INTERACTIONS
7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag tablets due to chelation <span class="opacity-50 text-xs">[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]</span> .
7.2 Transporters Use caution when concomitantly administering eltrombopag tablets and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag tablets, a dose reduction of rosuvastatin by 50% was recommended.
7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag tablets are coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag tablets are coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated.
7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag tablets are coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ).
7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine.
Bilirubin
Testing : Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice.
Creatinine
Testing : Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag tablets. Re-testing using other methods may also help in determining the validity of the test results.
AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. (5.2)
Increased
Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. (5.3)
Thrombotic/Thromboembolic
Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag tablets. Monitor platelet counts regularly. (5.4)
5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag tablets in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag tablets plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag tablets plus antivirals. Discontinue eltrombopag tablets if antiviral therapy is discontinued.
5.2 Hepatotoxicity Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . One patient (< 1%) with ITP treated with eltrombopag tablets in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag tablets in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag tablets, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose <span class="opacity-50 text-xs">[see Drug Interactions (7.5)]</span> . Eltrombopag tablets inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. 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 resolved or stabilized. Discontinue eltrombopag tablets if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag tablets is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag tablets and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag tablets is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag tablets. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST, and bilirubin prior to initiation of eltrombopag tablets, 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 as recommended in Table 6.
5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag tablets (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag tablets or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag tablets arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag tablets arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag tablets arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag tablets arm).
5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag tablets. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag tablets to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag tablets in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts <span class="opacity-50 text-xs">[see Dosage and Administration (2.1, 2.2, 2.3)]</span> . In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag tablets experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag tablets versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag tablets once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag tablets and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag tablets were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag tablets experienced a thrombotic complication within 30 days of completing treatment with eltrombopag tablets and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag tablets once daily for 2 weeks in preparation for invasive procedures.
5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag tablets daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag tablets. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag tablets and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.2)]</span> . Perform a baseline ocular examination prior to administration of eltrombopag tablets and, during therapy with eltrombopag tablets, regularly monitor patients for signs and symptoms of cataracts.
5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin, and incorrect test results may be generated if there is eltrombopag in the patient's specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag tablets. Re-testing using other methods may also help in determining the validity of the test results <span class="opacity-50 text-xs">[see Drug Interactions (7.5)]</span> .