Eltrombol^® (Tablets) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

ATC Code

B02BX05 (Eltrombopag)

Active Substance

Eltrombopag (Rec.INN registered by WHO)

Dosage Forms

	Eltrombol®	Film-coated tablets 25 mg
		Film-coated tablets 50 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
28 pcs. – polymer jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – polymer jars – cardboard packs (30 pcs.) – By prescription
7 pcs. – blister packs (2 pcs.) – cardboard packs (14 pcs.) – By prescription
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – By prescription

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
28 pcs. – polymer jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – polymer jars – cardboard packs (30 pcs.) – By prescription
7 pcs. – blister packs (2 pcs.) – cardboard packs (14 pcs.) – By prescription
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – By prescription

Clinical-Pharmacological Group

Thrombopoiesis stimulant

Pharmacotherapeutic Group

Hemostatic agents; vitamin K and other hemostatic agents; other systemic hemostatic agents

Pharmacological Action

Eltrombopag is an oral thrombopoietin receptor agonist. It interacts with the human thrombopoietin receptor site, causing proliferation and differentiation of megakaryocytes from bone marrow hematopoietic progenitor cells and leading to increased platelet production.

Platelet count in the blood typically increases within 1-2 weeks after starting eltrombopag treatment and decreases within 1-2 weeks after its discontinuation.

Eltrombopag in doses up to 150 mg/day for 5 days does not prolong the QT/QTc interval.

Pharmacokinetics

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

After oral administration, C_max is reached in 2-6 hours. Oral absorption is at least 52%. At a dose of 50 mg once daily, AUC is 91.9 µg x h/mL, at a dose of 75 mg – 146 µg x h/mL. When taken during a standard high-fat breakfast, AUC decreases by approximately 59%, C_max – by 65%, and T_max increases by 1 hour. The calcium content in food also plays a role in reducing bioavailability.

Plasma protein binding 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 undergoes intensive metabolism, primarily via cleavage, oxidation, and conjugation with glucuronic acid, glutathione, and cysteine. The oxidative metabolism of eltrombopag is mediated by the CYP1A2 and CYP2C8 isoenzymes. Glucuronidation of eltrombopag occurs with the participation of UGT1A1 and UGT1A3 glucuronyltransferases.

Excretion in feces is 59%, in urine – 31%. Unchanged Eltrombopag in feces is about 20% and is not detected in urine.

T_1/2 from plasma is approximately 21-32 hours in healthy volunteers and 26-35 hours in patients with idiopathic thrombocytopenic purpura.

In patients with moderate hepatic impairment, the AUC of eltrombopag increases by 41%, in patients with moderate to severe hepatic impairment – by 80-93%, compared to healthy volunteers.

Indications

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

ICD codes

Dosage Regimen

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

The initial dose is 50 mg once daily.

For patients with moderate to severe hepatic impairment or for patients of East Asian origin, the initial dose is 25 mg once daily.

After starting treatment, the dose should be adjusted to achieve and maintain a platelet count ≥ 50 x 10⁹/L to avoid the risk of bleeding. Do not exceed a dose of 75 mg/day.

When a platelet count from ≥ 200 x 10⁹/L to ≤ 400 x 10⁹/L is achieved, the daily dose should be reduced by 25 mg and this reduced dose should be used for 2 weeks until the effect develops.

If the platelet count exceeds 400 x 10⁹/L, discontinue eltrombopag and monitor platelet count twice weekly. When the platelet count reaches < 150 x 10⁹/L, resume therapy at a dose reduced by 25 mg.

If the platelet count exceeds 400 x 10⁹/L after 2 weeks of therapy with eltrombopag at the minimum effective dose, Eltrombopag should be discontinued.

To avoid an excessive increase in platelet count during eltrombopag therapy, the dosage regimen of concurrently used drugs for the treatment of idiopathic thrombocytopenic purpura should be adjusted.

The interval between eltrombopag doses should be at least 24 hours.

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

During treatment, hematological parameters and liver tests (ALT, AST, bilirubin) should be regularly monitored and the eltrombopag dosage regimen adjusted according to changes in platelet count.

The interval between taking eltrombopag and other medications, calcium-containing products, vitamins containing polyvalent cations (iron, calcium, aluminum, magnesium, selenium, zinc) should be at least 4 hours.

Adverse Reactions

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

From the organ of vision cataract, conjunctival hemorrhage.

From the blood coagulation system hemorrhagic complications after discontinuation of eltrombopag – menorrhagia, ecchymoses, thrombocytopenia.

Other myalgia, paresthesia.

Contraindications

Hypersensitivity to eltrombopag.

Not intended for use solely to normalize platelet count.

Use in Pregnancy and Lactation

Adequate and strictly controlled studies on the safety of eltrombopag use during pregnancy have not been conducted. Use is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is unknown whether Eltrombopag is excreted in human breast milk. If it is necessary to use eltrombopag during lactation, breastfeeding should be discontinued.

In experimental studies in animals, data on embryolethality and decreased offspring body weight were obtained when eltrombopag was administered at doses toxic to the maternal organism.

