CLINICAL NEWS patients ( 85 %) achieved HI-E for a median duration of 8.3 months ( range = 2.3-9.9 months ). Patients with HTB in the extension study also had high rates of durable response rates : 15 of 19 patients ( 79 %) achieved HI-E with a median duration of response of 11.6 months ( range = 2.3 months to not estimable ).
Of the 42 patients across both stages who were evaluable for RBC transfusion independence ( TI ; 8 LTB and 34 HTB ), 16 patients ( 38 %) achieved TI . Of the 22 patients with previous transfusions in the base study who carried over into the extension study , 11 ( 50 %) were transfusion-free for eight weeks or longer ( median duration of RBC-TI = 15.3 months ; range = 3.6 months to not estimable ).
Previous ESA use did not appear to affect response rates : 21 of the 34 patients ( 62 %) with prior ESA use and 11 of the 17 patients ( 65 %; p value not reported ) without prior ESA use who received higher dose concentrations of luspatercept achieved HI-E .
The recombinant fusion protein luspatercept could provide a new therapeutic approach in anemic patients with lower-risk MDS .
In clinical trials in patients with chronic hepatitis C , 11 patients treated with PROMACTA ( 1 %) experienced drug-induced liver injury [ see Warnings and Precautions ( 5.2 )].
Severe Aplastic Anemia : In the single-arm , open-label trial , 43 patients with severe aplastic anemia received PROMACTA . 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 8 . Adverse Reactions ( ≥10 %) from One Open-label Trial in Adults with Severe Aplastic Anemia
PROMACTA ( n = 43 )
Adverse Reaction (%)
Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Dyspnea 14 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Febrile neutropenia 14 Abdominal pain 12 Ecchymosis 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12
Rash was reported in 7 % 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 .
6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of PROMACTA . 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 .
Vascular Disorders : Thrombotic microangiopathy with acute renal failure .
Skin and Subcutaneous Tissue Disorders : Skin discoloration including hyperpigmentation and skin yellowing .
7 DRUG INTERACTIONS 7.1 Polyvalent Cations ( Chelation ) Eltrombopag chelates polyvalent cations ( such as iron , calcium , aluminum , magnesium , selenium , and zinc ) in foods , mineral supplements , and antacids . In a clinical trial , administration of PROMACTA with a polyvalent cation-containing antacid decreased plasma eltrombopag systemic exposure by approximately 70 % [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
Take PROMACTA 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 PROMACTA due to chelation [ see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
7.2 Transporters Coadministration of PROMACTA with the OATP1B1 and breast cancer resistance protein ( BCRP ) substrate , rosuvastatin , to healthy adult subjects increased plasma rosuvastatin AUC 0-INF by 55 % and C max by 103 % [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
Use caution when concomitantly administering PROMACTA and drugs that are substrates of OATP1B1 ( e . g ., atorvastatin , bosentan , ezetimibe , fluvastatin , glyburide , olmesartan , pitavastatin , pravastatin , rosuvastatin , repaglinide , rifampin , simvastatin acid , SN-38 [ active metabolite of irinotecan ], valsartan ) or 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 PROMACTA , a dose reduction of rosuvastatin by 50 % was recommended .
7.3 Protease Inhibitors HIV Protease Inhibitors : In a drug interaction trial , coadministration of PROMACTA with lopinavir / ritonavir ( LPV / RTV ) decreased plasma eltrombopag exposure by 17 % [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ]. No dose adjustment is recommended when PROMACTA is coadministered with LPV / RTV . Drug interactions with other HIV protease inhibitors have not been evaluated .
Hepatitis C Virus ( HCV ) Protease Inhibitors : Coadministration of PROMACTA with either boceprevir or telaprevir did not affect eltrombopag or protease inhibitor exposure significantly [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ]. No dose adjustments are recommended . Drug interactions with other HCV protease inhibitors have not been evaluated .
7.4 Peginterferon alfa-2a / b Therapy Coadministration of peginterferon alfa-2a ( PEGASYS ® ) or -2b ( PEGINTRON ® ) did not affect eltrombopag exposure in two randomized , double-blind , placebo-controlled trials with adult patients with chronic hepatitis C [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C
There are no adequate and well-controlled studies of eltrombopag use in pregnancy . In animal reproduction and developmental toxicity studies , there was evidence of embryolethality and reduced fetal weights at maternally toxic doses . PROMACTA should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus .
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 .
Eltrombopag was administered orally to pregnant rats at 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 .
Pregnant rabbits were treated with oral eltrombopag 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 ), 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 .
8.3 Nursing Mothers It is not known whether eltrombopag is excreted in human milk . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PROMACTA , a decision should be made whether to discontinue nursing or to discontinue PROMACTA taking into account the importance of PROMACTA to the mother .
8.4 Pediatric Use The safety and efficacy of PROMACTA in pediatric patients 1 year and older with chronic ITP were evaluated in two double-blind , placebocontrolled trials [ see Adverse Reactions ( 6.2 ), Clinical Studies ( 14.2 ) in the full prescribing information ]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [ see Clinical Pharmacology ( 12.3 ) in the full prescribing