Eltrombopag (Monograph)

Brand name: Promacta
Drug class: Hematopoietic Agents
ATC class: B02BX05
VA class: BL400
Chemical name: 3′-{(2Z)-2-[1-(3, 4-dimethylphenyl)-3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene] hydrazino}-2′-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2)
Molecular formula: C₂₅H₂₂N₄O₄2•(C₂H₇NO)
CAS number: 496775-62-3

Medically reviewed by Drugs.com on Feb 20, 2024. Written by ASHP.

Introduction

Small-molecule thrombopoietin receptor agonist (TPO-RA).

Uses for Eltrombopag

Immune Thrombocytopenia

Treatment of thrombocytopenia in adults and pediatric patients ≥1 year of age with persistent or chronic immune thrombocytopenia (ITP; also known as idiopathic thrombocytopenic purpura) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy; indicated for use only in patients in whom the degree of thrombocytopenia and clinical status increase risk of bleeding. Designated an orphan drug by FDA for treatment of ITP.

Use eltrombopag to increase platelet counts to a level sufficient to minimize risk of bleeding. Do not use to normalize platelet counts because excessive increases in platelet count may increase the risk of thromboembolic complications.

Not indicated for the treatment of thrombocytopenia associated with myelodysplastic syndrome.

Thrombopoietin receptor agonists (TPO-RAs) are used as second-line therapy for treatment of ITP, generally following lack of platelet response with corticosteroids and/or IV immune globulin (IVIG). Corticosteroids remain the standard initial therapy for newly diagnosed patients with ITP, but should be used for a limited duration only because of adverse effects. Individualize treatment decisions and consider comparative risks and benefits, and adverse effects of therapy.

Thrombocytopenia in Chronic Hepatitis C

Treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Indicated for use only in patients in whom the degree of thrombocytopenia prevents initiation or continuation of interferon-based therapy.

Safety and efficacy not established in combination with direct-acting antiviral agents without the use of interferon for treatment of chronic hepatitis C infection.

Severe Aplastic Anemia

First-line treatment, in combination with standard immunosuppressive therapy, of severe aplastic anemia in adults and pediatric patients ≥2 years of age.

Also used for treatment of severe aplastic anemia in patients with an insufficient response to immunosuppressive therapy.

Designated an orphan drug by FDA for use in treatment of aplastic anemia.

Eltrombopag is recognized as a first- and second-line treatment option for children and adults with aplastic anemia.

Eltrombopag Dosage and Administration

General

Pretreatment Screening

• Prior to initiating therapy, obtain baseline laboratory measurements (e.g., complete blood counts [CBCs] with differentials, measures of hepatic function [AST, ALT, bilirubin concentrations]).

• Perform a baseline ocular examination prior to initiating therapy.

Patient Monitoring

• Monitor clinical hematology and liver function tests regularly throughout therapy for all indications and modify dosage of eltrombopag based on platelet counts.

• When used for the treatment of immune thrombocytopenia (ITP), monitor CBCs with differentials, including platelet counts, weekly until a stable platelet count has been achieved, and then monitor monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Monitor liver function tests (e.g., ALT, AST, bilirubin) every 2 weeks during the dose adjustment phase and then monthly during establishment of a stable dosage; if any abnormalities are found, monitor serum liver function tests weekly until resolution or stabilization.

• When used for the treatment of chronic hepatitis C-associated thrombocytopenia, monitor platelet counts every week prior to initiating antiviral therapy. During antiviral therapy, monitor CBCs with differentials, including platelet counts weekly until a stable platelet count is achieved; monitor platelet counts monthly thereafter. Monitor liver function tests (e.g., ALT, AST, bilirubin) every 2 weeks during the dose adjustment phase and then monthly during establishment of a stable dosage; if any abnormalities are found, monitor serum liver function tests weekly until resolution or stabilization.

• When used for first-line treatment of severe aplastic anemia, monitor ALT, AST, and bilirubin every other day while hospitalized for horse antithymocyte globulin (h-ATG) therapy, then every 2 weeks during treatment.

• Perform ocular examinations during therapy. Routinely monitor patients for signs and symptoms of cataracts.

Administration

Oral Administration

Administer orally as tablets or an oral suspension.

Administer at lowest dosage to achieve and maintain a platelet count ≥50,000/mm³ as necessary to reduce bleeding risk or maintain a hematologic response.

