Troplastim^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gelespon, LLC (Russia)

Manufactured By

OHFK, JSC (Russia)

ATC Code

B02BX08 (Avatrombopag)

Active Substance

Avatrombopag (Rec.INN registered by WHO)

Dosage Form

Troplastim®

Film-coated tablets, 20 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs – cardboard packs (10 pcs.) – Prescription only
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – Prescription only
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – Prescription only

Clinical-Pharmacological Group

Thrombopoiesis stimulant

Pharmacotherapeutic Group

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

Pharmacological Action

Avatrombopag is a hemostatic agent, an oral, low-molecular-weight agonist of the thrombopoietin (TPO) receptor, which stimulates the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, leading to increased platelet production. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.

Pharmacokinetics

Plasma concentration-time profiles of avatrombopag after oral administration were characterized by a short lag time (0.5-0.75 h) and a maximum exposure value 6-8 hours after administration.

Avatrombopag demonstrated dose-dependent pharmacokinetics after a single dose ranging from 10 mg (0.5 times the approved minimum dose) to 80 mg (1.3 times the maximum recommended dose).

In a multiple-dose pharmacokinetic study in healthy volunteers, steady state was reached by day 5 of avatrombopag administration.

The binding of avatrombopag to human plasma proteins is more than 96%. The apparent V_d of avatrombopag in patients with thrombocytopenia and chronic liver disease, according to population pharmacokinetic analysis, is approximately 180 L, and the apparent V_d in patients with chronic immune thrombocytopenia is approximately 235 L, indicating extensive distribution of avatrombopag.

Oxidative metabolism of avatrombopag is primarily mediated by the CYP2C9 and CYP3A4/5 isoenzymes. Avatrombopag is a substrate for the P-glycoprotein transport protein, although clinically significant differences in platelet count increase are not expected when avatrombopag is co-administered with a strong P-glycoprotein inhibitor.

Avatrombopag inhibits organic anion transporters (OAT) 1 and 3 and the breast cancer resistance protein (BCRP).

It is excreted primarily via the intestine. After a single dose of ¹⁴C-avatrombopag 20 mg in healthy male volunteers, 88% of the drug dose was excreted via the intestine and 6% via the kidneys. Of the 88% of the drug substance excreted via the intestine, 77% were identified as the parent drug (34%) and the 4-hydroxy metabolite (44%). No metabolites of avatrombopag were detected in plasma. The mean T_1/2 of avatrombopag from plasma is approximately 19 hours. The mean clearance of avatrombopag is 6.9 L/h.

Indications

Treatment of thrombocytopenia in adult patients with chronic liver disease scheduled to undergo a procedure; with primary chronic immune thrombocytopenia and an unsatisfactory response to previous therapy.

ICD codes

Dosage Regimen

For oral administration.

A single dose is 20 mg. Depending on the baseline platelet count, the daily dose is 40-60 mg, and the frequency of administration is 2-3 times/day. Due to limited information, Avatrombopag should be taken for no more than 5 days.

Administration of avatrombopag should be started 10-13 days before the planned procedure. The procedure must be performed 5-8 days after the last dose of avatrombopag.

Adverse Reactions

Blood and lymphatic system disorders common – increased platelet count, decreased platelet count; uncommon – leukocytosis, anemia.

Immune system disorders unknown – hypersensitivity reactions.

Cardiac and vascular disorders uncommon – portal vein thrombosis, increased blood pressure, arrhythmia.

Musculoskeletal and connective tissue disorders uncommon – bone pain, myalgia, arthropathy, limb discomfort, muscle spasms, muscle weakness, musculoskeletal chest pain.

Infections and infestations uncommon – boil, septic thrombophlebitis, upper respiratory tract infection.

Neoplasms benign, malignant and unspecified (including cysts and polyps) uncommon – myelofibrosis.

Renal and urinary disorders uncommon – hematuria.

Metabolism and nutrition disorders common – increased blood glucose, decreased blood glucose, increased blood triglycerides, increased blood gastrin.

Gastrointestinal disorders common – increased LDH activity, increased ALT activity; increased AST activity.

Reproductive system and breast disorders uncommon – menorrhagia, nipple pain.

General disorders and administration site conditions very common – fatigue; common – asthenia; uncommon – pyrexia, chest discomfort, hunger, pain, peripheral edema.

Contraindications

Hypersensitivity to avatrombopag; thrombocytopenia in patients with myelodysplastic syndrome (MDS); children and adolescents under 18 years of age.

With caution

In patients with chronic liver diseases; in patients with known risk factors for thromboembolism and in patients who have previously taken Avatrombopag; with concomitant use with moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5 isoenzymes, or only CYP2C9 isoenzyme (e.g., fluconazole) in patients with chronic liver disease and chronic immune thrombocytopenia; with concomitant use of avatrombopag with interferon drugs, corticosteroids, danazol, dapsone, intravenous immunoglobulin and with moderate or strong dual inducers of CYP2C9 and CYP3A4/5 isoenzymes, or only CYP2C9 isoenzyme; if treatment with avatrombopag is discontinued while taking anticoagulants or antiplatelet drugs.

Use in Pregnancy and Lactation

Data on the use of avatrombopag in pregnant women are limited or absent. Results from animal studies are insufficient to assess reproductive toxicity. Avatrombopag is not recommended during pregnancy and for women of reproductive potential not using reliable contraception.

