Drug information of Eltrombopag

Mechanism of effect

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.

Pharmacodynamic

Not Available

Pharmacokinetics

Bioavailability: >52% (single 75-mg dose)

Peak Plasma Time: 2-6 hr

Effect of food

• A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC by ~59% and peak plasma concentration by 65% and delayed peak plasma concentrationby 1 hr
• Calcium content of this meal may have also contributed to this decrease in exposure

Protein bound: >99%

Concentration of eltrombopag in blood cells: ~ 50-79%

Metabolism

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

UGT1A1 and UGT1A3 are responsible for the glucuronidation

Half-life: 26-35 hr (in patients with ITP)

Excretion: Feces (59%); urine (31%)

Drug indications

prevent bleeding episodes in people with chronic immune thrombocytopenic purpura (ITP) prevent bleeding in adults with chronic hepatitis C who are treated with an interferon treat severe aplastic anemia in adults and children who are at least 2 years old.

Dosage

Adult

Chronic Immune Thrombocytopenia

Indicated in patients with insufficient response to corticosteroids, immunoglobulins, or splenectomy

Use only in patients with ITP whose clinical condition increases bleeding risk

Initial: 50 mg PO qDay

Maintenance: Adjust dose to achieve and maintain platelet count (Plt) >50 x 10^9/L to reduce risk of bleeding; not to exceed 75 mg/day

Chronic Hepatitis C-associated Thrombocytopenia

Initial: 25 mg PO qDay

Adjust dose in 25 mg increments q2weeks PRN to achieve target platelet count required to initiate/maintain antiviral therapy with pegylated interferon and ribavirin; not to exceed 100 mg/day

Severe Aplastic Anemia(SAA)

First-line therapy

• Initial dose: 150 mg PO qDay for 6 months
• Do not exceed initial dose; total duration is 6 months

Refractory SAA

• Initial dose: 50 mg PO qDay
• Adjust dose in 50-mg increments q2Weeks PRN to achieve target Plt ≥50 x 10^9/L as necessary; not exceed 150 mg/day; may take up to 16 weeks for hematologic response

Pediatric

Chronic Immune Thrombocytopenia

<1 year: Safety and efficacy not established

1-5 Years: Initiate at 25 mg qDay

≥6 years: Initiate at 50 mg PO qDay

Maintenance: Adjust dose to achieve and maintain platelet count (Plt) >50 x 10^9/L to reduce risk of bleeding; not to exceed 75 mg/day

Severe Aplastic Anemia

First-line therapy

• <2 years: Safety and efficacy not established
• 2-5 years: 2.5 mg/kg qDay for 6 months
• 6-11 years: 75 mg PO qDay for 6 months
• ≥12 years: 150 mg PO qDay for 6 months

Drug contraindications

None

Side effects

flu , Insomnia , Diarrhea , Headache , nausea , vomiting , vertigo , Urinary tract infection , Peripheral edema , fever , myalgia , Flu-like symptoms , Arthralgia , Increased ALT , Increased AST , Hyperbilirubinemia , itching , weakness , tiredness , Abdominal pain , Rash , Rhinorrhea

Abdominal pain, Alopecia , Anemia , Arthralgia , Asthenia , Back pain , Cataract , Chills , Cough , Decreased appetite , Diarrhea , Dizziness , Fatigue , Headache , Hyperbilirubinemia , Increased ALT , Increased AST , Increased blood bilirubin , Influenza , Influenza-like illness , Insomnia , Muscle spasms , Myalgia , Nasopharyngitis , Nausea , Oropharyngeal pain , Pain in extremity , Paresthesia , Peripheral edema , Pharyngitis , Pruritus , Pyrexia , Rash , Rhinorrhea , Skin discoloration including hyperpigmentation , Toothache , Transaminases increased , Upper respiratory tract infection , Urinary tract infection , Vomiting