Administer without a meal or with a meal containing a low amount of calcium (≤50 mg). Calcium-containing foods and medications may decrease the rate and extent of eltrombopag absorption; therefore, administer at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (e.g., dairy products, certain fruits and vegetables), or supplements that contain polyvalent cations (e.g., iron, calcium, aluminum, magnesium, selenium, zinc).

Consider administration of the drug in the evening, if possible (unless patients are also taking an antacid preparation containing polyvalent cations at that time), since calcium-containing foods (e.g., dairy products) are more frequently consumed at breakfast.

Oral Suspension

Prepare the suspension only with water. Do not use hot water. Following reconstitution, administer immediately or store for up to 30 minutes at 20–25°C; excursions permitted between 15–30°C. Discard any remaining suspension if not administered within 30 minutes of preparation.

Train patients or caregivers on proper dosing, preparation and administration of oral suspension.

Use a new oral dosing syringe to prepare each dose.

Tablets

Do not split, crush, or chew tablets and mix with food or liquids.

Dosage

Available as eltrombopag olamine; dosage expressed in terms of eltrombopag.

Pediatric Patients

Immune Thrombocytopenia.

Oral

Pediatric patients 1–5 years of age: Initially, 25 mg once daily. Adjust dosage based on platelet count (see Table 1); manufacturer recommends that a platelet count ≥50,000/mm³ be achieved and maintained as necessary to reduce risk of bleeding.

Pediatric patients ≥6 years of age: Initially, 50 mg once daily. For patients with Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai) or who have mild to severe hepatic impairment (Child-Pugh class A, B, or C), initiate at a reduced dosage of 25 mg once daily. For patients with both Asian ancestry and hepatic impairment, consider initiating eltrombopag at a reduced dosage of 12.5 mg once daily. Adjust dosage based on platelet count (see Table 1); manufacturer recommends that a platelet count ≥50,000/mm³ be achieved and maintained as necessary to reduce risk of bleeding.

In patients with ITP and hepatic impairment (Child-Pugh class A, B, or C), dosage should be increased no sooner than 3 weeks after initiation of eltrombopag or after any subsequent dosage increase.

Discontinue therapy if the platelet count has not reached a level sufficient to avoid clinically relevant bleeding after 4 weeks of treatment at the maximum recommended dosage. Monitor CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuance of therapy.

First-Line Treatment of Severe Aplastic Anemia

Oral

Initiate eltrombopag concurrently with standard immunosuppressive therapy.

Recommended initial dosage of eltrombopag for first-line treatment of severe aplastic anemia is based on age, Asian ancestry, and presence of hepatic impairment (see Tables 2 and 3). For patients with Asian ancestry or hepatic impairment (mild, moderate, or severe), reduce initial dose of eltrombopag by 50%.

If baseline ALT or AST >6 times the upper limit of normal (ULN), do not administer eltrombopag until transaminase levels decrease to <5 times the ULN.

Modify dosage based on platelet counts (see Table 4). The total duration of eltrombopag therapy for first-line treatment of severe aplastic anemia is 6 months.

Interrupt therapy, reduce dosage, or discontinue therapy if elevated liver transaminase levels and/or thromboembolic events occur (see Table 5).

Adults

Immune Thrombocytopenia.

Oral

Initially, 50 mg once daily.

For patients with Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai) or hepatic impairment (Child-Pugh class A, B, or C), initiate at a reduced dosage of 25 mg daily. For patients with both Asian ancestry and hepatic impairment, consider initiating eltrombopag at a reduced dosage of 12.5 mg once daily.

Adjust dosage based on platelet count (see Table 6); manufacturer recommends that a platelet count ≥50,000/mm³ be achieved and maintained as necessary to reduce risk of bleeding.

In patients with ITP and hepatic impairment (Child-Pugh class A, B, or C), do not increase dosage sooner than 3 weeks after initiation of eltrombopag or after any subsequent dosage increase.

Discontinue therapy if platelet count has not reached a level sufficient to avoid clinically relevant bleeding after 4 weeks of treatment at the maximum recommended dosage. Monitor CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuance of therapy.

Thrombocytopenia in Chronic Hepatitis C

Oral

Usual initial dosage is 25 mg once daily.

Adjust dosage in 25-mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy (see Table 7). Adjust dosage of eltrombopag during antiviral therapy to avoid dose reductions of peginterferon.

Discontinue eltrombopag when antiviral therapy is discontinued.

