Eltrombopag

Trade Names:
Promacta
- Tablets, oral 25 mg
- Tablets, oral 50 mg

Pharmacology

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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.

Pharmacokinetics

Absorption

C _max occurs in 2 to 6 h after oral administration.

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

Pharmacokinetics have not been studied.

In subjects with mild, moderate, or severe hepatic impairment, the eltrombopag AUC was 41%, 80%, and 93% higher, respectively, compared with healthy subjects.

Cl is approximately 27% greater in men compared with women.

Drug exposure is approximately 70% 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.

Contraindications

Standard considerations.

Dosage and Administration

PO Start with 50 mg once daily except in patients who are of East Asian ancestry (eg, Chinese, Japanese, Korean, Taiwanese) or who have moderate to severe hepatic impairment. Start with 25 mg once daily in patients who are of East Asian ancestry or who have moderate to severe hepatic impairment.

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). 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, 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. If the platelet count is more than 400 × 10 ⁹ /L after 2 wk of therapy at the lowest dose of eltrombopag, permanently 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.

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.
• Take 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

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

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

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

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 of any agent containing polyvalent cations.

Observe patients for evidence of excessive exposure to these agents.

Observe patients for evidence of excessive eltrombopag exposure.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Paresthesia (3%).

EENT

Cataracts (3%); conjunctival hemorrhage (2%).

GI

Nausea (6%); vomiting (4%); dyspepsia (2%).

Genitourinary

Menorrhagia (4%).

Hepatic

Increased ALT, increased AST (2%).

Hematologic-Lymphatic

Ecchymosis, thrombocytopenia (2%).

Musculoskeletal

Myalgia (3%).

Precautions

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 concomitant diseases or other drug therapy.

Renal Function

Use with caution.

Hepatic Function

Cl is reduced about 50%, and the half-life is prolonged 2-fold in patients with moderate or severe hepatic function impairment.

Bone marrow 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.

Thromboembolic complications

Thrombotic or thromboembolic complications may result from excessive increases in platelet counts, which may occur as a consequence of excessive eltrombopag doses.

Thrombocytopenia

Discontinuation of therapy may result in thrombocytopenia of greater severity than was present prior to treatment. The worsened thrombocytopenia may increase the risk of bleeding.

Overdosage

Symptoms

Platelet counts may increase excessively, resulting in thrombotic/thromboembolic complications.

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.

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