Odalade

White, round, biconvex film coated tablet with engraved 25 on one side and plain on the other.
Each film coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Mannitol, Povidone, Sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, Opadry white, titanium dioxide, isopropyl alcohol, sodium metabisulfite, talc.

Pharmacology: Pharmacodynamics: Mechanism of action: Thrombopoietin (TPO) is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-receptor.
Eltrombopag is a TPO-receptor agonist which interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades similar but not identical to that of endogenous TPO, inducing proliferation and differentiation of megakaryocytes and bone marrow progenitor cells.
Pharmacodynamics: Eltrombopag differs from TPO with respect to the effects on platelet aggregation. Unlike TPO, eltrombopag treatment of normal human platelets does not enhance adenosine diphosphate (ADP)-induced aggregation or induce P-selectin expression. Eltrombopag does not antagonize platelet aggregation induced by ADP or collagen.
Pharmacokinetics: In clinical trials, eltrombopag resulted in dose-dependent increases in platelet count following repeat daily dosing and reached a maximum in approximately 2 weeks, and returned to baseline within approximately 2 weeks after the last dose. Steady-state was achieved after approximately 1 week with once daily dosing.
Absorption: After oral administration to healthy volunteers, the Cmax of eltrombopag occurred at a Tmax between 2 and 6 hours. Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects.
Compared with the fasted state, the administration of eltrombopag with a high-fat, high-calcium meal decreased the AUC by 59%, decreased the Cmax by 65%, and delayed the Tmax by 1 hour in an open label, randomized crossover study. The decrease in exposure was primarily due to the high calcium content. A meal low in calcium (up to 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.
Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure.
The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in feces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%.
Distribution: Eltrombopag is greater than 99.9% protein bound to albumin. Eltrombopag is a substrate for BCRP, but not a substrate for P-glycoprotein or OATP1B1.
Biotransformation: Eltrombopag is extensively metabolized via cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest oxidation of eltrombopag is via CYP1A2 and CYP2C8 and UGT1A1 and UGT1A3 are responsible for glucuronidation.
Excretion: The main route of excretion of eltrombopag is through feces. 59% of the dose is excreted via this route with 20% of the dose excreted as unchanged drug. Approximately 31% of metabolized eltrombopag is excreted in the urine. Unchanged eltrombopag is not found in the urine.
The elimination half-life of eltrombopag is 21 to 32 hours.
Special populations: Gender: The steady state AUC of eltrombopag was found to be 50% higher in female patients compared with male patients according to a population pharmacokinetic analysis in healthy subjects and patients with idiopathic thrombocytopenic purpura.
Race/Ethnicity: Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with idiopathic thrombocytopenic purpura or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects.
The steady state AUC of eltrombopag was found to be 87% higher in East Asian patients as compared with non-East Asian patients (primarily Caucasian) in a population pharmacokinetic analysis in healthy subjects and patients with idiopathic thrombocytopenic purpura.
Renal impairment: Following administration of a single dose of eltrombopag 50 mg, the AUC was 32% to 36% lower in patients with mild to moderate renal impairment and 60% lower in patients with severe renal impairment compared with healthy patients. The relationship between renal impairment and unbound (active) eltrombopag exposure has not been evaluated.
Hepatic impairment: Following administration of a single dose of eltrombopag, the AUCinf was increased by 41% in patients with mild hepatic impairment (Child-Pugh A) and by approximately two-fold in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) compared with subjects with normal hepatic function. In another population pharmacokinetic analysis in patients with thrombocytopenia and chronic liver disease, the AUCtau was increased by 87% to 110% in patients with mild hepatic impairment and 141% to 240% in patients with moderate hepatic impairment compared with healthy volunteers after repeated doses of eltrombopag.
Toxicology: Preclinical safety data: Safety pharmacology and repeat dose toxicity: Treatment-related cataracts were detected in rodents and were dose and time-dependent. At times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 3 times the human clinical exposure based on AUC in HCV patients at 100 mg/day, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At ≥4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in HCV patients at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in pre-weaning juvenile rats dosed from Days 4-32 (approximately equating to a 2-year, old human at the end of the dosing period), ocular opacities were observed (histology not performed) at 9 times the maximum human clinical exposure in pediatric ITP patients at 75 mg/day, based on AUC. However, cataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical exposure in pediatric ITP patients, based on AUC. Cataracts have not been observed in dogs after 52 weeks of dosing at 2 times the human clinical exposure in ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC.
Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2 year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterized by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.6 times the human clinical exposure based on AUC in HCV patients at 100 mg/day. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times the human clinical exposure in ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC.
Carcinogenicity and mutagenicity: 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 (exposures up to 4 and 5 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in HCV patients at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure, based on Cmax in ITP patients at 75 mg/day and 7 times the human clinical exposure in HCV patients at 100 mg/day). 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.
Reproductive toxicity: Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).
Juvenile animal studies: At non-tolerated doses in pre-weaning rats, ocular opacities were observed. However, at tolerated doses, no ocular opacities were observed. There are no findings in juvenile rats to suggest a greater risk of toxicity with eltrombopag treatment in pediatric vs. adult patients.