First-Line Treatment of Severe Aplastic Anemia

Oral

Initiate concurrently with standard immunosuppressive therapy.

Usual initial dosage is 150 mg once daily.

In patients with Asian ancestry or hepatic impairment, reduce initial dosage to 75 mg once daily.

Total duration of therapy for first-line treatment of severe aplastic anemia is 6 months.

If baseline ALT or AST >6 times ULN, withhold therapy until transaminase levels decrease to <5 times ULN.

Adjust dosage of eltrombopag based on platelet counts (see Table 8).

Interrupt therapy, reduce dosage, or discontinue therapy if elevated liver transaminase levels and/or thromboembolic events occur (see Table 9).

Treatment of Refractory Severe Aplastic Anemia

Oral

Usual initial dosage is 50 mg once daily.

For patients with Asian ancestry or hepatic impairment, reduce initial dosage to 25 mg once daily. May titrate dosage up to a maximum of 150 mg daily based on hematologic response, which may take up to 16 weeks after initiation of therapy. Adjust the dosage in 50-mg increments every 2 weeks as necessary to achieve a target platelet count ≥50,000/mm³ (see Table 10).

If patients achieve tri-lineage response, including transfusion independence, for at least 8 weeks, may reduce dosage of eltrombopag by 50%. If counts remain stable after 8 weeks at the reduced dosage, discontinue eltrombopag and monitor blood counts. If platelet counts decrease to <30,000/mm³, hemoglobin decreases to <9 g/dL, or ANC decreases to <500/mm³, may reinitiate eltrombopag at the previous effective dosage.

Discontinue eltrombopag if no hematologic response has occurred after 16 weeks of therapy. Consider discontinuation of therapy if new cytogenetic abnormalities are observed. Discontinuation of eltrombopag may also be required if important liver test abnormalities or excessive platelet counts occur.

Prescribing Limits

Pediatric Patients

Immune Thrombocytopenia

Oral

Pediatric patients ≥1 year of age: Maximum 75 mg once daily. Do not administer more than one dose in any 24-hour period.

Adults

Immune Thrombocytopenia

Oral

Maximum 75 mg once daily. Do not administer more than one dose in any 24-hour period.

Thrombocytopenia in Chronic Hepatitis C

Oral

Maximum 100 mg daily.

Refractory Severe Aplastic Anemia

Oral

Maximum 150 mg daily.

Special Populations

Hepatic Impairment

Reduced initial dosages may be required in patients with mild to severe hepatic impairment (Child-Pugh class A, B, or C). (See Dosage under Dosage and Administration.)

Ethnicity

Patients with east Asian ancestry (e.g., Chinese, Japanese, Taiwanese, Korean, or Thai): Reduced initial dosages may be required (see Dosage under Dosage and Administration).

Cautions for Eltrombopag

Contraindications

• None.

Warnings/Precautions

Warnings

Hepatic Decompensation in Patients with Chronic Hepatitis C

Risk of hepatic decompensation when eltrombopag is used in combination with interferon and ribavirin in patients with chronic hepatitis C. (See Boxed Warning.) Patients with low albumin levels (<3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score ≥10 at baseline may be at greater risk.

Discontinue eltrombopag if antiviral therapy is discontinued.

Hepatotoxicity

Risk of severe and potentially fatal hepatotoxicity. (See Boxed Warning.)

Treatment of ITP, chronic hepatitis C-associated thrombocytopenia, and refractory severe aplastic anemia: Evaluate liver function tests (e.g., serum ALT, AST, and bilirubin concentrations) prior to starting therapy, every 2 weeks during initial dosage adjustment phase, and then monthly thereafter once a stable dosage has been achieved. If serum bilirubin concentration is elevated, obtain a fractionated measurement. If liver function tests abnormal, repeat tests within 3–5 days; if abnormalities persist, monitor liver function tests on a weekly basis until the abnormality resolves or stabilizes. Discontinue eltrombopag if ALT increases to ≥3 times ULN in patients with normal liver function, or increases to ≥3 times baseline (or >5 times ULN, whichever is lower) in patients with baseline elevations in transaminases and an ALT value that is either progressively increasing, persistent for ≥4 weeks, accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence of hepatic decompensation. Retreatment may be considered if benefits are thought to outweigh the risk of hepatotoxicity. Cautiously reintroduce eltrombopag while monitoring liver function weekly during the dosage adjustment phase. If abnormal liver function tests persist, worsen, or recur, permanently discontinue eltrombopag.