Use in Hepatic Impairment

Eltrombopag has hepatotoxic effects, so caution is required when using it in patients with liver diseases. In moderate and severe liver diseases, Eltrombopag should be used at the minimum effective initial dose and under careful monitoring of liver function tests. Determination of ALT, AST, bilirubin content is performed before starting treatment, every 2 weeks during the dose adjustment period, and monthly after determining the constant dose. If bilirubin content increases, fractionation should be performed. Liver tests should be performed at intervals of 3-5 days. In case of persistent abnormalities, monitoring should be performed weekly until they disappear, stabilize, and return to baseline values.

Eltrombopag should be discontinued if the ALT value exceeds the ULN by 3 times and is progressive, or persists for 4 weeks or more, or is accompanied by an increase in direct bilirubin content, or is accompanied by clinical symptoms of liver disease, or decompensation of liver function. Resumption of eltrombopag therapy is not recommended. If the potential benefit of resuming therapy outweighs the existing risk, eltrombopag should be started cautiously under the control of liver function indicators during the dose selection period. In case of persistent impairment of liver function tests, Eltrombopag should be permanently discontinued.

Use in Renal Impairment

The safety and efficacy of eltrombopag in patients with varying degrees of renal impairment have not been established. Renal function should be carefully monitored during treatment.

Pediatric Use

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

Geriatric Use

Dose selection should be conducted with caution in elderly patients.

Special Precautions

Eltrombopag has hepatotoxic effects, so caution is required when using it in patients with liver diseases. In moderate and severe liver diseases, Eltrombopag should be used at the minimum effective initial dose and under careful monitoring of liver function tests. Determination of ALT, AST, bilirubin content is performed before starting treatment, every 2 weeks during the dose adjustment period, and monthly after determining the constant dose. If bilirubin content increases, fractionation should be performed. Liver tests should be performed at intervals of 3-5 days. In case of persistent abnormalities, monitoring should be performed weekly until they disappear, stabilize, and return to baseline values.

Eltrombopag should be discontinued if the ALT value exceeds the ULN by 3 times and is progressive, or persists for 4 weeks or more, or is accompanied by an increase in direct bilirubin content, or is accompanied by clinical symptoms of liver disease, or decompensation of liver function. Resumption of eltrombopag therapy is not recommended. If the potential benefit of resuming therapy outweighs the existing risk, eltrombopag should be started cautiously under the control of liver function indicators during the dose selection period. In case of persistent impairment of liver function tests, Eltrombopag should be permanently discontinued.

Eltrombopag, like other thrombopoietin receptor agonists, increases the risk of development or progression of reticulin fiber deposition in the bone marrow.

Before starting eltrombopag treatment, an extended peripheral blood analysis should be performed to identify morphological abnormalities of blood cells. After determining the constant dose of eltrombopag, such an analysis should be performed monthly to identify new or worsening existing morphological abnormalities. If blood cell abnormalities develop or worsen, or cytopenia develops, discontinue Eltrombopag, consider performing a bone marrow biopsy, including special staining to detect fibrosis.

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

Due to excessive increase in platelet content during treatment, thrombotic/thromboembolic complications may develop.

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

Regular ophthalmological monitoring is required during treatment to detect symptoms of cataract.

The safety and efficacy of eltrombopag in patients with varying degrees of renal impairment have not been established. Renal function should be carefully monitored during treatment.

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

Dose selection should be conducted with caution in elderly patients.

Drug Interactions

Patients should be monitored for signs of excessive increase in the intensity of eltrombopag action when used concomitantly with moderate or strong inhibitors of the CYP1A2 and CYP2C8 isoenzymes, which are involved in the oxidative metabolism of eltrombopag.

Studies have shown that Eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and can increase the systemic bioavailability of other drugs that are substrates of this transporter (including benzylpenicillin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateglinide, repaglinide, rifampin). In clinical studies in healthy volunteers, administration of a single dose of rosuvastatin after repeated daily administration of eltrombopag increased the AUC of rosuvastatin by 55% and C_max by 103% (with this combination, a 50% reduction in the rosuvastatin dose is recommended).

Eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15 – enzymes involved in the metabolism of many drugs, such as acetaminophen, opioid analgesics, NSAIDs. When eltrombopag is combined with such drugs, the possibility of an excessive enhancement of the effect of these drugs cannot be excluded (clinical monitoring is required).

Enzymes UGT1A1 and UGT1A3 are involved in the glucuronidation of eltrombopag, therefore, with the concomitant use of moderate or strong inhibitors or inducers of these enzymes, an effect on the systemic bioavailability of eltrombopag is possible (clinical monitoring of the effectiveness of eltrombopag is necessary during concomitant use).

With the concomitant use of eltrombopag with antacids containing aluminum hydroxide, magnesium carbonate, sodium alginate, a decrease in the systemic bioavailability of eltrombopag by approximately 70% was observed (the interval between taking eltrombopag and such drugs should be at least 4 hours to avoid reduced absorption of eltrombopag).

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.