It is unknown whether Avatrombopag is excreted in human breast milk. Avatrombopag was detected in the milk of lactating rats. A risk to the breastfed infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from avatrombopag therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Use in Hepatic Impairment

Due to limited available information, Avatrombopag should be used in patients with Child-Pugh class C hepatic impairment only if the expected benefit outweighs the potential risk.

Use in Renal Impairment

No dose adjustment is required for mild to moderate renal impairment. The efficacy and safety of avatrombopag have not been studied in patients with severe renal impairment requiring hemodialysis.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required.

Special Precautions

It is known that patients with chronic liver diseases are at increased risk of thromboembolic complications.

Avatrombopag has not been studied in patients with prior thromboembolic complications. The potential increased risk of thrombosis during avatrombopag treatment should be considered in patients with known risk factors for thromboembolism, including, but not limited to, genetic prothrombotic disorders.

After discontinuation of avatrombopag treatment in patients with chronic immune thrombocytopenia, a relapse of thrombocytopenia may occur. After discontinuation of avatrombopag, the platelet count returns to baseline within 2 weeks in most patients, which increases the risk of bleeding and, in some cases, may lead to bleeding. The risk of bleeding is increased if avatrombopag treatment is discontinued while taking anticoagulants or antiplatelet drugs. Platelet counts should be carefully monitored and measures to prevent bleeding should be taken after discontinuation of avatrombopag treatment. In case of avatrombopag discontinuation, it is recommended to resume treatment of chronic immune thrombocytopenia in accordance with current treatment guidelines. Additional therapeutic measures may include discontinuation of anticoagulant and/or antiplatelet therapy, restoration of coagulation potential, or support of platelet hemostasis.

An increase in bone marrow reticulin occurs as a result of stimulation of TPO receptors, leading to an increase in the number of megakaryocytes in the bone marrow and, consequently, a possible increased release of cytokines. An increase in reticulin can be suspected based on morphological changes in peripheral blood cells, with subsequent confirmation by bone marrow biopsy. Therefore, before and during treatment with avatrombopag, examination of a peripheral blood smear and a complete blood count with differential leukocyte count is recommended to detect morphological changes.

The efficacy and safety of avatrombopag in the treatment of thrombocytopenia due to MDS is unknown.

In accordance with clinical practice, it is necessary to carefully monitor for early signs of worsening or development of hepatic encephalopathy, ascites, and a tendency to thrombosis or bleeding in patients with severe hepatic impairment by assessing the results of liver function tests, coagulation parameters, and imaging of the portal vascular system if necessary. Patients with Child-Pugh class C hepatic impairment taking Avatrombopag prior to an invasive procedure should be examined on the day of the procedure to detect a possible unexpectedly high increase in platelet count.

Drug Interactions

Concomitant use of avatrombopag with moderate and strong dual inhibitors of CYP2C9 and CYP3A4/5 isoenzymes (e.g., fluconazole) increases the exposure of avatrombopag. Concomitant use of avatrombopag with moderate and strong inhibitors of the CYP2C9 isoenzyme is presumed to increase the exposure of avatrombopag.

It is assumed that an increase in avatrombopag exposure as a result of its use for 5 days will not have a clinically significant effect on platelet count; dose adjustment is not recommended. However, these patients should be examined on the day of the procedure to detect a possible unexpectedly high increase in platelet count.

The initial dose of avatrombopag should be reduced when used concomitantly with a moderate or strong dual inhibitor of CYP2C9 and CYP3A4/5 isoenzymes. A reduction in the initial dose may also be appropriate in patients taking moderate or strong inhibitors of the CYP2C9 isoenzyme.

In patients who initiate treatment with moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5 isoenzymes, as well as moderate or strong inhibitors of the CYP2C9 isoenzyme while taking avatrombopag, platelet count should be monitored and the dose of avatrombopag adjusted if necessary.

Concomitant use of moderate or strong dual inducers of CYP2C9 and CYP3A4/5 isoenzymes (e.g., rifampicin, enzalutamide) decreases the exposure of avatrombopag and may lead to a decrease in platelet count. Concomitant use of moderate or strong inducers of the CYP2C9 isoenzyme is presumed to decrease the exposure of avatrombopag.

The recommended initial dose of avatrombopag should be increased when used concomitantly with moderate or strong dual inducers of CYP2C9 and CYP3A4/5 isoenzymes. The possibility of increasing the initial dose of avatrombopag should also be considered for patients taking moderate or strong inducers of the CYP2C9 isoenzyme.

In patients who initiate treatment with moderate or strong dual inducers of CYP2C9 and CYP3A4/5 isoenzymes, as well as moderate or strong inducers of the CYP2C9 isoenzyme while taking avatrombopag, platelet count should be monitored and the dose of avatrombopag adjusted if necessary.

In clinical studies, drugs used to treat chronic immune thrombocytopenia in combination with avatrombopag included corticosteroids, danazol, dapsone, and intravenous immunoglobulin. When avatrombopag is used concomitantly with other drugs for the treatment of chronic immune thrombocytopenia, platelet count should be monitored to ensure it does not exceed the recommended normal range.

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.