Important Safety Information

WARNING: RISK FOR 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...+

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Indications for PROMACTA® (eltrombopag) Tablets
PROMACTA is indicated in combination with standard immunosuppressive therapy 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.

Limitations of Use
PROMACTA is 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.

Efficacy

Treatment-Naive

PROMACTA + IST PROVIDED HIGHER LEVELS OF RESPONSE1,2

 

Response Rates at 6 Months (Cohort 3 + Extension Cohort)1

 

Study Design

  • Single-arm, open-label, sequential cohort trial in patients 2 years of age or older (N=153)1
  • All cohorts received h-ATG from Days 1 to 4 and CsA for 6 to 24 months1
  • Cohort 3 + extension cohort patients received PROMACTA®  (eltrombopag) from Day 1 to 6 months (n=92)1‡
  • –66 patients were ≥17 years of age; 26 patients were 2 to 16 years of age
  • Historical cohort: 17% complete response was reported in a combined analysis of 2 separate NHLBI trials (2003-2005 and 2005-2010) in 102 patients with SAA receiving h-ATG + CsA2

*Complete response was defined as hematologic parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least 1 week apart: ANC >1000/mcL, platelet count >100,000/mcL, and Hb count >10 g/dL.1

Overall response rate was defined as the number of partial responses (blood counts no longer meeting the standard criteria for severe pancytopenia in SAA) plus complete responses.1

Of these patients, 5 were not included in analyses of hematologic response at Month 6, as they had neither reached the 6-month assessment nor withdrawn earlier.1

 

A RESPONSE THAT CONTINUED AFTER PROMACTA DISCONTINUATION1,3

 

Sustained Response Off Treatment1,3

  • The median duration of response was the same for patients who achieved a complete response (n=46; 95% CI: 23.0-NE) or an overall response (n=70; 95% CI: 21.4-NE)1

For patients with a complete or partial response to PROMACTA at 6 months, there was a 72.3% probability of maintaining that response 18 months postdiscontinuation (n=67; 95% CI: 57.3-82.8)

 

ANC, absolute neutrophil count; CsA, cyclosporine A; h-ATG, horse antithymocyte globulin; Hb, hemoglobin; IST, immunosuppressive therapy; KM, Kaplan-Meier; NE, not estimable; NHLBI, National Heart, Lung, and Blood Institute; SAA, severe aplastic anemia.

§Relapse-free probability is the estimated probability that a subject will remain relapse free up to the specified time point. Estimates are obtained from the KM survival estimates; Greenwood formula is used for confidence interval (CI) of KM estimates.3

 

Relapsed/Refractory

PATIENTS WITH RELAPSED/REFRACTORY SAA EXPERIENCED A MULTILINEAGE RESPONSE WITH PROMACTA MONOTHERAPY1

 

Hematopoiesis Maintained After Discontinuation1,4

 

Study Design

  • Prospective, open-label, nonrandomized, single-arm, dose-modification, investigator-sponsored study conducted by the NIH to assess the safety and efficacy of PROMACTA in patients with SAA and IST-refractory thrombocytopenia (N=43)1,4,5
  • Primary end point was hematologic response, defined by meeting 1 or more of the following criteria1,5:
    • –Platelet count increase to 20,000/mcL above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks
    • –Hb count increase >1.5 g/dL for patients with pretreatment Hb count <9 g/dL or a reduction in ≥4 units of red blood cell transfusions for 8 consecutive weeks
    • –ANC increase of 100% or >500/mcL
  • Patients who responded in the initial phase were eligible to continue therapy in an extension phase1,5
  • Patients had a median age of 45 years and an insufficient response to at least 1 prior course of IST, or were relapsed/refractory and had responded to at least 1 prior cycle of IST, but were refractory to the most recent course of IST1,5

 

ANC, absolute neutrophil count; Hb, hemoglobin; IST, immunosuppressive therapy; NIH, National Institutes of Health; SAA, severe aplastic anemia.

