Included as part of the PRECAUTIONS section.

Hepatotoxicity

PROMACTA may cause hepatotoxicity. In the controlled clinical studies in chronic ITP, one patient experienced Grade 4 (NCI Common Terminology Criteria for Adverse Events [NCI CTCAE] toxicity scale) elevations in serum liver test values during therapy with PROMACTA, worsening of underlying cardiopulmonary disease, and death. One patient in the placebo group experienced a Grade 4 liver test abnormality. Overall, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of the PROMACTA and placebo groups, respectively. In the 3 controlled chronic ITP studies, four patients (1%) treated with PROMACTA and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the patients treated with PROMACTA in the controlled studies with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in the extension trial. Six of these patients again experienced liver test abnormalities (predominantly Grade 1) resulting in discontinuation of PROMACTA in one patient. In the extension chronic ITP trial, one additional patient had PROMACTA discontinued due to liver test abnormalities ( ≤ Grade 3).

In 2 controlled clinical studies in patients with chronic hepatitis C and thrombocytopenia, ALT or AST ≥ 3X ULN was reported in 34% and 38% of the PROMACTA and placebo groups, respectively. Most patients receiving PROMACTA in combination with peginterferon/ribavirin therapy will experience indirect hyperbilirubinemia. Overall, total bilirubin ≥ 1.5 X ULN was reported in 76% and 50% of patients receiving PROMACTA and placebo, respectively.

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. 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 the abnormality(ies) resolve, stabilize, or return to baseline levels. Discontinue PROMACTA if ALT levels increase to > 3X ULN in patients with normal liver function or > 3X baseline in patients with pre-treatment elevations in transaminases and are:

• progressive, or
• persistent for ≥ 4 weeks, or
• accompanied by increased direct bilirubin, or
• accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.

Reinitiating treatment with PROMACTA is not recommended. If the potential benefit for reinitiating treatment with PROMACTA is considered to outweigh the risk for hepatotoxicity, then cautiously reintroduce PROMACTA and measure serum liver tests weekly during the dose adjustment phase. If liver tests abnormalities persist, worsen or recur, then permanently discontinue PROMACTA.

Hepatic Decompensation in Patients with Chronic Hepatitis C

Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alfa interferons. In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy were reported more frequently for PROMACTA (7%) than placebo (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 of hepatic decompensation. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. Refer to alfa interferon prescribing information for discontinuation recommendations. PROMACTA should be discontinued if antiviral therapy is discontinued for hepatic decompensation.

Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis PROMACTA may increase the risk for development or progression of reticulin fiber deposition within the bone marrow. In the extension trial in chronic ITP, 151 patients have had bone marrow biopsies evaluated for increased reticulin and collagen fiber deposition. Bone marrow biopsies taken after 1 year of therapy showed predominantly myelofibrosis (MF) Grade 1 or less in 140/151 (93%) of patients. There were 11/151 (7%) of patients with MF Grade 2. Four patients had collagen deposition reported. One patient with a pre-existing MF Grade 1 developed a MF Grade 2 and subsequently discontinued treatment with PROMACTA. Clinical studies have not demonstrated clinical consequences to date. If new or worsening blood morphological abnormalities or cytopenias occur, consider a bone marrow biopsy including staining for fibrosis.

Thrombotic/Thromboembolic Complications

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 versus < 1% for placebo).

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 (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].

In a controlled trial in non-ITP thrombocytopenic patients with chronic liver disease undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg 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 10⁹/L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg PROMACTA once daily for 2 weeks in preparation for invasive procedures.

Laboratory Monitoring

Complete Blood Counts (CBCs)

Obtain CBCs with differentials (including platelet counts) weekly during the dose adjustment phase of therapy with PROMACTA and then monthly following establishment of a stable dose of PROMACTA. Obtain CBCs with differentials (including platelet counts) weekly for at least 4 weeks following discontinuation of PROMACTA. [See DOSAGE AND ADMINISTRATION]

Liver Tests

Monitor serum liver tests (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 UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. If abnormal levels are detected, repeat the tests within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels. Discontinue PROMACTA for the development of important liver test abnormalities.

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 4% 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% patients treated with PROMACTA and 5% patients treated with placebo.

Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology]. Perform a baseline ocular examination prior to administration of PROMACTA and, during therapy with PROMACTA, regularly monitor patients for signs and symptoms of cataracts.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Prior to treatment, patients should fully understand and be informed of the following risks and considerations for PROMACTA:

• For patients with ITP, therapy with PROMACTA is administered to achieve and maintain a platelet count ≥ 50 x 10⁹/L as necessary to reduce the risk for bleeding,
• For patients with chronic hepatitis C, therapy with PROMACTA is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.
• Therapy with PROMACTA may be associated with hepatobiliary laboratory abnormalities.
• Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving alfa interferon therapy.
• Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.
  • yellowing of the skin or the whites of the eyes (jaundice)
  • unusual darkening of the urine
  • unusual tiredness
  • right upper stomach area pain
• Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing PROMACTA, particularly if PROMACTA is discontinued while the patient is on anticoagulants or antiplatelet agents.
• Advise patients that too much PROMACTA may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
• Advise patients that during therapy with PROMACTA, they should continue to avoid situations or medications that may increase the risk for bleeding.
• Advise patients to have a baseline ocular examination prior to administration of PROMACTA and be monitored for signs and symptoms of cataracts during therapy.
• Advise patients to keep at least a 4-hour interval between PROMACTA and foods, mineral supplements, and antacids which contain polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans.

Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).

Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in 2 in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax in ITP patients at 75 mg/day and 7 times the human clinical exposure based on Cmax in chronic hepatitis C patients at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive ( < 3-fold increase in mutation frequency).

Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).

Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).

Use In Specific Populations

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.

Pregnancy Registry

A pregnancy registry has been established to collect information about the effects of PROMACTA during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the PROMACTA pregnancy registry by calling 1-888-825-5249.

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 ITP patients at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Increased pre- and postimplantation 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 ITP patients at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients 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 ITP patients at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients 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 ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients 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.

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.

Pediatric Use

The safety and efficacy of PROMACTA in pediatric patients have not been established.

Geriatric Use

Of the 106 patients in 2 randomized clinical studies of PROMACTA 50 mg in chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. In the 2 randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while fewer than 1% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

Hepatic impairment influences the exposure of PROMACTA [see CLINICAL PHARMACOLOGY].

A reduction in the initial dose of PROMACTA in patients with chronic ITP is recommended for patients with hepatic impairment (Child-Pugh Class A, B, C) [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. No dosage adjustment is necessary for HCV patients with hepatic impairment [see CLINICAL PHARMACOLOGY].

Renal Impairment

No adjustment in the initial PROMACTA dose is needed for patients with renal impairment [see CLINICAL PHARMACOLOGY]. Closely monitor patients with impaired renal function when administering PROMACTA.

Ethnicity

Patients of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) exhibit higher eltrombopag exposures. A reduction in the initial dose of PROMACTA is recommended for ITP patients of East Asian ancestry and patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C) [see DOSAGE AND ADMINISTRATION]. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.