ETP

Uses

Adult chronic immune (idiopathic) thrombocytopenic purpura (ITP), Hepatitis C Virus (HCV) related Thrombocytopenia.

ETP is also used to associated treatment for these conditions: Severe Aplastic Anemia (SAA), Thrombocytopenia, Refractory Aplastic anemia, Refractory immune thrombocytopenia

How ETP works

ETP is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. ETP is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, ETP 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.

Dosage

ETP dosage

Adult: Initially 50 mg once daily. East Asian patient 25 mg once daily. Then, adjust dose to maintain platelet count >50,000/microliter. Max: 75 mg daily.

Should be taken on an empty stomach.Take at least 4 hr before or after antacids, dairy products or other Ca-containing food products or mineral supplements containing polyvalent cations. After adjustment, platelet counts should be monitored at least weekly for 2-3 weeks. Wait for at least 2 weeks to see the effect of any dose adjustment on the patient's platelet response prior to considering another dose adjustment.

Side Effects

Insomnia; headache, paraesthesia; cataract, dry eye; nausea; Gl & hepatobiliary disorders; rash, pruritus, alopecia; arthralgia, myalgia, muscle spasm, bone pain; fatigue, peripheral oedema; thromboembolic events.

Toxicity

ETP 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).

Precaution

Not established for use in other thrombocytopenic conditions. Regularly monitor clinical haematology, platelet counts & serum liver test throughout therapy. Renal & hepatic impairment; hepatic disease. Thrombotic/thromboembolic complications. Increased risk of bleeding upon discontinuation of treatment. Bone marrow reticulin formation & risk of bone marrow fibrosis. Malignancies & progression of malignancies. Pregnancy & lactation. Childn <18 yr, elderly.

Interaction

Increased plasma Cmax & AUC of HMG-CoA reductase inhibitors. Caution with methotrexate, topotecan. Increased cone with fluvoxamine; decreased cone with rifampicin & lopinavir/ritonavir. Reduced absorption by antacids, dairy products & other products containing polyvalent cations (eg Fe, Ca, Mg, Al, Se, Zn). Reduced plasma AUC & Cmax with high-calorie & -fat meal. Monitor platelet counts when used in combination with lopinavir/ritonavir & other drugs for treatment of idiopathic thrombocytopenic purpura (ITP).

Food Interaction

• Avoid multivalent ions. Polyvalent cations in food or supplements will be chelated by eltrombopag; therefore, they should be separated by 4 hours before or 2 hours after taking eltrombopag.
• Take on an empty stomach. Separate the administration of eltrombopag from food by at least 1 hour before and 2 hours after eating.

[Moderate] ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of eltrombopag.

In healthy volunteers, a standard high-fat breakfast significantly decreased plasma eltrombopag peak plasma concentration (Cmax) by 65% and systemic exposure (AUC) by 59% and delayed Tmax by one hour.

The calcium content of this meal may have also contributed to this decrease in exposure.

In another study, adult subjects administered a single 25 mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate-calorie meal exhibited a 79% decrease in Cmax and 75% decrease in AUC of eltrombopag.

Administration of eltrombopag 2 hours after the high-calcium meal decreased eltrombopag Cmax by 48% and AUC by 47%, while administration 2 hours before the high-calcium meal decreased eltrombopag Cmax by 14% and AUC by 20%.

ADJUST DOSING INTERVAL: Polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc can significantly reduce the gastrointestinal absorption of eltrombopag due to chelation.

In one clinical trial, administration of a single 75 mg dose of eltrombopag with an antacid containing 1524 mg aluminum hydroxide and 1425 mg magnesium carbonate resulted in an approximately 70% decrease in eltrombopag Cmax and AUC.

MANAGEMENT: ETP should be taken on an empty stomach one hour before or two hours after a meal.

Additionally, eltrombopag should be taken at least 2 hours before or 4 hours after any products that contain polyvalent cations such as antacids, mineral supplements, dairy products, and fortified juices.

ETP multivitamins interaction

[Moderate] ADJUST DOSING INTERVAL: Products containing aluminum, calcium, iron, magnesium, zinc and other polyvalent cations such as antacids or mineral supplements can significantly reduce the gastrointestinal absorption of eltrombopag due to chelation.

In one clinical trial, administration of a single 75 mg dose of eltrombopag with an antacid containing 1524 mg aluminum hydroxide and 1425 mg magnesium carbonate resulted in an approximately 70% decrease in eltrombopag peak plasma concentration (Cmax) and systemic exposure (AUC).

ETP should be taken on an empty stomach at least 2 hours before or 4 hours after oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral solution), aluminum, calcium, iron, magnesium, zinc or other polyvalent cations.

ETP Drug Interaction

Major: pazopanibUnknown: 5-hydroxytryptophan, amphotericin b lipid complex, fluticasone / salmeterol, naproxen, candesartan / hydrochlorothiazide, ipratropium, dutasteride, sulfamethoxazole / trimethoprim, carbamazepine, ubiquinone, ethanol, acetaminophen, rituximab, tramadol, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione

ETP Disease Interaction

Major: hepatitis C, hepatotoxicity / hepatic dysfunctionModerate: cataracts, thrombotic / thromboembolic complications

Volume of Distribution

Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations.

Elimination Route

Peak absorption of ETP 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%.

Half Life

About 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura.

Elimination Route

ETP is eliminated primarily via the feces (59%), along with 31% being renally excreted.

Pregnancy & Breastfeeding use

Pregnancy Category - CAnimal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Contraindication

ETP is contraindicated in patients with severe hepatic impairment and who are hypersensitive to any of its excipients.

Special Warning

Renal Impairment: No dose adjustment is necessary in ITP patients with renal impairment.

Hepatic Impairment: Should not be used in ITP patients with liver cirrhosis (hepatic impairment unless the expected benefit outweighs the identified risk of portal venous thrombosis.

Innovators Monograph

You find simplified version here ETP