Eltrombopag Olamine Drug Information
Generic name: ELTROMBOPAG
Uses of Eltrombopag Olamine
Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag
tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are
indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
Treatment of Severe Aplastic Anemia Eltrombopag tablets are indicated in combination with
standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
Limitations of Use Eltrombopag tablets are not indicated for the treatment of
patients with myelodysplastic syndromes (MDS). Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
Dosage & Administration of Eltrombopag Olamine
| < 50 x 109/L following at least 2 weeks of eltrombopag tablets | 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.For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. |
| > 400 x 109/L | Stop eltrombopag tablets; 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 eltrombopag tablets | Discontinue eltrombopag tablets. |
Side Effects of Eltrombopag Olamine
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications . The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial . Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year.
Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8: Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo.
Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9: Treatment-related Adverse Reactions ( > 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial.
Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use.
In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients.
In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses . Pediatric Patients The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10: Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag.
Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11: Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep.
Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively.
ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1,520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients.
Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months.
The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1-M6 cohort. Table 12: Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse Reaction Eltrombopag n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
In the eltrombopag D1-M6 cohort, ALT increased (29%), AST increased (17%) and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag D1-M6 cohort.
In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%) and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients.
Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year.
The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13: Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients.
Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7.
Post-marketing Experience
The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing.
Warnings & Cautions for Eltrombopag Olamine
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.
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 drug-induced 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 h-ATG therapy and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6.
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 = 1.42, 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 = 2.66, showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag arm).
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 10 9 /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.
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.
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. Re-testing using other methods may also help in determining the validity of the test results .
Drug Interactions with Eltrombopag Olamine
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 due to chelation .
Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates
of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38, 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, a dose reduction of rosuvastatin by 50% was recommended.
Protease Inhibitors
HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag is co-administered 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 is co-administered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated.
Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is co-administered
with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ).
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. Re-testing using other methods may also help in determining the validity of the test results.
Pregnancy Safety for Eltrombopag Olamine
Pregnancy Risk Summary Available data from a small number of published case reports and post-marketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.
In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.
In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.
Pediatric Use of Eltrombopag Olamine
Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily.
See Dosage and Administration for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established.
In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older.
Overdosage Information for Eltrombopag Olamine
In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5,000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue.
The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption.
Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations . Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
Clinical Studies of Eltrombopag Olamine
Persistent or Chronic
ITP Adults The efficacy and safety of eltrombopag in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively ), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female.
Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag 50 mg or placebo.
Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3 to 12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16: Studies 773B and 773A: Platelet Count Response ( > 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia Study Eltrombopag 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p- value < 0.001 for eltrombopag versus placebo.
The platelet count response to eltrombopag was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg–dose groups of eltrombopag, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively.
The median duration of treatment with the 50 mg dose of eltrombopag was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag.
In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated.
The median ages of the patients treated with eltrombopag and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag relative to placebo and was based on patient response profiles throughout the 6-month treatment period.
In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag 51%, placebo 8%; non-splenectomized patients: eltrombopag 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial.
Table 17: RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3
Requiring rescue therapy, n (%) 24 25 Among 94 patients receiving other
ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy.
The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients The efficacy and safety of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials.
The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to eltrombopag (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets.
A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag.
The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag and 90% in the group treated with placebo.
Four patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of subjects on eltrombopag achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18: PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%) a 10/24 (42%) 11/25 (44%) 5/14 (36%) 1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%) a p- value = < 0.001 for eltrombopag versus placebo. More pediatric patients treated with eltrombopag (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy.
Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% versus 24% ). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy.
In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range.
The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 10 years and 60% were female.
Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag was consistent across the age cohorts.
Table 19: PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 28/45 (62%) a 10/16 (62%) 12/19 (63%) 6/10 (60%) 7/22 (32%) 0/8 (0%) 3/9 (33%) 4/5 (80%) a p- value = 0.011 for eltrombopag versus placebo. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% versus 50% ). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy.
Chronic Hepatitis C-Associated Thrombocytopenia
The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype.
Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin.
The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups.
The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag was 9 weeks.
If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag at the end of the pre-treatment phase or to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment.
The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag versus 8% (20/239) for placebo.
Table 20: ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Pre-antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag n = 450 % Placebo n = 232 % Eltrombopag n = 506 % Placebo n = 253 % Overall SVR d HCV genotype 2, 3 HCV genotype 1, 4, 6 23 35 18 14 24 10 19 34 13 13 25 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p- value < 0.05 for eltrombopag versus placebo. The majority of patients treated with eltrombopag (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared with placebo (45% versus 27%).
Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag in combination
with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T ) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab or high dose cyclophosphamide. A total of 153 patients received eltrombopag in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag starting dose but differed by treatment start day and duration.
The starting dose of eltrombopag for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians) and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). Cohort 1 (n = 30): eltrombopag on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine Cohort 2 (n = 31): eltrombopag on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine Cohort 3+ Extension cohort (n = 92): eltrombopag on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag in Study US01T. Data from the Cohort 3+ Extension cohort support the efficacy of eltrombopag for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21: Dosages of Immunosuppressive Therapy Administered With Eltrombopag in Study US01T Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 th percentile : 3 mg/kg, based on adjusted body weight b, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95 th percentile : 6 mg/kg, based on adjusted body weight b, orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. In the eltrombopag D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively.
Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1,000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses.
Table 22: Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Eltrombopag D1-M6 + h-ATG + cyclosporine n = 92 Month 6, n a Overall response, n (%) Complete response, n (%) 87 69 38 Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months.
Refractory Severe Aplastic Anemia Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T ) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag was discontinued after 16 weeks if no hematologic response was observed.
Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent.
The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results.
Table 23: Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag n = 43 Response rate a, n (%) 95% CI (%) 17 Median of duration of response in months (95% CI) NR b (3.0, NR b ) a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow-up: 8.1 months, range, 7.2 to 10.6 months).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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