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Precautions of Eltrombopag

1 Hepatic Decompensation in Patients With Chronic Hepatitis C  

In patients with chronic hepatitis C, Eltrombopag 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 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 plus antivirals.  Discontinue Eltrombopag if antiviral therapy is discontinued.

2 Hepatotoxicity  

Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. One patient (< 1%) with ITP treated with Eltrombopag in clinical trials experienced druginduced liver injury. Eleven patients (1%) with chronic hepatitis C treated with Eltrombopag 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, every 2 weeks during the dose  adjustment phase, and monthly following establishment of a stable dose. Eltrombopag 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 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 is considered to outweigh the risk for  hepatotoxicity, then consider cautiously reintroducing Eltrombopag and measure serum liver tests weekly  during the dose adjustment phase. Hepatotoxicity may reoccur if Eltrombopag is reinitiated. If liver test  abnormalities persist, worsen, or recur, then permanently discontinue Eltrombopag.

First-Line Treatment of Severe Aplastic Anemia

Measure ALT, AST, and bilirubin prior to initiation of Eltrombopag, every other day while hospitalized for hATG therapy, and then every 2 weeks during treatment.

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 (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 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 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 arm). The incidence of  progression to AML was 12% (21/179) in the Eltrombopag 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 arm).

4 Thrombotic/Thromboembolic Complications  

Thrombotic/thromboembolic complications may result from increases in platelet counts with Eltrombopag.  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 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 in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve  and maintain target platelet counts.

In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated  with Eltrombopag 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 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 once daily. Seven thrombotic complications (six patients) were reported in the group  that received Eltrombopag and three thrombotic complications were reported in the placebo group (two  patients). All of the thrombotic complications reported in the group that received Eltrombopag 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 experienced a thrombotic complication within 30 days of  completing treatment with Eltrombopag and at a platelet count above 200 x 109 /L. The risk of portal venous  thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of  Eltrombopag once daily for 2 weeks in preparation for invasive procedures.

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 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. 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 and 5% of  patients treated with placebo.

Cataracts were observed in toxicology studies of eltrombopag in rodents.  Perform a baseline ocular examination prior to administration of Eltrombopag and, during therapy with  Eltrombopag, regularly monitor patients for signs and symptoms of cataracts.

from FDA，2021.10