Eltrombopag

442.46700

442.47

610-469-9

S56D65XJ9G

DTXSID5057753

C71634

Orange solid

B02BX05|B - Blood and blood forming organs

2933990090

114.59000

4.13840

Orange to red solid

1.33

242-244ºC

656.8ºC at 760 mmHg

351ºC

1.666

Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.|In water, 3.5X10-2 mg/L at 25 °C (est)

Store at room temperature between 20 °C and 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F).

1.17X10-17 mm Hg at 25 °C (est)

Henry's Law constant = 2.44X10-20 atm-cu m/mol at 25 °C (est)

pKa1 = 3.99 (carboxyl); pKa2 = 9.11 (benzyl alcohol); pKa3 = 12.69 (amine) (est)

Practically insoluble in aqueous buffer across pH range to 1 to 7..4; sparingly soluble in water /Eltrombopag olamine/|Hydroxyl radical reaction rate constant = 9.28X10-11 cu cm/molec-sec at 25 °C (est)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including eltrombopag olamine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Eltrombopag olamine/

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P260, P264, P270, P273, P280, P301+P312, P305+P351+P338, P310, P314, P330, P391, and P501|Aggregated GHS information provided by 4 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Eltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation).|IDENTIFICATION AND USE: Eltrombopag is orange solid. It is a nonpeptide thrombopoietin receptor agonist, which is used as oral tablets for treatment of thrombocytopenia. HUMAN EXPOSURE AND TOXICITY: Eltrombopag may cause hepatic and biliary impairment. Grade 2 (or less) abnormalities in serum enzymes ALT, AST, and bilirubin concentrations have been reported in 10% of patients receiving the drug. Grade 4 (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) toxicity scale) elevations in serum liver enzymes, as well as worsening of underlying cardiopulmonary disease and subsequent death, were reported in one patient receiving eltrombopag. In patients with chronic hepatitis C, this drug in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ANIMAL STUDIES: 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. In a pre- and post-natal development study in rats, there were no adverse effects on pregnancy, parturition or lactation of female rats and no effects on the growth, development, neurobehavioral or reproductive function of the offspring at doses up to 20 mg/kg/day. In another rat developmental study embryotoxicity was observed at 60 mg/kg/day in the form of increased pre- and post-implantation loss (leading to a 27% decrease in live litter size) and a 20% to 21% decrease in fetal weight. In a male fertility study in rats testicular weights were slightly increased at 40 mg/kg/day, but there were no effects of eltrombopag on mating and fertility of the treated males, nor any effects on survival, growth or external morphology of the fetuses sired by the treated males. Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3 fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans.

In clinical trials in patients with ITP, ALT elevations occurred in 10% to 11% of eltrombopag vs 3% to 7% of placebo treated subjects, but the elevations were usually mild and transient, resolving once eltrombopag was discontinued and sometimes even with continued use. Instances in which there was recurrence of serum enzyme elevations with restarting eltrombopag have been reported and several patients were said to have developed serious liver disease on treatment, perhaps as a result of portal vein thrombosis. Because of such reports, eltrombopag has a boxed warning about hepatotoxicity and the possibility of hepatic decompensation when treating patients with chronic hepatitis C, in which situation monitoring of liver tests is recommended. Despite this, there have been no published reports of idiosyncratic clinically apparent liver injury attributable to eltrombopag therapy in the medical literature and the clinical characteristics, timing on onset, pattern of enzyme elevations and response to withdrawal of therapy of the liver injury attributed to the drug have not been described. Furthermore, with the development of more potent antiviral agents for hepatitis C, interferon is now rarely used and the indication for concurrent use of eltrombopag for thrombocytopenia during interferon therapy is rarely encountered.

