Overview:
Eltrombopag is a biphenyl derivative thrombopoietin receptor agonist primarily used to treat unusual and excessive bleeding caused by low platelet count seen in immune thrombocytopenia. It is used to increase the platelet count and treat severe aplastic anemia (Insufficient production of blood cells by bone marrow). The drug stimulates the bone marrow to synthesize thrombocytes (platelets).
Eltrombopag was approved for treating immune thrombocytopenic purpura on November 20, 2008, by the Food and Drug Administration (FDA). It was initially authorized for addressing thrombocytopenia in individuals with chronic immune thrombocytopenic purpura exhibition inadequate response to other therapies. Since then, its approved uses have expanded to include other conditions associated with low platelet counts, such as severe aplastic anemia and chronic thrombocytopenia due to Hepatitis C infection.
Indications:
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Eltrombopag is used to treat adults and pediatric patients (aged one year and older) with chronic immune thrombocytopenic purpura who have not responded well to other conventional treatment modalities, such as corticosteroids, immunoglobulins, or splenectomy (removal of spleen surgically).
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Individuals aged two years and above with aplastic anemia (insufficient production of blood cells by the bone marrow) are treated with Eltrombopag to increase the count of circulating platelets.
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It is used to increase the thrombocyte count in individuals infected by hepatitis C for a chronic period. This can help in the initiation and maintenance of interferon therapy for such individuals.
Eltrombopag is not used to treat thrombocytopenia caused due to any other factors.
Contraindications:
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Eltrombopag should not be used in patients with a history of thrombotic/thromboembolic complications due to the increased incidence of clot formation.
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For children with thrombocytopenia, it is contraindicated in those who have a history of myelodysplastic syndrome (a disorder caused by the inefficiency of bone marrow to produce hematopoietic cells) or any cytopenias associated with it due to the increased risk of developing bone marrow fibrosis and worsening cytopenias.
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Patients with profound liver impairment as the drug can further exacerbate the impairment.
Dosage:
Eltrombopag is given in different doses for different conditions. However, for every condition, assessing the levels of liver enzymes through a liver function test and complete hematological investigations before starting the therapy are mandatory.
Chronic Immune Thrombocytopenic Purpura (ITP):
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The initial dose to treat ITP is 50 milligrams. After assessing the levels of platelets, the dosage may be increased to a maximum of 75 milligrams.
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It is recommended to have the tablet on an empty stomach or one to two hours after consumption of food. It is also advised to have an interval of four hours between the medication and the consumption of calcium-rich foods like dairy products, cereals, or fortified drinks.
Severe Aplastic Anemia:
Eltrombopag is initiated in individuals with severe aplastic anemia at a starting dose of 150 milligrams once daily. The maximum allowed dosage per day is 150 milligrams.
Thrombocytopenia Due to Hepatitis C:
The advised initial dose for treating low platelet count (thrombocytopenia) associated with chronic hepatitis C is 25 milligrams once daily. Dosage can be adjusted after looking into the platelet count results.
Route of Administration:
Eltrombopag is available as a tablet and powder for consumption through the oral route.
For Patients:
What Is Immune Thrombocytopenic Purpura?
Immune thrombocytopenic purpura is an autoimmune disorder that causes abnormal bleeding as the thrombocyte (platelet) count goes below 150,000 cells/cu.mm. As the platelet count is extremely low, the clotting mechanism in the body is completely disrupted, thus resulting in hemorrhage in the affected individuals.
What Are the Causes of Immune Thrombocytopenic Purpura?
This cause of immune thrombocytopenic purpura is not known. However, the body is believed to produce antibodies against the thrombocytes, damaging and destroying the spleen and liver. This condition is noted in children after a viral infection, and in adults, the condition is observed over a long period (chronic condition).
What Are the Clinical Features of Immune Thrombocytopenic Purpura?
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The first symptom noticed in immune thrombocytopenic purpura is easy bruising. The bruises might appear without any apparent injury and can occur on various body parts.
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Small red or violet bleeding spots may be noted on the skin due to tiny bleeding under the skin. These spots are called petechiae. Petechiae can occur on the legs, arms, or other body parts.
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Immune thrombocytopenic purpura is associated with epistaxis (nose bleeding). This can occur spontaneously or go uninterrupted after a very minimal trauma.
