Promacta® is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Limitations of use: Promacta should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Promacta should not be used in an attempt to normalize platelet counts.
Promacta Dosage and Administration
Use the lowest dose of Promacta to achieve and maintain a platelet count ≥50 x 109/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use Promacta in an attempt to normalize platelet counts [see Warnings and Precautions (5.3)]. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting Promacta and decreased within 1 to 2 weeks after discontinuing Promacta [see Clinical Studies (14)].
Take Promacta on an empty stomach (1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)]. Allow at least a 4-hour interval between Promacta and other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium fortified juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.4)].
Initial Dose Regimen
Initiate Promacta at a dose of 50 mg once daily, except in patients who are of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C).
For patients of East Asian ancestry, initiate Promacta at a reduced dose of 25 mg once daily [see Clinical Pharmacology (12.3)].
For patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate Promacta at a reduced dose of 25 mg once daily [see Use in Specific Populations (8.6)].
For patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C), consider initiating Promacta at a reduced dose of 12.5 mg once daily [see Clinical Pharmacology (12.3)].
Monitoring and Dose Adjustment
After initiating Promacta, adjust the dose to achieve and maintain a platelet count ≥50 x 109/L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Promacta and modify the dosage regimen of Promacta based on platelet counts as outlined in Table 1. During therapy with Promacta, assess CBCs with differentials (including platelet count) weekly until a stable platelet count has been achieved. Obtain CBCs with differentials (including platelet counts) monthly thereafter.
Table 1. Dose Adjustments of Promacta
| Platelet Count Result |
Dose Adjustment or Response |
| <50 x 109/L following at least 2 weeks of Promacta |
Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. |
| ≥200 x 109/L to ≤400 x 109/L at any time |
Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. |
| >400 x 109/L |
Stop Promacta; increase the frequency of platelet monitoring to twice weekly.
Once the platelet count is <150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg.
For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
|
| >400 x 109/L after 2 weeks of therapy at lowest dose of Promacta |
Discontinue Promacta. |
In patients with hepatic impairment (Child-Pugh Class A, B, C), after initiating Promacta or after any subsequent dosing increase wait 3 weeks before increasing the dose.
Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with Promacta. Do not administer more than one dose of Promacta within any 24-hour period.
Discontinuation
Discontinue Promacta if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with Promacta at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of Promacta [see Warnings and Precautions (5.1)].
Dosage Forms and Strengths
12.5 mg tablets — round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid.
25 mg tablets — round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid.
50 mg tablets — round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid.
75 mg tablets — round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid.
Contraindications
None.
Warnings and Precautions
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 (2.1) and Use in Specific Populations (8.6)].
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 (2.2)].
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 (2.1)]. 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 (2) and Warnings and Precautions (5.2).]
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 [see Warnings and Precautions (5.1)].
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 (13.2)]. Perform a baseline ocular examination prior to administration of Promacta and, during therapy with Promacta, regularly monitor patients for signs and symptoms of cataracts.
Adverse Reactions
Clinical Trials Experience
In clinical studies, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of Promacta. Other serious adverse reactions included liver test abnormalities and thrombotic/thromboembolic complications [see Warnings and Precautions (5.1, 5.3)].
The data described below reflect exposure of Promacta to 446 patients with chronic ITP aged 18 to 85, of whom 65% were female across the ITP clinical development program including 3 placebo-controlled studies. Promacta was administered to 277 patients for at least 6 months and 202 patients for at least 1 year.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Table 2 presents the most common adverse drug reactions (experienced by ≥3% of patients receiving Promacta) from the 3 placebo-controlled studies, with a higher incidence in Promacta versus placebo.
Table 2. Adverse Reactions (≥3%) from Three Placebo-Controlled Studies
| Preferred Term |
Promacta 50mg
n = 241
(%) |
Placebo
n = 128
(%) |
| Nausea |
9 |
3 |
| Diarrhea |
9 |
7 |
| Upper respiratory tract infection |
7 |
6 |
| Vomiting |
6 |
<1 |
| Increased ALT |
5 |
3 |
| Myalgia |
5 |
2 |
| Urinary tract infection |
5 |
3 |
| Oropharyngeal pain |
4 |
3 |
| Increased AST |
4 |
2 |
| Pharyngitis |
4 |
2 |
| Back pain |
3 |
2 |
| Influenza |
3 |
2 |
| Paresthesia |
3 |
2 |
| Rash |
3 |
2 |
In the 3 controlled clinical studies, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with Promacta and in no patients who received placebo.
