Important Safety Information

PROMACTA can cause serious side effects, including liver problems. If you have chronic HCV and take PROMACTA with interferon and ribavirin treatment, PROMACTA may increase your risk of liver problems.

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Indications
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 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.

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 interferon-based therapy or limits the ability to maintain interferon-based therapy.

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)

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. (See Section 5.1 of the full Prescribing Information for additional information.)

RISK OF HEPATOTOXICITY
PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. (See Section 5.2 of the full Prescribing Information for additional information.)

Additional Information Regarding Hepatic Decompensation in Patients With Chronic Hepatitis C
In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving PROMACTA plus antiviral treatment (7%) than the placebo plus antiviral arm (4%). Patients with low albumin levels (<3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score ≥10 at baseline had a greater risk for hepatic decompensation on the arm receiving PROMACTA plus antiviral treatment. Discontinue PROMACTA if antiviral therapy is discontinued.

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

Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory values occurred approximately 3 months after initiation of PROMACTA. In all cases, the event resolved following PROMACTA discontinuation.

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. 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.

In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with PROMACTA experienced a thrombotic event compared to 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with PROMACTA vs <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), 7 thrombotic complications (6 patients) were reported within the group that received PROMACTA and 3 thrombotic complications (2 patients) within the placebo group. All of the thrombotic complications reported in the group that received PROMACTA were portal vein thrombosis, with thrombotic complications occurring in 5 of the 6 patients at a platelet count above 200 x 109/L. PROMACTA is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.

Increased Risk of Death and Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML)
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 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 6 cycles. The incidence of death (overall survival) was 32% (57/179) in the PROMACTA arm vs 29% (51/177) in the placebo arm (HR=1.42 [95% CI, 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 vs 6% (10/177) in the placebo arm (HR=2.66 [95% CI, 1.31-5.41]), showing an increased relative risk of progression to AML in this trial by 166% in the PROMACTA arm.

Cataracts
In the 3 controlled clinical trials in chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50-mg 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 2 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. Perform a baseline ocular examination prior to administration of PROMACTA and, during therapy with PROMACTA, regularly monitor patients for signs and symptoms of cataracts.

Laboratory Monitoring
In patients with chronic ITP, 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.

In patients with chronic hepatitis C-associated thrombocytopenia, monitor serum liver tests (see Hepatotoxicity section). Monitor CBCs with differentials, including platelet counts, every week prior to starting antiviral therapy. Obtain CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved, then monitor platelet counts monthly thereafter.

In patients with SAA, monitor serum liver tests (see Hepatotoxicity section). 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 of therapy with PROMACTA, discontinue therapy.

Drug 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.

Adverse Reactions
The most common adverse reactions in 3 placebo-controlled clinical trials in chronic ITP patients (≥3% and greater than placebo) for PROMACTA vs placebo were nausea (9% vs 3%), diarrhea (9% vs 7%), upper respiratory tract infection (7% vs 6%), vomiting (6% vs <1%), increased ALT (5% vs 3%), myalgia (5% vs 2%), urinary tract infection (5% vs 3%), oropharyngeal pain (4% vs 3%), increased AST (4% vs 2%), pharyngitis (4% vs 2%), back pain (3% vs 2%), influenza (3% vs 2%), paresthesia (3% vs 2%), and rash (3% vs 2%).

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 vs placebo were upper respiratory tract infection (17% vs 6%), nasopharyngitis (12% vs 4%), cough (9% vs 0%), diarrhea (9% vs 2%), pyrexia (9% vs 8%), rhinitis (9% vs 6%), abdominal pain (8% vs 4%), oropharyngeal pain (8% vs 2%), toothache (6% vs 0%), ALT increased (6% vs 0%), rash (5% vs 2%), AST increased (4% vs 0%), and rhinorrhea (4% vs 0%).

The most common adverse reactions in 2 randomized placebo-controlled clinical trials in thrombocytopenic patients with chronic hepatitis C (≥10% and greater than placebo) for PROMACTA vs placebo were: anemia (40% vs 35%), pyrexia (30% vs 24%), fatigue (28% vs 23%), headache (21% vs 20%), nausea (19% vs 14%), diarrhea (19% vs 11%), decreased appetite (18% vs 14%), influenza-like illness (18% vs 16%), asthenia (16% vs 13%), insomnia (16% vs 15%), cough (15% vs 12%), pruritus (15% vs 13%), chills (14% vs 9%), myalgia (12% vs 10%), alopecia (10% vs 6%), and peripheral edema (10% vs 5%).

The most common adverse reactions (≥20%) in a single-arm, open-label trial in 43 patients with 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.