ODALADE 25 is indicated: for the treatment of previously treated adult and pediatric patients 1 year and older with immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis who have failed treatment with steroids and platelet count below 30,000/mm³ with clinical bleeding; in patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia to: enable the initiation of interferon based therapy, optimize interferon based therapy; in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia (first-line SAA); for the treatment of cytopenias in patients with severe aplastic anemia (refractory SAA) who have had an insufficient response to immunosuppressive therapy.

ODALADE 25 treatment should remain under the supervision of certified hematologists only.
Dosage regimen: ODALADE 25 dosing regimens must be individualized based on the patient's platelet counts.
General target population: Immune thrombocytopenia: The lowest dose of ODALADE 25 should be used to achieve and maintain a platelet count ≥50,000/microL. Dose adjustments are based upon the platelet count response. ODALADE 25 should not be used to normalize platelet counts. Platelet counts generally increased within 1 to 2 weeks after starting ODALADE 25 and decreased within 1 to 2 weeks after discontinuation.
Initial dose regimen: Adults and pediatric patients aged 6 to 17 years: For adult and pediatric ITP patients aged 6 to 17 years, ODALADE 25 should be initiated at a dose of 25 mg once daily.
Pediatric patients aged 1 to 5 years: For pediatric ITP patients aged 1 to 5 years, ODALADE 25 should be initiated at a dose of 25 mg once daily.
Monitoring and dose adjustment: Adults and pediatric patients aged 1 to 17 years: After initiating ODALADE 25, the dose should be adjusted to achieve and maintain a platelet count ≥50,000/microL as necessary to reduce the risk for bleeding. A daily dose of 75 mg should not be exceeded.
Clinical hematology and liver function tests should be monitored regularly throughout therapy with ODALADE 25 and the dose of ODALADE 25 should be modified based on platelet counts as outlined in Table 1. During therapy with ODALADE 25 complete blood counts (CBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/microL for at least 4 weeks) has been achieved. CBCs including platelet count and peripheral blood smears should be obtained monthly thereafter. (See Table 1.)

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The standard dose adjustment, either decrease or increase, would be 25 mg once daily. However, in a few patients, a combination of different tablet strengths on different days or less frequent dosing may be required.
After any ODALADE 25 dose adjustment, platelet counts should be monitored at least weekly for 2 to 3 weeks. To see the effect of any dose adjustment on the patient's platelet response prior to considering another dose increase, one should wait for at least 2 weeks. In patients with any liver cirrhosis (i.e., hepatic impairment), one should wait 3 weeks before increasing the dose.
Discontinuation: Adults and pediatric patients aged 1 to 17 years: Treatment with ODALADE 25 should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at 75 mg once daily.
Chronic hepatitis C (HCV) associated thrombocytopenia: When ODALADE 25 is given in combination with antiviral therapies reference should be made to the full prescribing information of the respective co-administered medicinal products for comprehensive details of administration.
The lowest dose of ODALADE 25 to achieve and maintain a platelet count necessary to initiate and optimize antiviral therapy should be used. Dose adjustments should be based upon the platelet count response. ODALADE 25 should not be used to normalize platelet counts. Platelet counts generally increased within 1 week of starting ODALADE 25.
Initial dose regimen: Adults: ODALADE 25 should be initiated at a dose of 25 mg once daily.
Monitoring and dose adjustment: The dose of ODALADE 25 should be adjusted in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy (see Table 2). Platelet counts should be monitored every week prior to starting antiviral therapy.
During antiviral therapy the dose of ODALADE 25 should be adjusted as necessary to avoid dose reduction of peginterferon. Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved. CBCs, including platelet counts and peripheral blood smears should be obtained monthly thereafter. A dose of 100 mg ODALADE 25 once daily should not be exceeded.
For specific dosage instructions for peginterferon alfa or ribavirin, one should refer to their respective prescribing information. (See Table 2.)