Among 299 patients with chronic ITP who received Promacta in the single-arm extension study, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled studies. Table 3 presents the most common treatment-related adverse reactions (experienced by ≥3% of patients receiving Promacta) from the extension study.
Table 3. Treatment-Related Adverse Reactions (≥3%) from Extension Study
| Preferred Term |
Promacta 50mg
n = 299
(%) |
| Headache |
10 |
| Hyperbilirubinemia |
6 |
| ALT increased |
6 |
| Cataract |
5 |
| AST increased |
4 |
| Fatigue |
4 |
| Nausea |
4 |
In a placebo-controlled trial of eltrombopag in non-ITP thrombocytopenic patients with chronic liver disease (CLD), six eltrombopag-treated patients and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.3)].
Drug Interactions
Cytochrome P450
In vitro studies demonstrate that CYP1A2 and CYP2C8 are involved in the oxidative metabolism of eltrombopag. The significance of coadministration of Promacta with 1) moderate or strong inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine) and CYP2C8 (e.g., gemfibrozil, trimethoprim); 2) inducers of CYP1A2 (e.g., tobacco, omeprazole) and CYP2C8 (e.g., rifampin); or 3) other substrates of these CYP enzymes on the systemic exposure of Promacta has not been established in clinical studies. Monitor patients for signs and symptoms of excessive eltrombopag exposure when Promacta is administered concomitantly with moderate or strong inhibitors of CYP1A2 or CYP2C8.
In vitro, eltrombopag is an inhibitor of CYP2C8 and CYP2C9 using paclitaxel and diclofenac as the probe substrates. A clinical study where Promacta 75 mg once daily was administered for 7 days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this study.
Transporters
In vitro studies demonstrate that eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and breast cancer resistance protein (BCRP) and can increase the systemic exposure of other drugs that are substrates of these transporters (e.g., benzylpenicillin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateglinide, repaglinide, rifampin, doxorubicin). Administration of 75 mg of Promacta once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate, rosuvastatin, to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%.
Use caution when concomitantly administering Promacta and drugs that are substrates of OATP1B1 or BCRP. Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended for coadministration with eltrombopag.
In vitro studies demonstrate that eltrombopag is a BCRP substrate. The effect of coadministration of Promacta with moderate or strong BCRP inhibitors or inducers on the systemic exposure of Promacta has not been evaluated in clinical studies. Monitor patients closely for signs or symptoms of excessive exposure to Promacta when concomitantly administered with moderate or strong inhibitors of BCRP.
UDP-glucuronosyltransferases (UGTs)
In vitro studies demonstrate that eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15, enzymes involved in the metabolism of multiple drugs, such as acetaminophen, narcotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). The significance of this inhibition on the potential for increased systemic exposure of drugs that are substrates of these UGTs following coadministration with Promacta has not been evaluated in clinical studies. Monitor patients closely for signs or symptoms of excessive exposure to these drugs when concomitantly administered with Promacta.
In vitro studies demonstrate that UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. The significance of coadministration of Promacta with moderate or strong inhibitors or inducers on the systemic exposure of Promacta has not been evaluated in clinical studies. Monitor patients closely for signs or symptoms of excessive exposure to Promacta when concomitantly administered with moderate or strong inhibitors of UGT1A1 or UGT1A3.
Polyvalent Cations (Chelation)
Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. In a clinical study, administration of Promacta with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag systemic exposure by approximately 70%. The contribution of sodium alginate to this interaction is not known. Promacta must not be taken within 4 hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in Promacta absorption due to chelation [see Dosage and Administration (2)].
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 (2.1) and Warnings and Precautions (5.1)].
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.
Overdosage
In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications.
In one report, a subject who ingested 5,000 mg of Promacta had a platelet count increase to a maximum of 929 x 109/L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months follow-up, all events had resolved without sequelae.
In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with Promacta in accordance with dosing and administration recommendations [see Dosage and Administration (2.2)].
Promacta Description
Promacta (eltrombopag) Tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Each tablet contains eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid.
Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3' - {(2Z) - 2 - [1 - (3,4 - dimethylphenyl) - 3 - methyl - 5 - oxo - 1,5 - dihydro - 4H - pyrazol - 4 - ylidene]hydrazino} - 2' - hydroxy - 3 - biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C25H22N4O4●2(C2H7NO). The molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free acid. Eltrombopag olamine has the following structural formula:
Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.
