. Treatment with eltrombopagom is resumed in accordance with the recommendations on the dosage regimen.

    Since renal excretion is not the main way of excretion of eltrombopag, which actively binds to blood plasma proteins, it is more likely that hemodialysis is not an effective method of significantly accelerating the excretion of eltrombopag from the body.

    Interaction:

    Rosuvastatin: when used together with eltrombopagom should consider reducing the dose of rosuvastatin, as well as carry out a thorough monitoring of the patient's condition. In clinical studies of eltrombopag with concomitant therapy with rosuvastatin, a dose reduction of 50% was recommended. Co-administration of eltrombopag and other substrates of OATP1B1 and BCRP requires caution.

    Polyvalent cations (formation of chelate complexes): in order to avoid a significant decrease in absorption of eltrombopag, the drug should be taken at least 4 hours before or after taking antacids, dairy products and other substances,containing polyvalent cations (for example, mineral additives containing aluminum, calcium, iron, magnesium, selenium and zinc).

    Food: a single dose of eltrombopag 50 mg with a standard high-calorie breakfast containing a large amount of fat and dairy products reduces the system exposure by 59% (CI 90%: 54 and 64%) and the maximum concentration by 65% ​​(CI 90%: 59 and 70%). Foods with a low calcium content (<50 mg calcium), including fruits, lean ham, beef, fruit juice, soy milk and croup without calcium, iron and magnesium, do not significantly affect the plasma exposure of eltrombopagus, regardless of caloric content and fat content .

    Special instructions:

    Eltrombopag, like other thrombopoietin receptor agonists, increases the risk of developing or progressing the deposition of reticulin fibers in the bone marrow.

    Before starting treatment with eltrombopag, an extensive analysis of peripheral blood should be performed to detect morphological disorders of blood cells. Once a constant dose of eltrombopag has been determined, this analysis should be performed monthly to identify new or worsening existing morphological disorders.With the development or deterioration of blood cells, or the development of cytopenia should be canceled elthrombopag, consider the possibility of a bone marrow biopsy, including special staining for fibrosis.

    After the abolition of eltrombopag may develop more severe thrombocytopenia than before treatment. This increases the risk of bleeding, especially in patients receiving anticoagulants or antithrombotic agents. After the abolition of the eltrombopag, the cellular composition of the blood, including platelet counts, should be monitored for at least 4 weeks and alternative therapy should be considered for thrombocytopenia.

    Due to excessive increase in platelet count during the treatment, the development of thrombotic / thromboembolic complications is possible.

    Eltrombopag also stimulates thrombopoietin receptors on the surface of hematopoietic cells, which can increase the risk of hematological malignancy.

    During treatment, regular ophthalmic control is required to detect symptoms of cataract.

    Studies on the effect of eltrombopag on the ability to drive a car or work with mechanisms have not been carried out. Based on the pharmacological properties of elthrombopag, no adverse effects on such activities are expected. However, when evaluating a patient's ability to perform actions that require quick thinking, motor and cognitive skills, the clinical condition of the patient and the profile of unwanted effects of elthrombopag should be considered.

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