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Discontinuation: In patients with HCV genotype 1/4/6, independent of the decision to continue interferon therapy, discontinuation of ODALADE 25 therapy should be considered in patients who do not achieve virological response at week 12. If HCV-RNA remains detectable after 24 weeks of treatment, ODALADE 25 therapy should be discontinued. ODALADE 25 treatment should be terminated when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2 or important liver test abnormalities may also necessitate discontinuation of ODALADE 25.
First-line severe aplastic anemia: ODALADE 25 should be initiated concurrently with standard immunosuppressive therapy. The initial dose of ODALADE 25 should not be exceeded.
Initial dose regimen: Adult and adolescent patients aged 12 to 17 years: The recommended initial dose of ODALADE 25 is 75 mg once daily for 6 months.
Pediatric patients aged 6 to 11 years: The recommended initial dose of ODALADE 25 is 37.5 mg once daily for 6 months.
Pediatric patients aged 2 to 5 years: The recommended initial dose of ODALADE 25 is 1.25 mg/kg once daily for 6 months. (See Table 3.)

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Monitoring and dose adjustment for eltrombopag: Clinical hematology and liver tests should be performed regularly throughout therapy with ODALADE 25. The dosage regimen of ODALADE 25 should be modified based on platelet counts as outlined in Table 4. Table 5 summarizes the recommendations for dose interruption, reduction, or discontinuation of ODALADE 25 in the management of liver function abnormalities and thrombosis/embolism events. (See Table 4 and Table 5.)

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Discontinuation: The total duration of ODALADE 25 treatment is 6 months. Excessive platelet count responses (as outlined in Table 4) or certain adverse events (as outlined in Table 5) also necessitate discontinuation of ODALADE 25.
Refractory severe aplastic anemia: Initial dose regimen: Adults: ODALADE 25 should be initiated at a dose of 25 mg once daily.
Monitoring and dose adjustment: Hematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting ODALADE 25. The dose of ODALADE 25 should be adjusted in 25 mg increments every 2 weeks as necessary to achieve the target platelet count ≥50,000/microL. A dose of 150 mg daily should not be exceeded. Clinical hematology and liver tests should be monitored regularly throughout therapy with ODALADE 25 and the dosage regimen of ODALADE 25 should be modified based on platelet counts as outlined in Table 6. (See Table 6.)

