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The effectiveness and safety of Revolade have not been established for use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic syndrome (MDS). Hepatotoxicity: Revolade administration can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity, and potentially fatal liver injury.
Clinical data: In clinical studies of adult and pediatric patients (aged 1 to 17 years) with ITP who received Revolade, increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and indirect (unconjugated) bilirubin were observed (see ADVERSE REACTIONS).
These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate impaired liver function. In the two placebo-controlled Phase III studies in adults with ITP, adverse events of ALT increase were reported in 5.7% and 4.0% of Revolade and placebo-treated patients, respectively. In two placebo-controlled studies in pediatric patients (aged 1 to 17 years) with ITP, ALT ≥ 3 times the upper limit of normal (x ULN) was reported in 4.7% and 0% of the Revolade and placebo groups, respectively.
In two controlled clinical studies in thrombocytopenic patients with HCV, ALT or AST ≥ 3 x ULN were reported in 34% and 38% of the Revolade and placebo groups, respectively. Revolade administration in combination with peginterferon/ribavirin therapy is associated with indirect hyperbilirubinemia. Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the Revolade and placebo groups, respectively.
In a single-arm, open-label clinical study in definitive immunosuppressive therapy-naïve SAA patients who received Revolade concurrently with h-ATG and cyclosporine, ALT or AST >3 x ULN with total bilirubin >1.5 x ULN was reported in 43.5% (40/92) of patients. None of these elevations resulted in discontinuation.
In the single-arm, monotherapy study in patients with refractory SAA, concurrent ALT or AST >3 x ULN with total bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients.
Dosage adjustment: In patients with ITP, HCV, and refractory SAA, serum ALT, AST and bilirubin should be measured prior to initiation of Revolade, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1 (see PHARMACOLOGY under Actions), which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilize, or return to baseline levels. Revolade should be discontinued if ALT levels increase (≥3 x ULN) in patients with normal liver function, or ≥3 x baseline (or >5 x ULN, whichever is the lower) in patients with elevations in transaminases before treatment and that are: progressive, or, persistent for ≥4 weeks, or, accompanied by increased direct bilirubin, or, accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
In the first-line setting of severe aplastic anemia, ALT, AST, and bilirubin should be measured prior to initiation of Revolade. During treatment, increases in ALT levels should be managed as recommended in Table 15.
Caution should be exercised when administering Revolade to patients with hepatic disease. In ITP and refractory SAA patients, a lower starting dose of Revolade should be used when administering to patients with hepatic impairment (see Special populations (all indications): HEPATIC IMPAIRMENT under DOSAGE & ADMINISTRATION).
Severe liver injury: Isolated cases of severe liver injury were identified in clinical studies. The elevation of liver laboratory values improved or resolved following Revolade interruption or discontinuation. No cases of severe liver injury related to Revolade were identified in a clinical study in patients with definitive immunosuppressive therapy-naïve SAA or refractory SAA, however, the number of exposed patients in these indications was limited. As the highest authorized dose is administered to patients in the SAA indications (150 mg/day) and due to the nature of the reaction, drug-induced liver injury might be expected in this patient population.
Hepatic decompensation (use with interferon): Chronic HCV patients with liver cirrhosis may be at risk for hepatic decompensation, some with fatal outcomes, when receiving alpha-interferon therapy. In the two controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation occurred more frequently in the Revolade arm (13%) than in the placebo arm (7%). Patients with low albumin levels (<3.5 g/dL) or with a Model for End-Stage Liver Disease (MELD) score ≥10 at baseline had a greater risk of hepatic decompensation. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon prescribing information for discontinuation criteria should be referred to. Revolade should be terminated if antiviral therapy is discontinued for hepatic decompensation.
Thrombotic/thromboembolic complications: Platelet counts above the normal range present a theoretical risk for thrombotic/thromboembolic complications. In Revolade clinical studies in ITP, thromboembolic events were observed at low and normal platelet counts.
Caution should be used when administering Revolade to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome). Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing Revolade treatment if the platelet count exceeds the target levels (see DOSAGE & ADMINISTRATION).
