Promacta Information
Promacta (Eltrombopag olamine) Indications And Usage
Promacta (Eltrombopag olamine) 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 (Eltrombopag olamine) should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Promacta (Eltrombopag olamine) should not be used in an attempt to normalize platelet counts.
Promacta (Eltrombopag olamine) Dosage And Administration
Use the lowest dose of Promacta (Eltrombopag olamine) to achieve and maintain a platelet count ≥50 x 10/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use Promacta (Eltrombopag olamine) in an attempt to normalize platelet counts . In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting Promacta (Eltrombopag olamine) and decreased within 1 to 2 weeks after discontinuing Promacta (Eltrombopag olamine) .
Take Promacta (Eltrombopag olamine) on an empty stomach (1 hour before or 2 hours after a meal) . Allow at least a 4-hour interval between Promacta (Eltrombopag olamine) 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 .
Promacta (Eltrombopag olamine) 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.
Promacta (Eltrombopag olamine) Contraindications
Promacta (Eltrombopag olamine) Warnings And Precautions
Promacta (Eltrombopag olamine) 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 (Eltrombopag olamine) , 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 (Eltrombopag olamine) and placebo groups, respectively. In the 3 controlled studies, four patients (1%) treated with Promacta (Eltrombopag olamine) and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the patients treated with Promacta (Eltrombopag olamine) in the controlled studies with hepatobiliary laboratory abnormalities were re-exposed to Promacta (Eltrombopag olamine) in the extension study. Six of these patients again experienced liver test abnormalities (predominantly Grade 1) resulting in discontinuation of Promacta (Eltrombopag olamine) in one patient. In the extension study, one additional patient had Promacta (Eltrombopag olamine) discontinued due to liver test abnormalities (≤Grade 3)
Measure serum ALT, AST, and bilirubin prior to initiation of Promacta (Eltrombopag olamine) , 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 (Eltrombopag olamine) if ALT levels increase to ≥3X the upper limit of normal (ULN) and are:
Reinitiating treatment with Promacta (Eltrombopag olamine) is not recommended. If the potential benefit for reinitiating treatment with Promacta (Eltrombopag olamine) is considered to outweigh the risk for hepatotoxicity, then cautiously reintroduce Promacta (Eltrombopag olamine) and measure serum liver tests weekly during the dose adjustment phase. If liver tests abnormalities persist, worsen or recur, then permanently discontinue Promacta (Eltrombopag olamine) .
Pharmacokinetic evaluations in patients with hepatic impairment show that plasma eltrombopag AUC increases with increasing degree of hepatic impairment (as measured by Child-Pugh). Exercise caution when administering Promacta (Eltrombopag olamine) to patients with hepatic impairment (Child-Pugh Class A, B, C). Use a lower starting dose of Promacta (Eltrombopag olamine) in patients with any degree of hepatic impairment and monitor closely .
Thrombotic/thromboembolic complications may result from increases in platelet counts with Promacta (Eltrombopag olamine) . 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 (Eltrombopag olamine) 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 (Eltrombopag olamine) in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥50 x 10/L as necessary to decrease the risk for bleeding .
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 (Eltrombopag olamine) once daily. Seven thrombotic complications (six patients) were reported in the group that received Promacta (Eltrombopag olamine) and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received Promacta (Eltrombopag olamine) were of the portal venous system. Five of the six patients in the group that received Promacta (Eltrombopag olamine) experienced a thrombotic complication within 30 days of completing treatment with Promacta (Eltrombopag olamine) and at a platelet count above 200 x 10/L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg Promacta (Eltrombopag olamine) once daily for 2 weeks in preparation for invasive procedures.
Exercise caution when administering Promacta (Eltrombopag olamine) to patients with hepatic impairment (Child-Pugh Class A, B, C). Use a lower starting dose of Promacta (Eltrombopag olamine) in patients with any degree of hepatic impairment and monitor closely . Promacta (Eltrombopag olamine) is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.
Promacta (Eltrombopag olamine) Drug Interactions
In vitro
In vitro,
In vitro
Use caution when concomitantly administering Promacta (Eltrombopag olamine) 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
In vitro
In vitro
Promacta (Eltrombopag olamine) Use In Specific Populations
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 (Eltrombopag olamine) should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
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.
The disposition of Promacta (Eltrombopag olamine) 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 AUC was 41% higher in patients with mild hepatic impairment (Child-Pugh A) compared to subjects with normal hepatic function. Plasma eltrombopag AUC was approximately 2-fold higher in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C). The half-life of Promacta (Eltrombopag olamine) 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 and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC values. The half-life of Promacta (Eltrombopag olamine) 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 (Eltrombopag olamine) is recommended for patients with hepatic impairment (Child-Pugh Class A, B, C) .