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Tapering for tri-lineage (white, blood cells, red blood cells, and platelets) responders: Once platelet count is >50,000/microL, hemoglobin is >10 g/dL in the absence of red blood cell (RBC) transfusion, and absolute neutrophil count (ANC) is >1 x 10⁹/L for more than 8 weeks, the dose of ODALADE 25 should be reduced by up to 50%. If counts stay stable after 8 weeks at the reduced dose, then ODALADE 25 should be discontinued and blood counts monitored. If platelet counts drop to <30,000/microL, hemoglobin drops to <9 g/dL or ANC to <0.5 x 10⁹/L, ODALADE 25 may be reinitiated at the previous dose.
Discontinuation: If no hematological response has occurred after 16 weeks of therapy with ODALADE 25, therapy should be discontinued. Discontinuation should be considered if new cytogenetic abnormalities are observed. Excessive platelet count responses (as outlined in Table 6) or important liver test abnormalities also necessitate discontinuation of ODALADE 25.
Special populations (all indications): Renal impairment: No dose adjustment is necessary in patients with renal impairment. However, because of limited clinical experience, patients with impaired renal function should use ODALADE 25 with caution and close monitoring.
Hepatic impairment: ITP patients with liver cirrhosis (hepatic impairment, Child-Pugh score ≥5) should use ODALADE 25 with caution and close monitoring. If the use of ODALADE 25 is deemed necessary for ITP patients with hepatic impairment, the starting dose must be 25 mg once daily. After initiating the dose of ODALADE 25 in patients with hepatic impairment, one should wait 3 weeks before increasing the dose.
Chronic HCV patients with hepatic impairment and refractory severe aplastic anemia patients with hepatic impairment should initiate ODALADE 25 at a dose of 25 mg once daily.
The initial dose of ODALADE 25 in patients with hepatic impairment in the first-line setting should be determined as necessary based on clinical judgement, tolerability, and close monitoring of liver function.
Pediatric patients (below 18 years): The safety and efficacy of ODALADE 25 have not been established in pediatric patients with ITP younger than 1 year of age, chronic HCV, refractory SAA, and definitive immunosuppressive therapy-naïve SAA younger than 2 years of age.
Geriatric patients (65 years of age or older): There are limited data on the use of ODALADE 25 in patients aged 65 years and older. In the clinical studies of ODALADE 25, overall no clinically significant differences in safety of ODALADE 25 were observed between patients aged 65 years and older compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Method of administration: ODALADE 25 should be taken at least two hours before or four hours after any products such as antacids, dairy products, or mineral supplements containing polyvalent cations (e.g., aluminium, calcium, iron, magnesium, selenium, and zinc). ODALADE 25 may be taken with food containing little (<50 mg) or preferably no calcium.

Overdosing: The overall risk of exposure is limited.
Mild to moderate poisoning: It is anticipated that toxicity is likely an extension of pharmacologic events which may include the development of thrombocytosis, hepatotoxicity, bone marrow reticulin formation and bone marrow fibrosis. Rash, bradycardia, elevated aminotransferase concentrations, and thrombocytosis have been reported after overdose.
Severe poisoning: An excessive increase in platelet count may increase the risk of developing a thrombotic and/or thromboembolic events.
Treatment: In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In case of an overdose, oral administration of a metal cation containing preparation, such as calcium, aluminium, or magnesium preparations to chelate eltrombopag and thus limit absorption should be considered. Platelet counts should be closely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing and administration recommendations.
Because eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of eltrombopag.

ODALADE 25 is contraindicated in patients who have a history of hypersensitivity reactions to eltrombopag and/or its excipients.

Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.
Liver enzyme elevations may occur; for the treatment of chronic immune thrombocytopenia (ITP), chronic hepatitis C-associated thrombocytopenia, and refractory severe aplastic anemia, obtain ALT, AST, and bilirubin prior to treatment initiation, every 2 weeks during adjustment phase, then monthly (after stable dose established).
For the first-line treatment of severe aplastic anemia, obtain ALT, AST, and bilirubin prior to therapy initiation, every other day (while hospitalized for immunosuppressive therapy), and then every 2 weeks during treatment. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia; obtain fractionation for elevated bilirubin levels. Repeat abnormal liver function tests within 3 to 5 days; if confirmed abnormal, monitor weekly until resolves, stabilizes, or returns to baseline.
For the treatment of chronic ITP, chronic hepatitis C-associated thrombocytopenia, and refractory severe aplastic anemia, discontinue treatment for ALT levels >3 times the ULN in patients with normal hepatic function, or >3 times baseline (or >5 times ULN; whichever is lower) in those with preexisting transaminase elevations and which are progressively increasing, or persistent (>4 weeks), or accompanied by increased direct bilirubin, or accompanied by clinical signs of liver injury or evidence of hepatic decompensation.
Hepatotoxicity may reoccur with re-treatment, after therapy interruption; however, if the benefit of treatment outweighs the hepatotoxicity risk, initiate carefully, and monitor liver function tests weekly during the dose adjustment phase; permanently discontinue if liver abnormalities persist, worsen, or recur with rechallenge. In clinical trials, isolated cases of severe liver injury occurred ~3months after initiation of eltrombopag and resolved with discontinuation.
For the first-line treatment of severe aplastic anemia, withhold eltrombopag for ALT or AST >6 times ULN; reinitiate eltrombopag at a reduced dose when ALT or AST return to acceptable levels. Use with caution in patients with preexisting hepatic impairment (clearance may be reduced); dosage reductions are recommended in patients with ITP (except children 1 to 5 years) and severe aplastic anemia who have hepatic dysfunction (no initial dose reductions are necessary in patients with chronic hepatitis C-related thrombocytopenia); monitor closely.
May increase risk of hepatic decompensation when used in combination with interferon and ribavirin in patients with chronic hepatitis C.
In clinical trials, patients with low albumin (<3.5 g/dL) or a Model for End-Stage Liver Disease (MELD) score ≥10 at baseline had an increased risk of hepatic decompensation; closely monitor these patients during therapy. If antiviral therapy is discontinued for hepatic decompensation according to interferon/ribavirin recommendations, eltrombopag should also be discontinued. Indirect hyperbilirubinemia is commonly observed with eltrombopag when used in combination with peginterferon and ribavirin. In addition, ascites, encephalopathy, and thrombotic events were reported more frequently than placebo in chronic hepatitis C trials.
Bone marrow reticulin formation and risk of bone marrow fibrosis: Monitor peripheral blood smear for cellular morphologic abnormalities; analyze CBC monthly; discontinue treatment with onset of new or worsening abnormalities (eg, teardrop and nucleated RBC, immature WBC) or cytopenias and consider bone marrow biopsy (with staining for fibrosis).
Thrombotic/Thromboembolic complications: Thromboembolism may occur with excessive increases in platelet levels. Use with caution in patients with known risk factors for thromboembolism (eg, Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). Thrombotic events, primarily involving the portal venous system, were more commonly seen in eltrombopag-treated chronic hepatitis C patients with thrombocytopenia (when compared to placebo). Thrombotic events (including portal venous thrombosis) were also reported in a study of non-ITP thrombocytopenic patients with chronic liver disease undergoing elective invasive procedures receiving eltrombopag 75 mg once daily. Symptoms of portal vein thrombosis include abdominal pain, nausea, vomiting, and diarrhea. The risk for portal venous thrombosis is increased in thrombocytopenic patients with chronic liver disease receiving 75 mg once daily for 2 weeks as preparation for invasive procedures.
Cataracts: Cataract formation or worsening was observed in clinical trials. Monitor regularly for signs and symptoms of cataracts; obtain ophthalmic exam at baseline and during therapy. Use with caution in patients at risk for cataracts (eg, advanced age, long-term glucocorticoid use).
Hematologic: Do not use to normalize platelet counts.
ITP: Indicated only when the degree of thrombocytopenia and clinical conditions increase the risk for bleeding in patients with chronic ITP; use the lowest dose necessary to achieve and maintain platelet count ≥50,000/mm³. Discontinue if platelet count does not respond to a level to avoid clinically important bleeding after 4 weeks at the maximum recommended dose.
Chronic hepatitis C-associated thrombocytopenia: Use only when thrombocytopenia prevent the initiation and maintenance of interferon-base therapy; discontinue if antiviral therapy is discontinued. Safety and efficacy have not been established when combined with direct acting antiviral medications approved for chronic hepatitis C genotype 1 infection therapy.
Severe refractory aplastic anemia: Use the lowest dose to achieve and maintain hematologic response. Discontinue if no hematologic response has occurred a 16 weeks of therapy, excessive platelet count responses or important liver test abnormalities. Consider discontinuation if new cytogenetic abnormalities are observed.
Malignancies and progression of malignancies: Eltrombopag is not indicated for the treatment of myelodysplastic syndromes (MDS). A clinical trial comparing the combination of azacitidine plus eltrombopag to azacitidine alone in patients with intermediate-1, intermediate-2, or high-risk MDS was terminated due to lack of efficacy and safety concerns (including increased progression to acute myeloid leukaemia (AML)). Increased relative risks of death and progression to AML in the eltrombopag arm compared to placebo were observed in the study.
Effects on ability to drive and use machine: There have been no studies to investigate the effect of eltrombopag on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of eltrombopag. The clinical status of the patient and the adverse event profile of eltrombopag should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills.