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Bleeding from the gums soon after brushing, flossing, or eating hard substances will be noted.
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Blood will be seen in excretory materials like urine and feces.
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Women experience menorrhagia (heavy menstrual bleeding) due to immune thrombocytopenic purpura.
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The tendency to bleed is remarkable in such individuals, especially after minor trauma or surgeries.
Continuous bleeding situations should be addressed immediately as there may be heavy blood loss and a reduction in the volume of blood.
Why Is Eltrombopag Prescribed for Immune Thrombocytopenic Purpura?
Generally, the first-line treatment modalities are drugs like corticosteroids immunoglobulins or surgery like splenectomy to treat immune thrombocytopenic purpura. When none of these treatments produce the desired result, Eltrombopag is advocated.
Eltrombopag is prescribed for Immune Thrombocytopenic Purpura (ITP) because it is a thrombopoietin receptor agonist. Thrombopoietin is a natural hormone that stimulates the production of platelets in the bone marrow. In ITP, the immune system destroys platelets, leading to low platelet counts and an increased risk of bleeding. Eltrombopag works by mimicking the action of thrombopoietin, thereby stimulating the production of platelets and increasing their numbers in the bloodstream. By boosting platelet production, Eltrombopag helps to raise platelet counts, reducing the risk of bleeding and bruising in individuals with ITP. Eltrombopag can also be given to maintain a safer count of thrombocytes in the circulating blood.
How Should Eltrombopag Be Used?
Eltrombopag is available as a tablet to be consumed orally. The dosage should be taken as per the doctor’s prescription. The general limit for immune thrombocytopenic purpura is 75 milligrams. The tablet should be consumed as a whole before taking any food or two hours after consumption of food. In any case, if calcium or metal-containing foods are consumed, there should be a break of four hours between food consumption and drug intake. The medication’s storage requirement specifies a temperature range of 15 to 30 degrees Celsius.
What Are the Side Effects of Taking Eltrombopag?
Mild side effects seen are:
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Nausea.
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Vomiting.
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Gastrointestinal discomfort.
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Diarrhea.
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Fatigue.
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Skin rashes.
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Muscle aches.
Severe side effects noticed are:
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Increased platelet production can result in thrombosis or embolism-related complications. It is also noted in people with clotting disorders.
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People with existing liver issues may seem to have exacerbated liver damage, thus resulting in yellowing of eyes, urine (jaundice), itchy skin, or clay-like stools.
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There have been reports of cataracts developing in a small number of patients treated with Eltrombopag, although the direct association with the medication is not fully established.
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Excessive thrombocytopenia may be observed after discontinuing the drug, especially if the individual is also on antiplatelet drugs. This can result in uninterrupted hemorrhage.
What Are the Precautionary Measures to Be Followed While Taking Eltrombopag?
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Take Eltrombopag at the recommended time and on an empty stomach, usually at least one hour before or two hours after a meal. Avoid taking it with foods or supplements containing polyvalent cations, such as antacids, dairy products, or mineral supplements, as they may interfere with Eltrombopag's absorption.
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The drug dosage should not be missed. Stop the dose and continue the regular schedule in case of a missed dose. Doubling the dose is not advocated.
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Blood tests (complete blood count, peripheral blood smear examination) and liver function tests should be regularly done to monitor platelet count and the extent of liver damage continuously.
For Doctors:
Clinical Pharmacology:
Eltrombopag is a medication that stimulates thrombopoietin receptors by engaging with the transmembrane section (c-Mpl) on megakaryocytes, increasing platelet production. By activating this receptor, Eltrombopag stimulates signaling pathways that promote the proliferation and differentiation of megakaryocyte progenitor cells in the bone marrow, ultimately resulting in an increased production of platelets. This mechanism of action aids in raising platelet counts in patients with thrombocytopenia, particularly in conditions like Immune Thrombocytopenic Purpura (ITP) and severe aplastic anemia. Eltrombopag's effects are dose-dependent, and regular monitoring of platelet counts is necessary to adjust the dosage and ensure appropriate levels for reducing the risk of bleeding while avoiding excessive platelet counts that might lead to thrombotic events.
Drug Ingredients:
Active Ingredient: Eltrombopag olamine.
