PROMACTA ® ( eltrombopag ) tablets , for oral use PROMACTA ® ( eltrombopag ) for oral suspension Initial U . S . Approval : 2008
BRIEF SUMMARY : Please see package insert for full prescribing information .
WARNING : RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY
In patients with chronic hepatitis C , PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation [ see Warnings and Precautions ( 5.1 )].
PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity . Monitor hepatic function and discontinue dosing as recommended [ see Warnings and Precautions ( 5.2 )].
1 INDICATIONS AND USAGE 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia PROMACTA is 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 . PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding .
1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection PROMACTA is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy . PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferonbased therapy or limits the ability to maintain interferon-based therapy .
1.3 Treatment of Severe Aplastic Anemia
• PROMACTA is 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 .
• PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy .
1.4 Limitations of Use
• PROMACTA is not indicated for the treatment of patients with myelodysplastic syndromes ( MDS ) [ see Warnings and Precautions ( 5.3 )].
• Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection .
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C , PROMACTA 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 PROMACTA 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 PROMACTA plus antivirals . Discontinue PROMACTA if antiviral therapy is discontinued .
5.2 Hepatotoxicity PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity [ see Adverse Reactions ( 6.1 )]. One patient (< 1 %) with ITP treated with PROMACTA in clinical trials experienced drug-induced liver injury . Eleven patients ( 1 %) with chronic hepatitis C treated with PROMACTA 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 PROMACTA , every 2 weeks during the dose adjustment phase , and monthly following establishment of a stable dose . PROMACTA 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 PROMACTA 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 PROMACTA is considered to outweigh the risk for hepatotoxicity , then consider cautiously reintroducing PROMACTA and measure serum liver tests weekly during the dose adjustment phase . Hepatotoxicity may reoccur if PROMACTA is reinitiated . If liver test abnormalities persist , worsen , or recur , then permanently discontinue PROMACTA .
First-Line Treatment of Severe Aplastic Anemia Measure ALT , AST , and bilirubin prior to initiation of PROMACTA , 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 in the full prescribing information .
5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized , double-blind , placebo-controlled , multicenter trial in patients with International Prognostic Scoring System ( IPSS ) intermediate-1 , intermediate-2 or high risk MDS with thrombocytopenia , receiving azacitidine in combination with either PROMACTA ( 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 PROMACTA 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 PROMACTA 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 PROMACTA arm ). The incidence of progression to AML was 12 % ( 21 / 179 ) in the PROMACTA 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 PROMACTA arm ).
5.4 Thrombotic / Thromboembolic Complications Thrombotic / thromboembolic complications may result from increases in platelet counts with PROMACTA . 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 PROMACTA 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 PROMACTA in an attempt to normalize platelet counts . Follow the dose adjustment guidelines to achieve and maintain target platelet counts [ see Dosage and Administration ( 2.1 , 2.2 , 2.3 ) in the full prescribing information ].
In two controlled clinical trials in patients with chronic hepatitis C and thrombocyto penia , 3 % ( 31 / 955 ) treated with PROMACTA 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 PROMACTA 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 PROMACTA once daily . Seven thrombotic complications ( six patients ) were reported in the group that received PROMACTA and three thrombotic complications were reported in the placebo group ( two patients ). All of the thrombotic complications reported in the group that received PROMACTA 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 PROMACTA experienced a thrombotic complication within 30 days of completing treatment with PROMACTA 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 PROMACTA once daily for 2 weeks in preparation for invasive procedures .
5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP , cataracts developed or worsened in 15 ( 7 %) patients who received 50 mg of PROMACTA 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 PROMACTA . In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia , cataracts developed or worsened in 8 % of patients treated with PROMACTA and 5 % of patients treated with placebo .
Cataracts were observed in toxicology studies of eltrombopag in rodents [ see Nonclinical Toxicology ( 13.2 ) in the full prescribing information ]. Perform a baseline ocular examination prior to administration of PROMACTA and , during therapy with PROMACTA , regularly monitor patients for signs and symptoms of cataracts .
6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with PROMACTA are described in other sections .
• Hepatic Decompensation in Patients with Chronic Hepatitis C [ see Warnings and Precautions ( 5.1 )]
• Hepatotoxicity [ see Warnings and Precautions ( 5.2 )]
• Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [ see Warnings and Precautions ( 5.3 )]
• Thrombotic / Thromboembolic Complications [ see Warnings and Precautions ( 5.4 )]
• Cataracts [ see Warnings and Precautions ( 5.5 )]
6.1 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 PROMACTA . Other serious adverse reactions included thrombotic / thromboembolic complications [ see Warnings and Precautions ( 5.4 )]. The data described below reflect exposure of PROMACTA 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 [ see Clinical Studies ( 14.1 ) in the full prescribing information ]. PROMACTA 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 PROMACTA ) from the three placebo-controlled trials , with a higher incidence in PROMACTA versus placebo .
Table 8 . Adverse Reactions ( ≥ 3 %) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia
PROMACTA 50 mg
Placebo n = 241 n = 128
Adverse Reaction (%) (%)
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 PROMACTA and in no patients who received placebo .
Among 302 patients with persistent or chronic ITP who received PROMACTA 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 PROMACTA ) from the extension trial .
Table 9 . Treatment-related Adverse Reactions ( ≥ 3 %) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia
PROMACTA 50 mg n = 302
Adverse Reaction (%)
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 PROMACTA and placebo ,