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WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, TREPTORA in combination with interferon and ribavirin may increase the risk of hepatic decompensation. TREPTORA may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

COMPOSITION

TREPTORA (eltrombopag) tablets contain Eltrombopag Olamine INN equivalent to 25 mg TREPTORA (eltrombopag) tablets contain Eltrombopag Olamine INN equivalent to 50 mg

DESCRIPTION

TREPTORA (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. 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).

PHARMACEUTICAL DOSAGE FORM AND STRENGTHS

TREPTORA (eltrombopag) is presented as 25 mg and 50 mg film coated tablet for oral administration.

THERAPEUTIC INDICATIONS

Treatment of Thrombocytopenia in Patients with Chronic ITP
TREPTORA (eltrombopag) is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. TREPTORA (eltrombopag) should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.

Treatment of Thrombocytopenia in Patients with Hepatitis C Infection

TREPTORA (eltrombopag) is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. TREPTORA (eltrombopag) 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.

Treatment of Severe Aplastic Anemia

TREPTORA (eltrombopag) is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.

LIMITATIONS OF USE

  • TREPTORA (eltrombopag) is not indicated for the treatment of patients with myelodysplastic syndromes (MDS).
  • Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.

WARNINGS AND PRECAUTIONS

Hepatic Decompensation in Patients with Chronic Hepatitis C
In patients with chronic hepatitis C, TREPTORA (eltrombopag) in combination with interferon and ribavirin may increase the risk of hepatic decompensation.

Hepatotoxicity

TREPTORA (eltrombopag) may increase the risk of severe and potentially life-threatening hepatotoxicity. Measure serum ALT, AST, and bilirubin prior to initiation of TREPTORA (eltrombopag), every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. TREPTORA (eltrombopag) inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. 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 resolved or stabilized. Discontinue TREPTORA (eltrombopag) if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are:
  • progressively increasing, or
  • persistent for greater than or equal to 4 weeks, or
  • accompanied by increased direct bilirubin, or
  • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
If the potential benefit for reinitiating treatment with TREPTORA (eltrombopag) is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing TREPTORA (eltrombopag) and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if TREPTORA is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue TREPTORA (eltrombopag).Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory values occurred approximately three months after initiation of TREPTORA (eltrombopag).

Increased Risk of Death and Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML)

Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result from increases in platelet counts with TREPTORA (eltrombopag). 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 TREPTORA (eltrombopag) 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 TREPTORA (eltrombopag) in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts.

Cataracts

It has been seen in the three controlled clinical trials of originator molecule in adults with chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of TREPTORA (eltrombopag) daily and 8 (7%) placebo-group patients.

ADVERSE REACTIONS

  • Hepatic Decompensation in Patients with Chronic Hepatitis C
  • Hepatotoxicity
  • Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia
  • Thrombotic/Thromboembolic Complications
  • Cataracts

DRUG INTERACTIONS

Polyvalent Cations (Chelation)
Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. In a clinical trial of originator molecule, it has been seen that administration of TREPTORA (eltrombopag) with a polyvalent cation-containing antacid decreased plasma eltrombopag systemic exposure by approximately 70%. Take TREPTORA (eltrombopag) at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of TREPTORA (eltrombopag) due to chelation.
Transporters
Coadministration of TREPTORA (eltrombopag) with the OATP1B1 and breast cancer resistance protein (BCRP) substrate, rosuvastatin, to healthy adult subjects increased plasma rosuvastatin AUC0-INF by 55% and Cmax by 103%. Use caution when concomitantly administering TREPTORA (eltrombopag) and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or BCRP (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). 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.
Protease Inhibitors
HIV Protease Inhibitors: In a drug interaction trial of originator molecule, coadministration of TREPTORA (eltrombopag) with lopinavir/ritonavir (LPV/RTV) decreased plasma eltrombopag exposure by 17%. No dose adjustment is recommended when TREPTORA (eltrombopag) is coadministered with LPV/RTV. Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus (HCV) Protease Inhibitors: Coadministration of TREPTORA (eltrombopag) with either boceprevir or telaprevir did not affect eltrombopag or protease inhibitor exposure significantly. No dose adjustments are recommended. Drug interactions with other HCV protease inhibitors have not been evaluated.
Peginterferon alfa-2a/b Therapy
Coadministration of peginterferon alfa-2a (PEGASYS®) or -2b (PEGINTRON®) did not affect eltrombopag exposure in two randomized, double-blind, placebo-controlled trials in case of originator molecule with adult patients with chronic hepatitis C.

USE IN SPECIFIC POPULATIONS

Pregnancy
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 embryo lethality and reduced fetal weights at maternally toxic doses. TREPTORA (eltrombopag) should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether eltrombopag is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from eltrombopag, a decision should be made whether to discontinue nursing or to discontinue TREPTORA (eltrombopag) taking into account the importance of TREPTORA (eltrombopag) to the mother.

Pediatric Use

The safety and efficacy of TREPTORA (eltrombopag) in pediatric patients younger than 1 year with ITP have not yet been established.

Geriatric Use

No overall differences in safety or effectiveness were observed between these patients and younger patients in the placebo-controlled trials of originator molecule, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

Hepatic impairment influences the exposure of TREPTORA (eltrombopag). Reduce the initial dose of TREPTORA (eltrombopag) in patients with chronic ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia who also have hepatic impairment (Child-Pugh Class A, B, C). No dosage adjustment is necessary for patients with chronic hepatitis C and hepatic impairment.

Renal Impairment

No adjustment in the initial dose of TREPTORA (eltrombopag) is needed for patients with renal impairment. Closely monitor patients with impaired renal function when administering TREPTORA (eltrombopag).

Ethnicity

Patients of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) exhibit higher eltrombopag exposures. A reduction in the initial dose of TREPTORA (eltrombopag) is recommended for patients of East Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C.

OVERDOSAGE

In the event of overdose, platelet counts may increase excessively and result in thrombotic/ thromboembolic complications. 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 TREPTORA (eltrombopag) in accordance with dosing and administration recommendations.

PHARMACEUTICAL INFORMATIONS

Storage condition
Store below 30°C, store in a cool & dry place. Keep away from light. Keep out of the reach of children.