The inactive ingredients of Promacta are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: hypromellose, polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5 mg tablet), FD&C Yellow No. 6 aluminum lake (25 mg tablet), FD&C Blue No. 2 aluminum lake (50 mg tablet), or Iron Oxide Red and Iron Oxide Black (75 mg tablet).
Promacta - Clinical Pharmacology
Mechanism of Action
Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.
Pharmacokinetics
A population pharmacokinetic model analysis suggests that the pharmacokinetic profile for eltrombopag following oral administration is best described by a 2-compartment model. Based on this model, the estimated exposures of eltrombopag after administration to patients with ITP are shown in Table 4.
Table 4. Geometric Mean (95% Confidence Intervals) of Steady-State Plasma Eltrombopag Pharmacokinetic Parameters in Adults With Chronic Immune (Idiopathic) Thrombocytopenia
| Regimen of Promacta |
AUC(0-τ)
(mcg.hr/mL) |
Cmax
(mcg/mL) |
| 50 mg once daily (N = 34) |
108
(88, 134) |
8.01
(6.73, 9.53) |
| 75 mg once daily (N = 26) |
168
(143, 198) |
12.7
(11.0, 14.5) |
Absorption: Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%.
An open-label, randomized, crossover study was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and Cmax by 65% and delayed tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
Distribution: The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (>99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.
Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.
Elimination: The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in ITP patients.
Race: The influence of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic approach in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). After adjusting for body weight differences, East Asians had approximately 50% higher plasma eltrombopag AUC(0-τ) values as compared to non-East Asian patients who were predominantly Caucasian. In a separate population PK analysis of Promacta in 28 healthy adults (non-East Asians) and 79 patients with chronic liver disease (45 East Asians), East Asian patients had approximately 110% higher plasma eltrombopag AUC(0-τ) values as compared to non-East Asian patients, after adjusting for body weight differences. A reduction in the initial dose of Promacta is recommended for patients of East Asian ancestry and East Asian patients with hepatic impairment (Child-Pugh Class A, B, C) [see Dosage and Administration (2.1)].
An approximately 40% higher systemic eltrombopag exposure in healthy African-American subjects was noted in at least one clinical pharmacology study. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.
Gender: The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic approach in 111 healthy adults (14 females) and 88 patients with ITP (57 females). After adjustment for body weight differences, females had approximately 23% higher plasma eltrombopag AUC(0-τ) values than males.
QT/QTc Prolongation
There is no indication of a QT/QTc prolonging effect of Promacta at doses up to 150 mg daily for 5 days. The effects of Promacta at doses up to 150 mg daily for 5 days (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg, single oral dose) crossover trial in healthy adult subjects. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
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).
Animal Pharmacology/Toxicology
Eltrombopag is phototoxic in vitro. There was no evidence of in vivo cutaneous or ocular phototoxicity in rodents.
Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At ≥6 times the human clinical exposure based on AUC, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At ≥4 times the human clinical exposure based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. The clinical relevance of these findings is unknown [see Warnings and Precautions (5.6)].
Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.
Clinical Studies
The efficacy and safety of Promacta in adult patients with chronic ITP were evaluated in 3 randomized, double-blind, placebo-controlled studies and in an open-label extension study.
Studies 1 and 2
In studies 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count <30 x 109/L were randomized to receive either Promacta or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the studies, Promacta or placebo was discontinued if the platelet count exceeded 200 x 109/L. The primary efficacy endpoint was response rate, defined as a shift from a baseline platelet count of <30 x 109/L to ≥50 x 109/L at any time during the treatment period.
The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109/L) were similar among all treatment groups.
Study 1 randomized 114 patients (2:1) to Promacta 50 mg or placebo. Study 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of Promacta, 30 mg, 50 mg, or 75 mg each administered daily.
Table 5 shows for each study the primary efficacy outcomes for the placebo groups and the patient groups who received the 50 mg daily regimen of Promacta.
Table 5. Studies 1 and 2 Platelet Count Response (≥50 x 109/L) Rates
| Study |
Promacta
50 mg Daily |
Placebo |
| 1 |
43/73 (59%)a |
6/37 (16%) |
| 2 |
19/27 (70%)a |
3/27 (11%) |
aP value <0.001 for Promacta versus placebo.
The platelet count response to Promacta was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of Promacta and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg dose groups of Promacta,