Interactions

Sucralfate , Rosuvastatin , Zileuton , Calcium citrate , Magnesium hydroxide , Iron , Efavirenz , Iron polysaccharide , Sodium bicarbonate , Selenium , Iron sucrose , Simvastatin , Ferrous sulfate , Ferrous fumarate , carbonyl iron , Ferrous Gluconate , riociguat , magnesium citrate , pravastatin , fluvastatin , Calcium acetate , Calcium chloride , Eluxadoline , sodium citrate + citric acid , Fluvoxamine , Magnesium oxide , Magnesium sulfate , Calcium Gloconate , Calcium carbonate , Pitavastatin , Aluminium Mg , ELBASVIR/GRAZOPREVIR , magnesium chloride , Biolectra Magnesium , Iron Dextran Complex , Remdesivir , lasmiditan , talazoparib , Artesunate

aluminum hydroxide, atorvastatin, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, carbonyl iron, efavirenz, eluxadoline, ferrous fumarate, ferrous gluconate, ferrous sulfate, fluvastatin, fluvoxamine, iron dextran complex, iron sucrose, magnesium chloride, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium sulfate, pitavastatin, polysaccharide iron, pravastatin, riociguat, rose hips, rosuvastatin, selenium, simvastatin, sodium bicarbonate, sodium citrate/citric acid, talazoparib

Alerts

If patient with hepatic impairment (Child-Pugh Class A, B, C) initiates therapy for first- line treatment of severe aplastic anemia, reduce initial dose

In aplastic anemia, use lowest dose to achieve and maintain hematologic response; discontinue if no hematologic response observed after 16 weeks of therapy, excessive platelet count responses or liver test abnormalities

Chronic hepatitis C with cirrhosis may increase risk of hepatic decompensation and death when treated with alfa interferons; no dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment

Not indicated for the treatment of patients with myelodysplastic syndromes (MDS); increased risk of death and progression of MDS to acute myeloid leukemia observed in a clinical trial showing an increased relative risk of progression to AML by 166%

Thrombotic/thromboembolic complications may result from increases in platelet counts with therapy

Portal vein thrombosis reported in patients with chronic liver disease receiving therapy

Consider potential risk of thromboembolism when administering to patients with known risk factors for thromboembolism (eg, Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease).

Risk of thrombocytopenia and hemorrhage after discontinuation

Not for normalizing platelet counts; for use only when degree of thrombocytopenia and clinical conditions increase risk for bleeding in patients with chronic immune idiopathic thrombocytopenia

May develop or worsen cataracts; screen before administering and during treatment

Discontinue if platelet count does not respond to a level to avoid clinically important bleeding after 4 weeks at maximum recommended dose

In hepatitis C, use only when thrombocytopenia prevents initiation and maintenance of interferon-based therapy; discontinue if antiviral therapy discontinued

Drug interactions overview

• Polyvalent cations
• Eltrombopag chelates polyvalent cations (eg, iron, calcium, aluminum, magnesium, selenium, zinc) in foods, mineral supplements, and antacids
• Administer at least 2 hr before or 4 hr after any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption
• OATP1B1 or BCRP transporters
• Use caution when coadministering with OATP1B1 substrates (eg, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan)
• Monitor closely for signs/symptoms of excessive exposure to OATP1B1 or BCRP substrates and consider reducing the dose of these drugs, if appropriate

Black Box Warnings

Risk for hepatic decompensation in chronic hepatitis C patients

• Risk of hepatotoxicity
• In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase risk of hepatic decompensation
• May increase risk of severe and potentially life-threatening hepatotoxicity

Monitor hepatic function and discontinue dosing as recommended

Points of recommendation

Take Eltrombopag exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

Take Eltrombopag on an empty stomach, at least 1 hour before or 2 hours after a meal.

Do not take Eltrombopag with dairy products or calcium-fortified juice.

Mix the oral suspension powder only with water. Use a new dosing syringe each time you mix the medicine, to measure the water and to give the correct dose.

Swallow the tablet whole and do not crush, chew, or break it.

You will need frequent blood tests to check your liver function. Your eyes may also need to be checked for signs of cataract formation.

Eltrombopag doses are sometimes based on weight in children. Your child's dose needs may change if the child gains or loses weight.

It may take up to 4 weeks of taking this medicine before it is completely effective in preventing bleeding episodes. Keep taking the medication as directed and tell your doctor if you have any bruising or bleeding episodes after 4 weeks of treatment.

Store at room temperature away from moisture and heat. Keep the tablets in their original container, along with the packet or canister of moisture-absorbing preservative. After mixing Eltrombopag oral suspension, store the liquid at room temperature and use it within 30 minutes.

After you stop taking Eltrombopag, your risk of bleeding or bruising may be even higher than it was before you started treatment. Be extra careful to avoid cuts or injury for at least 4 weeks after you stop taking this medicine. Your blood will need to be tested weekly during this time.

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

Pregnancy level

Not Assigned

Related drugs

Romiplostim