Pregnancy: There are no adequate and well-controlled studies of eltrombopag in pregnant women to inform a drug associated risk. In animal developmental and reproductive toxicology studies, oral administration of eltrombopag to pregnant rats and rabbits throughout organogenesis resulted in developmental toxicity in rats. The effect of eltrombopag on human pregnancy is unknown. Pregnant women or women of childbearing potential should be advised of the potential risk of eltrombopag to a fetus. Eltrombopag should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Contraception: Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag.
Lactation: There is no information regarding the presence of eltrombopag or its metabolites in human milk, or their effects on the breastfed infant, or on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. A decision must be made whether to discontinue breastfeeding or to continue/abstain from eltrombopag therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Tabulated summary of reactions from clinical trials: Adverse drug reactions from clinical studies are listed as follows by MedDRA body system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Tables 7, 8, 9, 10 and 11.)

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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been reported during post-approval use of eltrombopag. Because they are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. (See Table 12.)

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Eltrombopag is a substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2C8 (minor), UGT1A1, UGT1A3. Eltrombopag inhibits BCRP/ABCG2, OATP1B1/1B3 (SLCO1B1/1B3), UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B15, UGT2B7.
Effects of other drugs on eltrombopag: Cyclosporine: A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg cyclosporine (a BCRP inhibitor). This decrease in exposure is not considered clinically meaningful. Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient's platelet count. Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is coadministered with cyclosporine. Eltrombopag dose may need to be increased based on these platelet counts.
Polyvalent Cations Chelation: Eltrombopag chelates with polyvalent cations such as aluminium, calcium, iron, magnesium, selenium, and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUCinf and Cmax. Eltrombopag should be taken at least two hours before or four hours after any products such as antacids, dairy products, or mineral supplements containing polyvalent cations to avoid significant reduction in eltrombopag absorption.
Lopinavir/ritonavir: Co-administration of eltrombopag with lopinavir/ritonavir may cause a decrease in the concentration of eltrombopag. Therefore, caution should be used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet count should be monitored at least weekly for 2 to 3 weeks in order to ensure appropriate medical management of the dose of eltrombopag when lopinavir/ritonavir therapy is initiated or discontinued.
HCV protease inhibitors: Co-administration of repeat doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of eltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent.
Effects of eltrombopag on other drugs: Rosuvastatin: Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin increased plasma rosuvastatin Cmax and AUCinf. When co-administered with eltrombopag, a reduced dose of rosuvastatin should be considered and careful monitoring should be undertaken. A dose reduction of rosuvastatin by 50% was recommended for co-administration of rosuvastatin and eltrombopag. Concomitant administration of eltrombopag and other OATP1B1 and BCRP substrates should be undertaken with caution.
Cytochrome P450 substrates: Administration of eltrombopag 75 mg once daily for 7 days did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when eltrombopag and CYP450 substrates, inducers or inhibitors are co-administered.
HCV Protease inhibitors: Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure. Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUCtau, increased Cmax by 19%, and decreased Cmin by 32%. Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir.
Drug-food/drink interactions: Food, especially dairy products, may decrease the absorption of eltrombopag.
Take eltrombopag on an empty stomach at least 1 hour before or at least 2 hours after a meal. Take eltrombopag at least 2 hours before and 4 hours after foods high in calcium.

Incompatibilities: Not applicable.

Shelf life: 2 years.
Special precautions for storage: Store below 30°C.

Haemostatics

B02BX05 - eltrombopag ; Belongs to the class of other systemic hemostatics. Used in the treatment of hemorrhage.

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