Inactive Ingredients: Magnesium stearate, microcrystalline cellulose, or lactose monohydrate may be added to stabilize the drug.
Half-Life:
After oral administration, Eltrombopag is well-absorbed and reaches peak plasma concentrations in about two to six hours.
Pharmacokinetics:
Absorption:
Absorption of Eltrombopag occurs primarily in the small intestine, where it is absorbed into the bloodstream. Maximum levels are achieved within two to six hours after ingestion. However, it is important to note that certain foods, especially those like mineral supplements, calcium foods like spinach, tofu, milk, and its products, can interfere with Eltrombopag absorption; hence the recommendation is to avoid these substances around the time of taking the medication.
Distribution:
Eltrombopag's distribution in the body involves binding to plasma proteins, primarily to albumin. It has a relatively high binding affinity to serum albumin, estimated at around 99 percent. After absorption into the bloodstream, Eltrombopag circulates in the plasma, with most of it bound to albumin and a smaller fraction remaining unbound and available to exert its pharmacological effects.
Metabolism:
Eltrombopag undergoes extensive metabolism, primarily in the liver. The metabolic pathway involves multiple enzymes to form various metabolites, mainly through the cytochrome P450 (CYP) system, specifically the CYP1A2 and CYP2C8 enzymes. The primary metabolic pathways include oxidation and conjugation processes. The metabolites also conjugate with glucuronic acid, sulfate, or glutathione to produce conjugated metabolites. The main metabolites of Eltrombopag resulting from these metabolic processes are not known to contribute significantly to its pharmacological activity. Instead, they are typically inactive and are excreted from the body.
Excretion:
Eltrombopag and its metabolites are primarily eliminated from the body via the fecal route. After undergoing extensive metabolism in the liver, the resulting metabolites of Eltrombopag are predominantly eliminated through fecal bile. Minimal amounts of unchanged Eltrombopag are excreted in urine.
Pharmacodynamics:
Eltrombopag acts as an agonist for the thrombopoietin receptor (c-Mpl) found on megakaryocytes in the bone marrow. By binding to this receptor, Eltrombopag activates signaling pathways stimulating megakaryocyte progenitor cells' proliferation, differentiation, and maturation. This stimulation results in an increased production of thrombocytes from the bone marrow. Eltrombopag's mechanism of action mimics the activity of endogenous thrombopoietin, the natural ligand for the thrombopoietin receptor, thereby promoting platelet formation and release into the circulation.
Clinical Toxicity:
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Some patients receiving Eltrombopag have reported thrombotic issues like deep vein thrombosis, embolism, or arterial thromboembolic events. It is vital to observe patients for indications and manifestations of thrombotic events during Eltrombopag therapy and adjust treatment or discontinue the medication if any such complications occur. Patients should be asked for a history of any cardiovascular disorder, intake of antiplatelet or anticoagulant medication for proper prescription, and titration of drug dosage.
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Irregularities in liver functioning, such as heightened liver enzyme levels and potential hepatotoxicity, have been observed in some cases. Frequent evaluation of hepatic function tests is done during Eltrombopag treatment.
Drug Interactions:
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Co-administration with medications metabolized by CYP1A2 (such as caffeine, Theophylline) or CYP2C8 (such as Pioglitazone) may lead to altered plasma concentrations of these drugs.
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Co-administration of Eltrombopag with proton pump inhibitors, such as Omeprazole, may reduce the absorption of Eltrombopag.
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Increased platelet counts due to Eltrombopag may necessitate careful monitoring and potential dosage adjustments of oral anticoagulant medications (such as Warfarin), as higher platelet counts could affect coagulation parameters.
Guidelines for Specific Population:
Pregnant and Lactating Mothers:
Eltrombopag is a pregnancy category C drug. Thus, Eltrombopag is not advised to be used in pregnant individuals as it has the potential to increase the likelihood of causing harm to the growing fetus. Similarly, it is not recommended for use by lactating mothers as Eltrombopag may be excreted through human milk.
Geriatric People:
Elderly individuals may have age-related physiological changes, altered organ function (such as decreased liver or kidney function), and an increased likelihood of having multiple medical conditions or taking multiple medications (polypharmacy). These factors can affect Eltrombopag's metabolism, distribution, and elimination. So, it should be prescribed only after all the other treatment modalities fail.
