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hematologic improvement – erythroid ( HI-E ). In LTB patients , HI-E was defined as a hemoglobin increase of ≥1.5 g / dL from baseline for ≥14 days ; in HTB patients , HI-E was defined as a reduction in RBC transfusion of 4 RBC units or more or a ≥50 percent reduction in RBC units over eight weeks versus pre-treatment transfusion burden .
The PACE-MDS study was conducted in two stages : a 12-week base study ( consisting of the dose-finding cohorts and expansion cohorts ) and an extension study . In the base study , 58 patients received up to five doses ( over a maximum of 12 weeks ) of luspatercept administered subcutaneously once every 21 days at either lower dose concentrations ( 0.125- 0.5 mg / kg ) or higher dose concentrations ( 0.75- 1.75 mg / kg ).
Six patients discontinued from the base study and 20 patients did not enroll in the extension study . After reviewing safety and efficacy data after 12 weeks , the investigators
There was “ a clear dosedependent efficacy response ” across both study stages , with higher response rates at higher luspatercept doses .
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
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 lifethreatening 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 Chronic ITP PROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune ( idiopathic ) thrombocytopenia ( ITP ) who have had an insufficient response to cortico - steroids , immunoglobulins , or splenectomy .
Limitations of Use : 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 .
Limitations of Use :
• 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 .
• Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection .
1.3 Treatment of Severe Aplastic Anemia PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy .
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 thrombo cytopenia , 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 )]. 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 .
Isolated cases of severe liver injury were identified in clinical trials . The elevation of liver laboratory values occurred approximately three months after initiation of PROMACTA . In all cases , the event resolved following PROMACTA discontinuation .
5.3 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 thrombo - embolism ( 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 thrombo - cytopenia 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 thrombocyto penic patients with chronic liver disease treated with 75 mg of PROMACTA once daily for 2 weeks in preparation for invasive procedures .
5.4 Cataracts In the three controlled clinical trials in adults with 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 serious 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 )]
• Thrombotic / Thromboembolic Complications [ see Warnings and Precautions ( 5.3 )]
• Cataracts [ see Warnings and Precautions ( 5.4 )]
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 .
Chronic Immune ( Idiopathic ) 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 ( 5.3 )]. The data described below reflect exposure of PROMACTA to patients with 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