The disposition of a single 50 mg dose of Promacta (Eltrombopag olamine) in patients with mild, moderate, and severe renal impairment was compared to subjects with normal renal function. Average total plasma eltrombopag AUC 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 (Eltrombopag olamine) dose is needed for patients with renal impairment. Closely monitor patients with impaired renal function when administering Promacta (Eltrombopag olamine) .
Promacta (Eltrombopag olamine) 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 (Eltrombopag olamine) had a platelet count increase to a maximum of 929 x 10/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 (Eltrombopag olamine) in accordance with dosing and administration recommendations .
Promacta (Eltrombopag olamine) Description
Promacta (Eltrombopag olamine) (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 CHNO●2(CHNO). 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 (Eltrombopag olamine) are: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. 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 (Eltrombopag olamine) Clinical Pharmacology
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.
Absorption:
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 AUC by approximately 59% and C by 65% and delayed t by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
Elimination:
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:
(0-τ)
Promacta (Eltrombopag olamine) Nonclinical Toxicology
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 assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C). In the mouse lymphoma assay, eltrombopag was marginally positive (
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).
Eltrombopag is phototoxic . There was no evidence of 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 .
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.
Promacta (Eltrombopag olamine) Clinical Studies
The efficacy and safety of Promacta (Eltrombopag olamine) in adult patients with chronic ITP were evaluated in 3 randomized, double-blind, placebo-controlled studies and in an open-label extension study.
In studies 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count
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 10/L) were similar among all treatment groups.
Study 1 randomized 114 patients (2:1) to Promacta (Eltrombopag olamine) 50 mg or placebo. Study 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of Promacta (Eltrombopag olamine) , 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 (Eltrombopag olamine) .
a
P
The platelet count response to Promacta (Eltrombopag olamine) 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 (Eltrombopag olamine) and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg dose groups of Promacta (Eltrombopag olamine) , the study drug was discontinued due to an increase in platelet counts to >200 x 10/L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50 mg dose of Promacta (Eltrombopag olamine) was 42 days in Study 1 and 43 days in Study 2.
Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with Promacta (Eltrombopag olamine) . Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with Promacta (Eltrombopag olamine) .
In this study, 197 patients were randomized (2:1) to receive either Promacta (Eltrombopag olamine) 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of Promacta (Eltrombopag olamine) could be adjusted based on individual platelet counts. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with Promacta (Eltrombopag olamine) for 6 weeks. Patients were permitted to receive rescue treatments at any time during the study as clinically indicated. The primary endpoint was the odds of achieving a platelet count ≥50 x 10/L and ≤400 x 10/L for patients receiving Promacta (Eltrombopag olamine) relative to placebo and was based on patient response profiles throughout the 6-month treatment period.
The median age of the patients treated with Promacta (Eltrombopag olamine) and placebo was 47 years and 52.5 years, respectively. Approximately half of the patients treated with Promacta (Eltrombopag olamine) and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts ≤15 x 10/L (50% and 48%, respectively). A similar percentage of patients treated with Promacta (Eltrombopag olamine) and placebo (37% and 34%, respectively) had a prior splenectomy.
In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count ≥50 x 10/L and ≤400 x 10/L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with Promacta (Eltrombopag olamine) , compared to 10% of patients treated with placebo (splenectomized patients: Promacta (Eltrombopag olamine) 51%, placebo 8%; non-splenectomized patients: Promacta (Eltrombopag olamine) 66%, placebo 11%). The proportion of responders in the Promacta (Eltrombopag olamine) treatment group was between 37% and 56% compared to 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with Promacta (Eltrombopag olamine) were significantly more likely to achieve a platelet count between 50 x 10/L and 400 x 10/L during the entire 6-month treatment period compared to those patients treated with placebo.
Outcomes of treatment are presented in Table 6 for all patients enrolled in the study.
Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients in the Promacta (Eltrombopag olamine) group and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the study.
Promacta (Eltrombopag olamine) How Supplied/storage And Handling
The 12.5 mg tablets are round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side and are available in bottles of 30: NDC 0007-4643-13.
The 25 mg tablets are round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side and are available in bottles of 30: NDC 0007-4640-13.
The 50 mg tablets are round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side and are available in bottles of 30: NDC 0007-4641-13.
The 75 mg tablets are round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side and are available in bottles of 30: NDC 0007-4642-13.
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Promacta (Eltrombopag olamine) Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
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