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Included as part of the PRECAUTIONS section.

Risk for Hepatotoxicity

PROMACTA administration may cause hepatotoxicity. In the controlled clinical studies, 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 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 study. Six of these patients again experienced liver test abnormalities(predominantly Grade 1) resulting in discontinuation of PROMACTA in one patient. In the extension study, one additional patient had PROMACTA discontinued due to liver test abnormalities ( ≤ Grade 3).

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 the upper limit of normal (ULN) 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.

Pharmacokinetic evaluations in patients with hepatic impairment show that plasma eltrombopag AUC(0-τ) increases with increasing degree of hepatic impairment (as measured by Child-Pugh). Exercise caution when administering PROMACTA to patients with hepatic impairment (Child-Pugh Class A, B, C). Use a lower starting dose of PROMACTA in patients with any degree of hepatic impairment and monitor closely [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

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 study, 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 excluded a risk of bone marrow fibrosis with clinical consequences. If new or worsening blood morphological abnormalities or cytopenias occur, consider a bone marrow biopsy including staining for fibrosis.

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 (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 a platelet count of ≥ 50 x 10⁹/L as necessary to decrease the risk for bleeding [see DOSAGE AND ADMINISTRATION].

In a controlled study 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 of the portal venous system. 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.

Exercise caution when administering PROMACTA to patients with hepatic impairment (Child-Pugh Class A, B, C). Use a lower starting dose of PROMACTA in patients with any degree of hepatic impairment and monitor closely [see DOSAGE AND ADMINISTRATION]. PROMACTA is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.

Hematologic Malignancies

PROMACTA stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk for hematologic malignancies. In the controlled clinical studies, patients were treated with PROMACTA for a maximum of 6 months. During this period no hematologic malignancies were reported in patients treated with PROMACTA. One hematologic malignancy (non-Hodgkin's lymphoma) was reported in the extension study. PROMACTA is not indicated for the treatment of thrombocytopenia due to diseases or treatments that cause thrombocytopenia (e.g., myelodysplasia or chemotherapy) other than chronic ITP.

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 (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. 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 studies, cataracts developed or worsened in 15 (7%) patients who received 50 mg PROMACTA daily and 8 (7%) placebo-group patients. In the extension study, cataracts developed or worsened in 4% of patients who underwent ocular examination prior to therapy with PROMACTA. 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).

Information for Patients

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

• Therapy with PROMACTA is administered to achieve and maintain a platelet count ≥ 50 x 10⁹/L as necessary to reduce the risk for bleeding; PROMACTA is not used to normalize platelet counts.
• Therapy with PROMACTA may be associated with hepatobiliary laboratory abnormalities. 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. If bilirubin is elevated, perform fractionation.
• Inform 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
• Following discontinuation of PROMACTA, thrombocytopenia and risk of bleeding may reoccur, particularly if PROMACTA is discontinued while the patient is on anticoagulants or antiplatelet agents.
• Therapy with PROMACTA may increase the risk of reticulin fiber formation within the bone marrow. Detection of peripheral blood cell abnormalities may necessitate a bone marrow examination.
• Too much PROMACTA may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
• PROMACTA stimulates certain bone marrow cells to make platelets. Drugs acting in this manner may increase the risk for progression of underlying MDS or other hematological conditions. Platelet counts and CBCs must be performed regularly while taking PROMACTA.
• Patients must be closely monitored with weekly platelet counts and CBCs for at least 4 weeks following discontinuation of PROMACTA.
• Even during therapy with PROMACTA, patients should continue to avoid situations or medications that may increase the risk for bleeding.
• Patients must be advised 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).

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 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). 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).

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 the human clinical exposure based on AUC). 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 the human clinical exposure based on AUC). 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 the human clinical exposure based on AUC). 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). 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 dose, 22% were 65 years of age and older, and 9% were 75 years of age and older. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

The disposition of PROMACTA following a single 50 mg dose in patients with mild, moderate, and severe hepatic impairment was compared to subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh A) compared to subjects with normal hepatic function. Plasma eltrombopag AUC0-∞ was approximately 2-fold higher in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C). The half-life of PROMACTA was prolonged 2-fold in these patients. This clinical study did not evaluate protein binding effects.

Similar results were seen in a population pharmacokinetic (PK) analysis in thrombocytopenic patients with chronic liver disease following repeat doses of eltrombopag. However, compared to healthy volunteers, the population PK analysis demonstrated that mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC(0-τ) and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC(0-τ) values. The half-life of PROMACTA was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical study did not evaluate protein binding effects.

A reduction in the initial dose of PROMACTA is recommended for patients with hepatic impairment (Child-Pugh Class A, B, C) [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Renal Impairment

The disposition of a single 50 mg dose of PROMACTA in patients with mild, moderate, and severe renal impairment was compared to subjects with normal renal function. Average total plasma eltrombopag AUC0-∞ was 32% to 36% lower in subjects with mild to moderate renal impairment and 60% lower in subjects with severe renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.

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

Last reviewed on RxList: 12/28/2011
This monograph has been modified to include the generic and brand name in many instances.