WARNING: RISK FOR HEPATOTOXICITY
PROMACTA may cause hepatotoxicity:
>Measure serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of PROMACTA, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. If bilirubin is elevated, perform fractionation.
>Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels.
>Discontinue PROMACTA if ALT levels increase to ≥3X the upper limit of normal (ULN) and are:
>persistent for ≥4 weeks, or
>accompanied by increased direct bilirubin, or
>accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
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
|Platelet Count Result||Dose Adjustment or Response|
|<50 x 109/L following at least 2 weeks of PROMACTA||Increase daily dose by 25 mg to a maximum of 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.|
|≥200 x 109/L to ≤400 x 109/L at any time||Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.|
|>400 x 109/L||Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly.
Once the platelet count is <150 x 109/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.
|>400 x 109/L after 2 weeks of therapy at lowest dose of PROMACTA||Discontinue PROMACTA.|
In patients with hepatic impairment (Child-Pugh Class A, B, C), after initiating PROMACTA or after any subsequent dosing increase wait 3 weeks before increasing the dose.
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
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