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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Indication for PROMACTA® (eltrombopag) Tablets
PROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with 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.

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

Limitations of Other Therapies

OTHER THERAPEUTIC OPTIONS HAVE LIMITATIONS1-8

Corticosteroids

  • 85% of patients lose response within 6 to 12 months1
  • 69% of patients say they would avoid corticosteroids whenever possible2

Monoclonal Antibodies

  • 33% of patients lose response within 12 months3‐5
  • No difference in rate of treatment failure vs placebo was reported in a 2015 Lancet article on the only randomized study of rituximab in ITP6
    • Monoclonal antibodies are not indicated for ITP7

Splenectomy

  • ~1/3 of patients fail to respond to or relapse after splenectomy8
  • It is not possible to predict how patients are going to respond to splenectomy

There are no head-to-head studies comparing PROMACTA® (eltrombopag) to the treatments above.

Time to and Length of Response

A RAPID RESPONSE IS IMPORTANT FOR YOUR ADULT ITP PATIENTS WHO FAILED THEIR FIRST THERAPY9,10

Rapid: Responses Seen As Early as Day 89,10

  • Primary end point—response at Day 43—was 28%, 70%, and 81% for 30-mg, 50-mg, and 75-mg doses, respectively
  • Maximum response seen at Week 2

 

Study Design

  • Phase 2, 6-week, double-blind, placebo-controlled trial of 117 adult patients with previously treated ITP
  • Primary end point was response rates, defined as a shift from baseline platelet count <30,000/mcL to ≥50,000/mcL at any time during the study period up to 42 days of dosing with 30 mg, 50 mg, or 75 mg of eltrombopag

Hemorrhage was the most common serious adverse reaction, and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included thrombotic/thromboembolic complications.9

PATIENTS MAY BENEFIT FROM THE LONG-TERM DISEASE CONTROL OF PROMACTA9,11,12

  • More than 10 years of experience successfully treating patients with ITP9-11
  • Specifically designed to treat disorders that affect bone marrow function, such as ITP9
  • Offers a nonimmunosuppressive option for disease control9,11
  • Controls platelet count fluctuations, resulting in a consistent response you can rely on9,11

Higher Response Rates Seen When Used Prior to Splenectomy11

  • In the long-term EXTEND study, 89.3% of nonsplenectomized patients vs 80% of splenectomized patients demonstrated at least 1 platelet count ≥50,000/mcL

A DURABLE RESPONSE—PROVEN IN THE LONGEST AND LARGEST TRIAL IN cITP9,11,13

Durable: Only PROMACTA Has 7+ Years of Platelet Response

In the Primary End Point of the EXTEND Study11:

  • After 6+ years of therapy, no new or increased adverse reactions were identified

In the Secondary End Point of the EXTEND Study:

 

Study Design9,11,12

  • The open-label EXTEND study evaluated long-term safety and efficacy of eltrombopag in adults with ITP who had completed a previous eltrombopag study
    • Interim results showed that treatment with eltrombopag was safe, well tolerated, and effective in maintaining platelet counts up to 3 years
  • This study reviewed more than 8 years of continuous treatment. Of 302 patients enrolled, 135 (45%) completed the study; 60% were treated for at least 2 years and 35% at least 3 years
    • The “n” value represents the total number of patients with median platelet counts ≥50,000/mcL by Week 2 and at least that throughout

Effect on Bleeding Events

34% REDUCTION IN BLEEDING EVENTS SEEN AS EARLY AS DAY 1514,15

Rapid: Reductions Seen in Your Patients As Early as Day 1511,14,15

For the Primary End Point:

  • The proportion of responders was between 37% and 56%, with the minimum of 37% at Day 8 and the maximum of 56% at Day 3614,15

 

Study Design

  • Phase 3, 6-month, double-blind, randomized, placebo-controlled study of 197 patients with previously treated ITP and baseline platelet counts <30,000/mcL
  • Primary end point was the odds of response, defined as a platelet count ≥50,000/mcL and ≤400,000/mcL, during treatment

DURABLE: REDUCTIONS MAINTAINED IN YOUR PATIENTS THROUGH 1 YEAR11

 

Durable responses

Effect on Concomitant Therapy

REDUCES THE NEED FOR CONCOMITANT ITP THERAPY11,12

In the Long-Term EXTEND Trial:

 

Reductions in Concomitant Therapy

aDefined as the need for a new medication, increased dose of any concomitant medication, platelet transfusion, or splenectomy.11

HRQoL

PATIENTS REPORTED IMPROVEMENTS IN KEY PHYSICAL AND MENTAL HEALTH PARAMETERS14,15

  • Patients self-reported improvements at Week 26

 

Physical Health Parameters

 

Mental Health Parameters

P values represent significance with PROMACTA vs baseline.
aPatients in both arms were permitted local SOC, including but not limited to corticosteroids, IVIg, danazol, azathioprine, mycophenolate, anti-D, cyclosporine, cyclophosphamide, rituximab, and vincristine/vinblastine.
bThe vitality domain is defined as physical or mental fatigue.