First-line treatment of severe aplastic anemia: Monitor ALT, AST, and bilirubin concentrations prior to initiation of eltrombopag, every other day while hospitalized for h-ATG therapy, and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels according to the manufacturer's guidelines.

Other Warnings and Precautions

Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia

A trial comparing azacitidine in combination with either eltrombopag or placebo in patients with high-risk myelodysplastic syndrome with thrombocytopenia was terminated early due to lack of efficacy and safety concerns, including risk of progression to acute myeloid leukemia (AML).

Thrombotic/Thromboembolic Complications

Increases in platelet counts induced by eltrombopag may result in thrombotic or thromboembolic complications. Thromboembolic events, including both venous and arterial events, observed even with normal or low platelet counts.

To minimize risk of thrombosis and thromboembolic complications, do not use eltrombopag to normalize platelet counts; follow dosage adjustment guidelines, and consider potential increased risk of thromboembolism in patients with preexisting risk factors for thromboembolism (e.g., factor V Leiden, antithrombin III [ATIII] deficiency, antiphospholipid syndrome).

Thrombosis of the portal venous system reported in patients with chronic liver disease receiving eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.

Cataracts

Development or worsening of cataracts reported. Perform a baseline ocular examination prior to eltrombopag therapy; monitor periodically for signs and symptoms of cataracts during therapy.

Specific Populations

Pregnancy

Available data in pregnant women insufficient to assess drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

May cause fetal harm; embryolethality and reduced fetal weights reported in animal studies. (See Females and Males of Reproductive Potential.)

Lactation

Not known whether eltrombopag is distributed into human milk. Breast-feeding is not recommended.

Females and Males of Reproductive Potential

Sexually-active females of reproductive potential should use effective contraception during and for at least 7 days after stopping treatment with eltrombopag.

Pediatric Use

Safety and efficacy established in pediatric patients ≥1 year of age with persistent or chronic ITP and in pediatric patients ≥2 years of age with immunosuppressant therapy-naive severe aplastic anemia (in combination with h-ATG and cyclosporine).

Safety and efficacy not established for treatment of ITP in pediatric patients < 1 year of age, for treatment of thrombocytopenia associated with chronic hepatitis C in pediatric patients, and for treatment of refractory severe aplastic anemia in pediatric patients.

Geriatric Use

No substantial differences in safety and efficacy in geriatric patients ≥65 years of age relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

AUC of eltrombopag is increased in patients with hepatic impairment, including those with chronic hepatitis C.

Patients with ITP or severe aplastic anemia: The manufacturer recommends initial dosage reductions for patients with mild to severe hepatic impairment (Child-Pugh class A, B, or C).

Chronic hepatitis C: No dosage adjustment is recommended.

Renal Impairment

AUC of eltrombopag is reduced in patients with mild, moderate, or severe renal impairment.

Ethnicity

AUC of eltrombopag is increased in patients with Asian ancestry (i.e., Japanese, Chinese, Taiwanese, Korean, or Thai); dosage adjustments recommended.

Common Adverse Effects

Across all indications, the most common adverse reactions (≥20%) associated with eltrombopag were anemia, nausea, pyrexia, increased ALT concentrations, cough, fatigue, headache, and diarrhea.

Drug Interactions

Metabolized by CYP1A2 and CYP2C8; also undergoes glucuronidation by UGT isoenzymes 1A1 and 1A3. Potential to inhibit CYP2C8 and CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15 and the organic anion-transporting polypeptide (OATP) 1B1 and breast cancer resistance protein (BCRP).

Drugs Metabolized by Hepatic Microsomal Enzymes

Inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2, CYP2C19, CYP2C9, or CYP3A4 not demonstrated. Probe substrates for CYP2C8 not evaluated.

Drugs Transported by OATP1B1 or BCRP

Substrates of OATP1B1 or BCRP: Potential pharmacokinetic interaction (increased concentrations) of concomitantly administered OATP1B1 substrates (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or BCRP substrates (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Use concomitantly with caution and consider dosage reduction of the substrate drug if appropriate.

Specific Drugs and Foods

Eltrombopag Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics of eltrombopag are dose proportional over the dosage range of 50 to 150 mg daily.

Peak plasma concentrations occur 2–6 hours following oral administration.

