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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PROMACTA safely and effectively. See full prescribing information for PROMACTA.
PROMACTA (eltrombopag) tablets, for oral use
Initial U.S. Approval: 2008
PROMACTA (eltrombopag) Tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Each tablet contains eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid.
Mechanism of Action
Eltrombopag is an orally bioavailable, small-molecule 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.
Absorption: Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%.
An open-label, randomized, crossover study was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-8 by approximately 59% and Cmax by 65% and delayed tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
Distribution: The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (>99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.
Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.
Elimination: The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in ITP patients.
INDICATIONS AND USAGE
PROMACTA is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Limitations of use:
--PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
--PROMACTA should not be used in an attempt to normalize platelet counts.
WARNINGS AND PRECAUTIONS
--PROMACTA may cause hepatotoxicity. Increases in serum aminotransferase levels and bilirubin were observed. Liver chemistries must be measured before the initiation of treatment and regularly during treatment.
--Thrombotic/thromboembolic complications may result from increases in platelet counts with PROMACTA. Portal vein thrombosis has been reported in patients with chronic liver disease receiving PROMACTA. Monitor platelet counts regularly.
--Monitor CBCs with differentials (including platelet counts) weekly during the dose adjustment phase of therapy with PROMACTA and then monthly following establishment of a stable dose of PROMACTA.
--Eltrombopag is an inhibitor of OATP1B1 and BCRP transporters. Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 and BCRP (e.g., rosuvastatin) and consider reduction of the dose of these drugs.
--Polyvalent cations (e.g., iron, calcium, aluminum, magnesium, selenium, and zinc) significantly reduce the absorption of eltrombopag; PROMACTA must not be taken within 4 hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements.
USE IN SPECIFIC POPULATIONS
--Pregnancy: PROMACTA may cause fetal harm. Enroll pregnant patients in the PROMACTA pregnancy registry by calling 1-888-825-5249.
--Nursing Mothers: A decision should be made to discontinue PROMACTA or nursing, taking into account the importance of PROMACTA to the mother.
--Reduce the initial dose in patients with hepatic impairment (Child-Pugh Class A, B, C).
The most common adverse reactions (occurring in 3% of patients receiving PROMACTA and at a higher rate in PROMACTA versus placebo) were: nausea, diarrhea, upper respiratory tract infection, vomiting, increased ALT, myalgia, urinary tract infection, oropharyngeal pain, increased AST, pharyngitis, back pain, influenza, paresthesia, and rash.
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE AND ADMINISTRATION
Use the lowest dose of PROMACTA to achieve and maintain a platelet count 50 x 109/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use PROMACTA in an attempt to normalize platelet counts [see Warnings and Precautions ]. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting PROMACTA and decreased within 1 to 2 weeks after discontinuing PROMACTA.
Take PROMACTA on an empty stomach (1 hour before or 2 hours after a meal). Allow at least a 4-hour interval between PROMACTA and other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium fortified juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.
Initial Dose Regimen
Initiate PROMACTA at a dose of 50 mg once daily, except in patients who are of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C).
For patients of East Asian ancestry, initiate PROMACTA at a reduced dose of 25 mg once daily.
For patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate PROMACTA at a reduced dose of 25 mg once daily [see Use in Specific Populations ].
For patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C), consider initiating PROMACTA at a reduced dose of 12.5 mg once daily.
Monitoring and Dose Adjustment
After initiating PROMACTA, adjust the dose to achieve and maintain a platelet count =50 x 109/L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 1. During therapy with PROMACTA, assess CBCs with differentials (including platelet count) weekly until a stable platelet count has been achieved. Obtain CBCs with differentials (including platelet counts) monthly thereafter.
Table 1. Dose Adjustments of PROMACTA
Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with PROMACTA. Do not administer more than one dose of PROMACTA within any 24-hour period.
Discontinue PROMACTA if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with PROMACTA at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of PROMACTA
DOSAGE FORMS AND STRENGTHS
12.5 mg, 25 mg, 50 mg, and 75 mg tablets. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid.
Package Insert data:
PROMACTA is a registered trademark of GlaxoSmithKline.
Research Triangle Park, NC 27709
©2011, GlaxoSmithKline. All rights reserved.
Revised: December 2011