Eltrombopag chelates polyvalent cations (e.g., iron, calcium, aluminum, magnesium, selenium, zinc) found in food, mineral supplements, and antacids. Plasma concentration of eltrombopag was reduced by 70% in patients receiving concomitant antacid therapy containing aluminum hydroxide, magnesium carbonate, and sodium alginate; a 59% reduction in AUC for eltrombopag was reported in association with a high-calcium, high-fat breakfast. Patients should avoid medications and foods containing polyvalent cations, including antacids, dairy products, and mineral supplements, for 4 hours before and after each dose of eltrombopag.|Moderate to strong inhibitors of UGT1A1 or UGT1A3: Potential pharmacokinetic interaction resulting in increased systemic exposure to eltrombopag.1 Use with caution.|Substrates of UDP-glucuronosyltransferases (UGTs): Potential pharmacokinetic interaction resulting in increased systemic exposure to multiple UGT substrates, including acetaminophen, opioid narcotics, and nonsteroidal anti-inflammatory agents. Use with caution.|Substrates of organic anion-transporting polypeptide (OATP) 1B1: Potential pharmacokinetic interaction (increased concentrations of concomitantly administered OATP1BI substrates [e.g., benzylpenicillin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateglinide, repaglinide, rifampin]). Consider reduction of OATP1B1 substrate dosage if manifestations of excessive systemic exposure to these drugs occur. The area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin increased by 55 and 103%, respectively, with administration of a single 10-mg dose of rosuvastatin in healthy adults receiving 75 mg of eltrombopag daily for 5 days. In clinical trials, a 50% reduction in rosuvastatin dosage was recommended for patients receiving concomitant eltrombopag.|For more Interactions (Complete) data for Eltrombopag (8 total), please visit the HSDB record page.

Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.

Eltrombopag is highly protein bound (>99%).

Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction.|FDA Label|Revolade is indicated for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1 year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.|Treatment of secondary thrombocytopenia|Treatment of Idiopathic Thrombocytopenia Purpura (ITP)|Treatment of aplastic anaemia|Drug: Eltrombopagolamine

The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches to activating the thrombopoietin receptor were sought.

Hematologic Growth Factors

Nonpeptide thrombopoietin receptor agonist|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. /Included in US product label/|Promacta is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. /Included in US product label/|Promacta is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. /Included in US product label/|Promacta should be used only in patients with immune (idiopathic) thrombocytopenia (ITP) whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. Promacta should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.

/BOXED WARNING/ WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C. In patients with chronic hepatitis C, Promacta in combination with interferon and ribavirin may increase the risk of hepatic decompensation.|In patients with chronic hepatitis C, Promacta in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with Promacta plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with Promacta plus antivirals. Discontinue Promacta if antiviral therapy is discontinued.|Retreatment with eltrombopag after discontinuance for hepatotoxicity is not recommended. However, the manufacturer suggests that retreatment may be considered if the anticipated clinical benefit of eltrombopag outweighs the potential risk of hepatotoxicity. If treatment is reinitiated, the manufacturer recommends that serum ALT, AST, and bilirubin concentrations be evaluated weekly during the dosage adjustment phase. If abnormal liver function tests persist, worsen, or recur, eltrombopag should be permanently discontinued.|Eltrombopag may cause hepatic and biliary impairment. Grade 2 (or less) abnormalities in serum ALT, AST, and bilirubin concentrations have been reported in 10% of patients receiving the drug. Grade 4 (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) toxicity scale) elevations in serum liver enzymes, as well as worsening of underlying cardiopulmonary disease and subsequent death, were reported in one patient receiving eltrombopag. Liver function tests (e.g., serum ALT, AST, and bilirubin concentrations) should be evaluated prior to starting therapy and monitored every 2 weeks during the initial dosage adjustment phase, then monthly thereafter once a stable dosage has been achieved. If serum bilirubin concentration is elevated, a fractionated measurement must be obtained. If liver function tests are abnormal, the tests should be repeated again within 3-5 days; if the abnormalities persist, liver function tests should be monitored on a weekly basis until the abnormality resolves, stabilizes, or returns to a baseline value. Eltrombopag should be discontinued if serum ALT (SGPT) levels increase to 3 times the upper limit of normal (ULN) or greater and are progressive, persistent (for at least 4 weeks), or are accompanied by an increased direct bilirubin concentration or clinical symptoms of hepatotoxicity or hepatic decompensation.|For more Drug Warnings (Complete) data for Eltrombopag (17 total), please visit the HSDB record page.