Steady-state concentrations achieved approximately 1 week following once-daily administration.

Systemic exposure following administration of oral suspension approximately 22% higher than tablet formulation.

Onset

Increases in platelet counts generally observed within 1–2 weeks after beginning therapy.

Duration

Decreases in platelet counts generally observed within 1–2 weeks after discontinuance of therapy.

Food

Food (standard high-fat breakfast) decreases rate and extent of absorption; calcium content of meal may contribute to decreased absorption.

Distribution

Extent

Distributes into blood cells; concentrations in blood cells about 50–79% of plasma concentrations.

Not known whether eltrombopag is distributed into human milk.

Plasma Protein Binding

>99%.

Elimination

Metabolism

Extensively metabolized, predominantly through pathways including cleavage, oxidation (CYP1A2 and CYP2C8), and conjugation with glucuronic acid (via UGT1A1 and UGT1A3), glutathione, or cysteine.

Metabolites associated with glucuronidation and oxidation detected.

Elimination Route

Excreted in feces (59%) and urine (31%). Unchanged drug excreted in feces accounts for 20% of the dose; no unchanged drug detectable in urine.

Half-life

Patients with ITP: 26–35 hours.

Special Populations

Asian ancestry (i.e., Japanese, Chinese, Taiwanese, Korean, or Thai) with ITP or chronic hepatitis C: plasma eltrombopag concentrations approximately 50–55% higher compared with patients with non-Asian ancestry.

African-American subjects: exposure was approximately 40% higher than in white subjects in one study, but similar in other clinical pharmacology trials.

Mild hepatic impairment (Child-Pugh class A): Eltrombopag AUC is 41% higher.

Moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C): Eltrombopag AUC is approximately 2-fold higher; half-life prolonged 2-fold.

Patients with chronic hepatitis C and hepatic impairment have increased plasma concentrations and prolonged half-life of eltrombopag.

Stability

Storage

Oral

Oral Suspension

20–25°C (excursions permitted to 15–30°C). Following reconstitution, administer immediately or store for up to 30 minutes at 20–25°C (excursions permitted between 15–30°C). Discard mixture if not used within 30 minutes.

Tablets

20–25°C (excursions permitted to 15–30°C); dispense in original bottle.

Actions

• A small-molecule, nonpeptide, thrombopoietin (TPO)-receptor agonist.

• Interacts with the transmembrane domain of the TPO receptor, initiating a cascade of intracellular signaling events leading to proliferation and differentiation of bone marrow progenitor cells within the megakaryocytic lineage and subsequently increasing the production of platelets.

• Did not prolong QT or QT corrected for rate (QT_c) interval in healthy adults.

Advice to Patients

• Carefully read the patient information (medication guide) provided by the manufacturer before initiating therapy, and each time the prescription is refilled.

• Inform patients that risks associated with long-term administration of eltrombopag are not known.

• Understand that the goal of therapy is to achieve and maintain a platelet count of ≥50,000/mm ³ to reduce the risk of bleeding, not to normalize platelet count.

• Risk of hepatic failure; immediately report symptoms suggestive of jaundice (e.g., yellowing of skin or eyes), unusual darkening of urine, unusual fatigue, or right-upper quadrant (i.e., stomach area) pain to clinician.

• Risk of hepatic decompensation in patients with chronic hepatitis C and cirrhosis when receiving eltrombopag with alfa interferon therapy.

• Risk of hepatobiliary laboratory abnormalities.

• Risk of worsening thrombocytopenia with possible bleeding following discontinuance of eltrombopag, especially if the drug is discontinued while the patient is receiving concomitant anticoagulant or antiplatelet drugs.

• Increased risk of thrombosis or thromboembolism with high platelet counts resulting from excessive eltrombopag dosage. Risk of thrombosis even with normal or low platelet counts. Immediately report symptoms suggestive of thrombosis (e.g., swelling, pain, or tenderness in leg) to clinician.

• Increased risk of developing a hematologic malignancy, especially in patients with myelodysplastic syndrome (MDS).

• Avoid situations or medications that may increase risk of bleeding.

• Risk of new or worsened cataracts.

• Take without a meal or with a meal with low calcium content and at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids that contain polyvalent cations.

• Train patients or caregivers on proper dosing, preparation, and administration of the oral suspension.

• Use a new oral dosing syringe to prepare each dose of the oral suspension.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinicians of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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