Sign Out
The effectiveness and safety of Revolade have not been established for use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic syndromes (MDS).
Hepatotoxicity: Eltrombopag administration can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity and potentially fatal liver injury.
n clinical studies of adult and pediatric patients (aged 1 to 17 years) with chronic ITP who received Revolade, increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and indirect 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 two placebo controlled studies in adults with chronic 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 chronic 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 2 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 the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients.
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, 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.
Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory values occurred approximately three months after initiation of Revolade. In all cases, the event resolved following Revolade discontinuation. No cases were identified from clinical trials in refractory SAA, however the number of exposed patients in this indication was limited. As the highest authorized dose is given to patients in SAA indication (150 mg/day) and due to the nature of the reaction, drug induced liver injury might be expected in this patient's population.
Caution should be exercised when administering Revolade to patients with hepatic disease. In ITP and SAA patients a lower starting dose of Revolade should be used when administering to patients with hepatic impairment (see Dosage & Administration).
Hepatic decompensation (use with interferon): Chronic HCV patients with cirrhosis may be at risk for hepatic decompensation, some with fatal outcomes, when receiving alpha interferon therapy. In 2 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 trials 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, 21 thromboembolic/thrombotic events (TEEs) were observed in 17 out of 446 patients (3.8%). 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 from clinical trials in refractory SAA, however the number of exposed patients in this indication was limited. As the highest authorized dose is given to patients in SAA indication (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient's 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).
In 2 controlled 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 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 platelet counts return to baseline levels within 2 weeks in the majority of patients (see Pharmacology: 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.
Bone Marrow Reticulin Formation and Risk of Bone Marrow Fibrosis: Thrombopoietin (TPO) receptor agonists, including eltrombopag, may increase the risk for development or progression of reticulin fibers within the bone marrow.
Prior to initiation of Revolade, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of Revolade, perform complete blood count (CBC) with white blood cell count (WBC) differential monthly. If immature or dysplastic cells are observed, examine peripheral blood smears for new or worsening morphological abnormalities (e.g., teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Revolade and consider a bone marrow biopsy, including staining for fibrosis.
Malignancies and progression of malignancies: There is a theoretical concern that 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 trials for the treatment of thrombocytopenia due to MDS.
A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk myelodysplastic syndrome (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 Revolade in rodents (see Pharmacology: Toxicology under Actions).
In controlled 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 so 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.
Effects on the Ability to Drive and Operate Machinery: There have been no studies to investigate the effect of eltrombopag on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of eltrombopag. The clinical status of the patient and the adverse event profile of eltrombopag should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills.
Females and males of reproductive potential: Contraception: Based on animal reproduction studies, Revolade can cause fetal harm when administered to a pregnant woman (see Use in Pregnancy & Lactation). Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using Revolade during treatment and for at least 7 days after stopping treatment with Revolade.
Infertility: There is no effect of Revolade on fertility based on animal studies (see Pharmacology: Toxicology under Actions). Eltrombopag did not affect female or male fertility in rats at doses 2 and 3 times respectively the human clinical exposure based on AUC (see Pharmacology: Toxicology under Actions).