Peak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%.|Eltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted.|Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations.|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 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 (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.|Following single intravenous administration, plasma clearance of eltrombopag (parent compound) was 0.45 mL/min/kg in rats, 0.44 mL/min/kg in dogs and 3.3 mL/min/kg in monkeys, with half-lives of 12, 14 and 7.7 hours, respectively. Volume of distribution corresponded to 2 times the total body water in the monkey (1.39 L/kg), but less than one-half total body water in rats and dogs (0.196 L/kg and 0.47 L/kg, respectively).|An open-label, randomized, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-8 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.|For more Absorption, Distribution and Excretion (Complete) data for Eltrombopag (10 total), please visit the HSDB record page.

Eltrombopag is 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.|The metabolic profiles of eltrombopag in vitro were qualitatively similar in rats, dogs and monkeys. There has been no evidence for the formation of any human specific metabolites. In vivo eltrombopag was the predominant circulating component in all species. In rats there was adequate coverage for the circulating metabolites in humans. M14 which accounts for a 20% in human urine excretion was present up to 9.2% in mice urine but was not detected in rats and information is not available in dogs.|Following incubation of 14(C)-eltrombopag with human liver microsomes and supersomes resulted in the formation of metabolite J (a mono-oxygenation product of eltrombopag). CYP1A2 and CYP2C8 were the primary enzymes involved in the in vitro oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 metabolized eltrombopag to form metabolite K (glucuronide conjugate). Following incubation of [14C]eltrombopag with human hepatocytes, the major metabolic pathways observed were conjugation with glucuronic acid (metabolite K) or cysteine (metabolite G). Other minor pathways were conjugation with glutathione (metabolite F) and oxidation that led to formation of an M+14 metabolite. Additional metabolites detected included metabolite J (mono-oxygenated) and metabolite O (oxidation of a methyl to a carboxylic acid). Human kidney microsomes exhibited minimal capacity to metabolize eltrombopag in vitro.|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.

About 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura.|Following single intravenous administration, plasma clearance of eltrombopag (parent compound) was 0.45 mL/min/kg in rats, 0.44 mL/min/kg in dogs and 3.3 mL/min/kg in monkeys, with half-lives of 12, 14 and 7.7 hours, respectively.|The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in ITP patients.

Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered mechanism of action at work.|Eltrombopag is an orally bioavailable, small-molecule thrombopoietin (TPO)-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation from bone marrow progenitor cells.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|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.

/CASE REPORTS/ 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.|/CASE REPORTS/ Eltrombopag may cause hepatic and biliary impairment. Grade 2 (or less) abnormalities in serum ALT, AST, and bilirubin concentrations have been reported in 10% of patients receiving the drug. Grade 4 (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) toxicity scale) elevations in serum liver enzymes, as well as worsening of underlying cardiopulmonary disease and subsequent death, were reported in one patient receiving eltrombopag.|/SURVEILLANCE/ In patients with chronic hepatitis C, Promacta in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with Promacta plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with Promacta plus antivirals. Discontinue Promacta if antiviral therapy is discontinued.

eltrombopag

Oral: tablets, 25 mg, 50 mg and 75 mg Eltrombopag (as Eltrombopag Olamine), Revolade (GlaxoSmithKline).|Table: Eltrombopag Olamine Preparations [Table#8208]

Human drugs -> Revolade -> EMA Drug Category|Other systemic hemostatics, Antihemorrhagics -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients