Eltrombopag

Pronunciation: el-TROM-boe-pag
Class: Antithrombin agent

Trade Names

Promacta
- Tablets, oral 12.5 mg
- Tablets, oral 25 mg
- Tablets, oral 50 mg
- Tablets, oral 75 mg

Pharmacology

Small-molecule thrombopoietin (TPO) receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.

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Pharmacokinetics

Absorption

Bioavailability was approximately 52%. T max occurs 2 to 6 h after oral administration. Food decreased AUC by 59%, C max by 65%, and delayed T max by 1 h.

Distribution

Concentration in blood cells is approximately 50% to 79% of plasma concentrations. Binding to plasma proteins is more than 99%.

Metabolism

Extensively metabolized, predominantly through pathways involving cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. CYP1A2 and CP2C8 are responsible for oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for glucuronidation.

Elimination

Excretion is 59% in feces (20% unchanged) and 31% in urine. Elimination half-life is 21 to 32 h in healthy individuals and 26 to 35 h in patients with idiopathic thrombocytopenic purpura (ITP).

Special Populations

Renal Function Impairment

The AUC was 32% to 36% lower in patients with mild to moderate renal impairment and 60% lower in patients with severe renal impairment compared with healthy patients.

Hepatic Function Impairment

Following repeat doses of eltrombopag in thrombocytopenic patients, the AUC increased 87% to 110% in patients with mild hepatic impairment, and 141% to 240% in patients with moderate hepatic impairment. Half-life was prolonged 3- and 4-fold in mild and moderate hepatic impairment patients, respectively.

Gender

The AUC was about 23% higher in females compared with males.

Race

Drug exposure is approximately 110% higher in some Asian subjects of Chinese, Japanese, Korean, or Taiwanese ancestry with ITP compared with non-Asian subjects, who were predominantly white. An approximately 40% higher systemic exposure in healthy black subjects was found in at least 1 study.

Indications and Usage

Treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had insufficient response to corticosteroids, immune globulin, or splenectomy.

Contraindications

None well documented.

Dosage and Administration

Adults

PO Start with 50 mg once daily.

Dose adjustments

Adjust dose to achieve and maintain a platelet count of at least 50 × 10 9 /L as necessary to reduce the risk of bleeding. If the platelet count is less than 50 × 10 9 /L following at least 2 wk of therapy, increase the daily dose by 25 mg (max, 75 mg/day). For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. If the platelet count is 200 × 10 9 /L to 400 × 10 9 /L at any time, decrease the dose by 25 mg. Wait 2 wk to assess the effects of this or any subsequent dose adjustments. If the platelet count is more than 400 × 10 9 /L, stop therapy, and increase the frequency of platelet monitoring to twice weekly. Once the platelet count is less than 150 × 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. If the platelet count is more than 400 × 10 9 /L after 2 wk of therapy at the lowest dose of eltrombopag, discontinue therapy. Discontinue treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 wk of therapy at a maximum dosage of 75 mg/day.

East Asian ancestry (eg, Chinese, Japanese, Taiwanese, Korean)

Initiate at a reduced dosage of 25 mg once daily.

Hepatic function impairment
Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C)

Initiate at a reduced dosage of 12.5 mg once daily. For patients of East Asian ancestry, initiate at a reduced dosage of 12.5 mg once daily. After initiating eltrombopag or after any subsequent dosing increase, wait 3 wk before increasing the dose.

General Advice

  • Use the lowest dose to achieve and maintain a platelet count at least 50 x 10 9 /L as necessary to reduce the risk of bleeding.
  • Adjust dose based on platelet count response.
  • Eltrombopag is not to be used to normalize platelet counts.
  • Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy.
  • Should be taken on an empty stomach, 1 h before or 2 h after a meal.
  • Allow at least 4 h between administration of eltrombopag and other medications (eg, antacids), calcium-rich foods (eg, dairy products), or supplements containing polyvalent cations (eg, aluminum, calcium, iron, magnesium, selenium, zinc).
  • Do not administer more than 1 dose in any 24-h period.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Food

A standard high-fat breakfast decreased plasma eltrombopag AUC 0-∞ and C max approximately 59% and 65%, respectively, and delayed T max by 1 h. The calcium content of this meal may contribute to this decrease in exposure. Eltrombopag should be taken on an empty stomach, 1 h before or 2 h after a meal.

Moderate or strong inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine)

Eltrombopag plasma concentrations may be elevated; monitor patients for signs and symptoms of adverse reactions.

Moderate or strong inhibitors of CYP2C8 (eg, gemfibrozil, trimethoprim)

Eltrombopag plasma concentrations may be elevated; monitor patients for signs and symptoms of adverse reactions.

Organic anion–transporting polypeptide (OATP1B1) or breast cancer resistance protein (BCRP) substrates (eg, atorvastatin, benzylpenicillin, doxorubicin, fluvastatin, methotrexate, nateglinide, pravastatin, repaglinide, rifampin, rosuvastatin)

Plasma concentrations of these agents may be elevated, increasing the pharmacologic effects and adverse reactions. Adjust the dose of these agents as needed.