The prespecified domain analyses were observational in nature; as such, there were no prespecified statistical procedures controlling for type 1 errors.15

  • Patients receiving PROMACTA reported significant improvement from baseline on 5 of the 8 domains of the Short Form 36 Health Survey, version 2 (SF-36v2)* that measure HRQoL (P<0.05)14,15
    • Domains included physical and mental function
    • Significant changes were also shown in both summary scores and in the Functional Assessment of Cancer Therapy–Thrombocytopenia (FACT-Th6) score

*The acute recall version of the SF-36v2 questionnaire was used to measure HRQoL expressed in 8 domain scores and 2 component summary scores (physical and mental). These domains included physical function, physical role (role limitations due to physical health), bodily pain, general health, vitality (physical or mental fatigue), social function, emotional role (role limitations due to emotional problems), and mental health.14,15

Physical and mental component summary scores were normalized to the 1998 US Census.14

CHANGES PERSISTED UP TO 5 YEARS IN FATIGUE AND BLEEDING/BRUISING11,16,17

  • ~80% of patients self-reported improvements in at least 1 measure of HRQoL in the EXTEND study16

Bleeding

 

anti-D, anti-D (ρ) immunoglobulin; cITP, chronic immune thrombocytopenia; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy–Fatigue; HRQoL, health-related quality of life; ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; SOC, standard of care.

References:

  1. McCrae K. Immune thrombocytopenia: no longer ‘idiopathic.’ Cleve Clin J Med. 2011;78(6):358-373.
  2. Matzdorff AC, Arnold G, Salama A, Ostermann H, Eberle S, Hummler S. Advances in ITP – therapy and quality of life – a patient survey. PLoS One. 2011;6(11):e27350. doi:10.1371/journal.pone.0027350.
  3. Patel VL, Mahévas M, Lee SY, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012;119(25):5989-5995.
  4. Stasi R. Pathophysiology and therapeutic options in primary immune thrombocytopenia. Blood Transfus. 2011;9(3):262-273.
  5. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008;112(4):999-1004.
  6. Ghanima W, Khelif A, Waage A, et al; for RITP Study Group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9978):1653-1661.
  7. Rituxan [prescribing information]. South San Francisco, CA: Genentech Inc; 2018.
  8. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186.
  9. Promacta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019.
  10. Data on file. Study TRA100773A. Novartis Pharmaceuticals Corp; October 2007.
  11. Data on file. Study TRA105325 (EXTEND). Novartis Pharmaceuticals Corp; March 2016.
  12. Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130(23):2527-2536.
  13. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161(3):411-423.
  14. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomized, phase 3 study. Lancet. 2011;377(9763):393-402.
  15. Data on file. Study TRA102537 (RAISE). Novartis Pharmaceuticals Corp; February 2009.
  16. Khelif A, Saleh MN, Salama A, et al. Patient-reported health-related quality of life improves over time in patients with chronic immune thrombocytopenia receiving long-term treatment with eltrombopag. Blood. 2016;128(22):3750. http://www.bloodjournal.org/content/128/22/3750. Accessed September 12, 2018.
  17. Khelif A, Saleh MN, Salama A, et al. Patient-reported health-related quality of life improves over time in patients with chronic immune thrombocytopenia receiving long-term treatment with eltrombopag. Presented at: 58th American Society of Hematology Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Poster 3750.

Indication for PROMACTA® (eltrombopag) Tablets
PROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with 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.

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

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
  • During therapy with PROMACTA, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Monitor platelet counts monthly thereafter
  • Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of PROMACTA
  • When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, then follow standard monthly monitoring

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 in 3 placebo-controlled clinical trials in chronic ITP patients (≥3% and greater than placebo) for PROMACTA were nausea (9%), diarrhea (9%), upper respiratory tract infection (7%), vomiting (6%), increased ALT (5%), myalgia (5%), urinary tract infection (5%), oropharyngeal pain (4%), increased AST (4%), pharyngitis (4%), back pain (3%), influenza (3%), paresthesia (3%), and rash (3%).

The most common adverse reactions in 2 placebo-controlled clinical trials in chronic ITP patients 1 year and older (≥3% and greater than placebo) for PROMACTA were upper respiratory tract infection (17%), nasopharyngitis (12%), cough (9%), diarrhea (9%), pyrexia (9%), abdominal pain (8%), oropharyngeal pain (8%), toothache (6%), ALT increased (6%), rash (5%), AST increased (4%), and rhinorrhea (4%).

 

 

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