In adult ITP studies, thromboembolic/thrombotic events (TEEs) were observed in 42 out of 763 patients (5.5%). The TEEs included: embolism including pulmonary embolism, deep vein thrombosis, transient ischemic attack, myocardial infarction, ischemic stroke, and suspected prolonged reversible ischemic neurologic deficiency.
No cases of TEEs were identified in a clinical study in refractory SAA patients, however the number of exposed patients in this indication was limited. As the highest authorized dose is administered to patients in the SAA indication (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population.
Revolade should not be used in patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is considered appropriate, caution should be exercised when administering Revolade to patients with hepatic impairment (see DOSAGE & ADMINISTRATION and HEPATIC IMPAIRMENT under ADVERSE REACTIONS).
In the two controlled Phase III studies in thrombocytopenic patients with HCV receiving interferon-based therapy, 31 out of 955 patients (3%) treated with Revolade experienced a TEE and 5 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (1% in patients treated with Revolade versus <1% for placebo). No specific temporal relationship between start of treatment and occurrence of TEE was observed. The majority of TEEs resolved and did not lead to the discontinuation of antiviral therapy.
In a controlled study in thrombocytopenic patients with chronic liver disease (n=288, safety population) undergoing elective invasive procedures, the risk of portal vein thrombosis was increased in patients treated with 75 mg Revolade once daily for 14 days. Six of 143 (4%) adult patients with chronic liver disease receiving Revolade experienced TEEs (all of the portal venous system) and two out of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five Revolade treated patients with a TEE experienced the event within 14 days of completing Revolade dosing and at a platelet count above 200,000 microL.
Revolade is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.
Bleeding following discontinuation of Revolade: Following discontinuation of Revolade in the ITP and HCV settings, platelet counts returned to baseline levels within 2 weeks in the majority of patients (see Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions), which increases the bleeding risk and in some cases may lead to bleeding. Platelet counts must be monitored weekly for 4 weeks following discontinuation of Revolade.
Malignancies and progression of malignancies: There is a theoretical concern that thrombopoietin-receptor (TPO-R) agonists may stimulate the progression of existing hematological malignancies such as MDS. The effectiveness and safety of Revolade have not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.
A randomized, double-blind, placebo-controlled, multicenter study in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either Revolade or placebo, was terminated due to futility and increased MDS progression, including to AML. A total of 356 patients (179 on Revolade, 177 on placebo) were randomized 1:1 and stratified by the International Prognostic Scoring System (IPSS): intermediate-1 (n = 64 [36%]), intermediate-2 (n = 79 [44%]), high-risk (n = 36 [20%]) in the Revolade arm versus intermediate-1 (n = 65 [37%]), intermediate-2 (n = 79 [45%]), high-risk (n = 33 [19%]) in the placebo arm. Patients were treated with either Revolade, at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, or placebo in combination with azacitidine for at least six cycles. Based on central review assessment, there were 76 (42%) and 67 (38%) progression-free survival events, in the Revolade group and the placebo group, respectively. Twenty-one (12%) and 10 (6%) patients progressed to AML by central review assessment in the Revolade group and the placebo group, respectively. In the final analysis, overall survival favored the placebo arm: a total of 57 (32%) patients died on the Revolade arm versus 51 (29%) patients in the placebo arm.
Cataracts: Cataracts were observed in toxicology studies of eltrombopag in rodents (see Pharmacology: Toxicology: NON-CLINICAL SAFETY DATA under Actions).
In the two controlled Phase III studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n = 1439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the Revolade group and 5% of the placebo group.
Routine monitoring of patients for cataracts is recommended.
Interference with serological testing: Eltrombopag is highly colored and has the potential to interfere with some laboratory tests. Serum discoloration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, evaluation of contemporaneous aminotransferase values may help in determining the validity of low total bilirubin levels in the presence of clinical jaundice and blood urea should be evaluated in the event of an unexpectedly high serum creatinine. Re-testing using another method may also help in determining the validity of the result.