Polyvalent cations (eg, aluminum, calcium, iron, magnesium, selenium, zinc)

Eltrombopag plasma concentrations may be reduced, decreasing the efficacy. Observe patients for evidence of excessive eltrombopag exposure. Do not administer eltrombopag within 4 h of any agent containing polyvalent cations.

UGT enzyme substrates (eg, acetaminophen, narcotics, NSAIDs [eg, ibuprofen])

Observe patients for evidence of excessive exposure to these agents.

UGT1A1 (eg, atazanavir, indinavir) or UGT1A3 (eg, gemfibrozil) moderate or strong inhibitors

Observe patients for evidence of excessive eltrombopag exposure.

Adverse Reactions

CNS

Headache (10%); fatigue (4%); paresthesia (3%).

Dermatologic

Rash (3%); alopecia (2%).

EENT

Cataract (5%); oropharyngeal pain, pharyngitis (4%).

GI

Diarrhea, nausea (9%); vomiting (6%); dry mouth (2%).

Genitourinary

UTI (5%).

Hepatic

Hyperbilirubinemia, increased ALT (6%); increased AST (4%).

Musculoskeletal

Myalgia (5%); back pain (3%); musculoskeletal pain (2%).

Respiratory

Upper respiratory tract infection (7%).

Miscellaneous

Influenza (3%); blood alkaline phosphatase increased (2%).

Precautions

Warnings

Hepatotoxicity

Eltrombopag may cause hepatotoxicity. Discontinue eltrombopag if ALT levels increase to 3 times the ULN or more and are progressive, persistent for 4 wk or more, accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.


Monitor

Measure serum ALT, AST, and bilirubin prior to starting treatment, every 2 wk during the dose-adjustment phase, and monthly following establishment of a stable dose. Perform fractionation if bilirubin is elevated. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 d; if abnormalities are confirmed, monitor serum liver tests weekly until the abnormality(ies) resolves, stabilizes, or returns to baseline values. Discontinue treatment if ALT levels increase to 3 or more times ULN and are progressive, persistent for at least 4 wk, accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Prior to starting therapy, monitor CBCs with differentials, including platelet counts, during the dose adjustment phase of therapy and then monthly following establishment of a stable dose and for at least 4 wk following discontinuation of treatment. Perform a baseline ocular examination prior to administration of eltrombopag and, during therapy with eltrombopag, regularly monitor patients for signs and symptoms of cataracts. Monitor patients with impaired renal function during treatment.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Select dose with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Renal Function

No adjustment in the initial dose is needed.

Hepatic Function

A reduction in the initial dose is recommended for patients with hepatic impairment (Child-Pugh class A, B, or C).

Bone marrow reticulin formation/fibrosis

The risk for development or progression of reticulum fiber deposition within bone marrow may be increased.

Cataracts

May develop or worsen.

Malignancies

The risk of hematologic malignancies may be increased.

Thrombotic/Thromboembolic complications

Thrombotic or thromboembolic complications may result from increases in platelet counts. Reported complications included venous and arterial events and were observed at low and at normal platelet counts.

Discontinuation of therapy

Thrombocytopenia and the risk of bleeding may be worse than experienced prior to therapy, especially if discontinued while patients are on anticoagulants or antiplatelet agents.

Overdosage

Symptoms

Platelet counts may increase excessively, resulting in thrombotic/thromboembolic complications, bradycardia, elevated ALT/AST, fatigue, and rash.

Patient Information

  • Instruct patients to take on an empty stomach, 1 h before or 2 h after a meal.
  • Instruct patients to allow at least 4 h between administration of eltrombopag and antacids, calcium-rich foods (eg, dairy products), or supplements containing aluminum, calcium, iron, magnesium, selenium, and zinc.
  • Instruct patients to immediately report yellowing of the skin or whites of the eyes, unusual darkening of the urine, unusual tiredness, or right upper stomach area pain to health care provider.
  • Inform patients that routine monitoring will need to be performed during therapy.
  • Advise patients to avoid situations or medications that increase the risk of bleeding.
  • Inform patients that following discontinuation of eltrombopag, thrombocytopenia and the risk of bleeding may develop that is worse than that experienced prior to therapy, especially if discontinued while on anticoagulants or antiplatelet agents.
  • Inform patients that eltrombopag increases the risk of reticulin fiber formation within the bone marrow and further fiber formation may progress to marrow fibrosis.
  • Advise patients that eltrombopag stimulates certain bone marrow cells to make platelets and may increase the risk for progression of underlying myelodysplastic syndromes or hematological malignancies.
  • Advise pregnant women to enroll in the eltrombopag pregnancy registry by calling 1-888-825-5249.

Copyright © 2009 Wolters Kluwer Health.

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