A response meeting 2 or 3 of the criteria for hematologic response.4

In the extension phase, 8 patients achieved a multilineage response; 4 of these patients subsequently tapered off treatment with PROMACTA and maintained the response (median follow-up, 8.1 months; range, 7.2-10.6 months).1

 

RESPONSE LED TO TRANSFUSION INDEPENDENCE1

 

Median Transfusion-Free Period Was >6 Months1

 

 

References:

  1. Promacta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019.
  2. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540-1550, S1-S39. doi:10.1056/NEJMoa1613878.
  3. Data on file. Study ETB115AUS01T. Novartis Pharmaceuticals Corp; February 2018.
  4. Data on file. Study ELT112523. Novartis Pharmaceuticals Corp; February 2014.
  5. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123(12):1818-1825.

Indications for PROMACTA® (eltrombopag) Tablets
PROMACTA is indicated in combination with standard immunosuppressive therapy 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.

Limitations of Use
PROMACTA is 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.

Important Safety Information for PROMACTA® (eltrombopag) Tablets

WARNING: RISK FOR 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.

RISK OF HEPATOTOXICITY
PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

Hepatotoxicity
PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity.

Treatment of ITP, chronic hepatitis C, and refractory severe aplastic anemia

  • Measure serum alanine aminotransferase (ALT), aspartate aminotransferase (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 UGT1A1 and OATP1B1, 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 ≥3 times the upper limit of normal (ULN) in patients with normal liver function or ≥3 times baseline in patients with pretreatment elevations in transaminases and are progressively increasing; or persistent for ≥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 outweighs 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

  • ALT, AST, and bilirubin should be measured prior to initiation of PROMACTA
  • During treatment, increases in ALT levels should be managed based on recommendation in Dosing and Administration section for hepatic impairment  
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
  • Portal vein thrombosis has been reported in patients with chronic liver disease receiving PROMACTA
  • 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
Increased Risk of Death and Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML)
  • In a clinical trial of patients with intermediate to high-risk MDS and thrombocytopenia receiving PROMACTA, an increased number of progressions from MDS to AML and deaths have been observed compared to placebo
  • PROMACTA is not indicated for the treatment of patients with MDS
Cataracts
  • Development or worsening of cataracts with PROMACTA has been reported with a frequency of 5% to 11% in 6 clinical studies
  • Perform a baseline ocular examination prior to initiating PROMACTA. Regularly monitor patients for signs and symptoms of cataracts while on PROMACTA
Laboratory Monitoring
  • Monitor serum liver tests
  • Monitor clinical hematology tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts
  • Hematologic response may take up to 16 weeks after starting PROMACTA. If no hematologic response has occurred after 16 weeks with PROMACTA, discontinue therapy
Drug/Drug and Drug/Food Interactions
  • PROMACTA must be taken at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids, calcium-rich foods, and mineral supplements
  • Take PROMACTA on an empty stomach (1 hour before or 2 hours after a meal)

Adverse Reactions
Across all indications, the most common adverse reactions (≥20% in any indication) were: anemia, nausea, pyrexia, ALT increased, cough, fatigue, headache, and diarrhea.

The most common adverse reactions (≥5%) in a single-arm trial of 92 patients 2 years and older with severe aplastic anemia (SAA) who had not received prior immunosuppressive therapy were increased ALT (29%) and AST (17%), blood bilirubin increased (17%), rash (8%), and skin discoloration including hyperpigmentation (5%). Upper respiratory infection, particularly in pediatric patients, was also reported. The most common adverse reactions (≥20%) in a single-arm, open-label trial in 43 patients with refractory SAA who received PROMACTA were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%). In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported, including 5 patients who had complex changes in chromosome 7. If new cytogenetic abnormalities are observed, consider discontinuation of PROMACTA.

Please see full Prescribing Information for PROMACTA, including Boxed WARNING, and Medication Guide.