REVOLADE

Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration.

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).

It has the molecular formula

C 25 H 22 N 4 O 4.

• 2(C 2 H 7 NO).

The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.5 g/mol for eltrombopag free acid.

Eltrombopag olamine has the following structural formula: Eltrombopag olamine is very slightly soluble in water, slightly soluble in methanol, and practically insoluble in 0.1 M hydrochloric acid.

Eltrombopag tablets contain eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid.

The inactive ingredients of eltrombopag tablets are: Tablet Core: colloidal silicon dioxide, magnesium stearate, mannitol, silicified microcrystalline cellulose, partially pregelatinized maize starch, povidone and sodium starch glycolate.

FD&C Yellow #6 aluminum lake (25-mg tablet), FD&C blue#2 aluminum lake (50-mg tablet), black iron oxide and iron oxide red (75-mg tablet), hypromellose, polyethylene glycol, polysorbate 80 (12.5-mg tablet) and titanium dioxide.

• for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.

• for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.

Eltrombopag tablets 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.

• in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia.

• for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.

• Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (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. 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.

Eltrombopag tablets 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. 1.3 Treatment of Severe Aplastic Anemia.

• Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia.

• Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use.

• Eltrombopag tablets are 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.

Mechanism of Action Eltrombopag is a

TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag tablets resulted in dose-dependent increases in platelet counts following repeated (daily) dosing.

The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag tablets.

At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag tablets did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of to 150 mg/day in healthy adult subjects.

AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects.

Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation.

Eltrombopag is absorbed with a peak concentration occurring to 6 hours after oral administration.

Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%.

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 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour.

The decrease in exposure is primarily due to the high calcium content.

A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.

The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14.

Table 14.

Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium.

The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study.

In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%).

Eltrombopag is a substrate of

BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.

The plasma elimination half-life of eltrombopag is approximately to 32 hours in healthy subjects and to 35 hours in patients with ITP.

Absorbed eltrombopag is 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 of eltrombopag.

UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine.

Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine.

Specific Populations Ethnicity Eltrombopag concentrations in

East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects.

Eltrombopag exposure in healthy

African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials.

The effect of

African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.

Following a single dose of eltrombopag tablets (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function.

Plasma eltrombopag

AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function.

The half-life of eltrombopag was prolonged 2-fold in these patients.

This clinical trial did not evaluate protein-binding effects.

Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function.

The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment.

Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag tablets had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score.

Patients with chronic hepatitis

C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-τ) compared with healthy subjects.

Following a single dose of eltrombopag tablets (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects.

The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.

The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials.

Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight.

East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients.

AUC (0-τ) and C max in pediatric patients aged to 17 years was similar to that observed in adults.

The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15.

Table 15.

Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50-mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 101 12 to 17 years (n = 62) 6.80 103 6 to 11 years (n = 68) 10.3 153 1 to 5 years (n = 38) 11.6 162 a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates.

Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%.

The contribution of sodium alginate to this interaction is not known.

Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag tablets (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%.

Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent.

The coadministration of a single dose of eltrombopag tablets (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%.

Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag.

Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans.

The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%.

Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent.

In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15.

Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP.

The following clinically significant adverse reactions associated with eltrombopag tablets are described in other sections.

• Hepatic Decompensation in Patients with Chronic Hepatitis C.

• Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia.

• Cataracts Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea.

To report SUSPECTED ADVERSE

REACTIONS, contact Hikma Pharmaceuticals USA Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Persistent or Chronic Immune Thrombocytopenia Adults

In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag tablets.

Other serious adverse reactions included thrombotic/thromboembolic complications.

The data described below reflect exposure of eltrombopag tablets to patients with persistent or chronic ITP aged to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial.

Eltrombopag tablets were administered to 330 patients for at least 6 months and 218 patients for at least 1 year.

Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag tablets) from the three placebo-controlled trials, with a higher incidence in eltrombopag tablets versus placebo.

Table 8.

Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria.

In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag tablets and in no patients who received placebo.

Among 302 patients with persistent or chronic ITP who received eltrombopag tablets in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials.

Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag tablets) from the extension trial.

Table 9.

Reactions (≥3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag tablets and placebo, respectively.

Four patients (1%) treated with eltrombopag tablets and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities.

Seventeen of the patients treated with eltrombopag tablets in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag tablets in the extension trial.

Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag tablets in one patient.

In the extension persistent or chronic

ITP trial, six additional patients had eltrombopag tablets discontinued due to liver test abnormalities (less than or equal to Grade 3).

In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag tablets and 7% of patients in the placebo group.

All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use.

In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag tablets.

Seventy-two percent of patients had preexisting risk factors, including corticosteroid use.

The safety of eltrombopag tablets was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag tablets -treated patients and 179 placebo-treated patients).

Thromboembolic events were reported in 6% of eltrombopag tablets -treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag tablets -treated patients versus 0% of placebo-treated patients.

In a placebo-controlled trial of eltrombopag tablets in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag tablets and one patient in the placebo group developed portal vein thromboses.

The data described below reflect median exposure to eltrombopag tablets of 91 days for 107 pediatric patients (aged to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials.

Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag tablets) across the two placebo-controlled trials, with a higher incidence for eltrombopag tablets versus placebo.

Table 10.

Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Tablets Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN.

In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag tablets.

Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis.

Chronic Hepatitis C-associated Thrombocytopenia

In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag tablets.

Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag tablets compared with placebo).

Table 11.

Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag tablets + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep.

Rash was reported in 9% and 7% of patients receiving eltrombopag tablets and placebo, respectively.

In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag tablets compared with 3% for placebo.

Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag tablets and placebo, respectively.

ALT or

AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag tablets and placebo, respectively.

In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag tablets and 5% of patients treated with placebo.

The safety of eltrombopag tablets was also assessed in all patients treated with eltrombopag tablets in the two controlled trials, including patients who initially received eltrombopag tablets in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 eltrombopag tablets -treated patients).

Hepatic failure was reported in 0.8% of eltrombopag -treated patients and 0.4% of placebo-treated patients.

Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag tablets was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy.

In this trial, eltrombopag tablets was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine.

Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag tablets, h-ATG, and cyclosporine at the recommended dose and schedule.

In this cohort, eltrombopag tablets was administered at up to 150 mg once daily on Day to Month 6 (D1-M6) in combination with h-ATG on Days to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months.

The median duration of exposure to eltrombopag tablets in this cohort was 183 days with 70% of patients exposed for > 24 weeks.

Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag tablets in the D1-M6 cohort.

Table 12.

Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse reaction Eltrombopag tablets n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration, including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

In the eltrombopag tablets

D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia.

New or worsening liver function laboratory abnormalities (CTCAE Grade and Grade 4) in the eltrombopag tablets D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively.

In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag tablets D1-M6 cohort.

In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications.

In one report, a subject who ingested 5000 mg of eltrombopag tablets had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion.

The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue.

The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks.

After 2 months’ follow-up, all events had resolved without sequelae.

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 eltrombopag tablets in accordance with dosing and administration recommendations.

Consider contacting the Poison

Help line or a medical toxicologist for additional overdose management recommendations.

• Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg).

Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements.

• Persistent or Chronic ITP: Initiate eltrombopag tablets at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged to 5 years.

Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast.

• Asian ancestry.

Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day.

• Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets at 25 mg orally once daily for all patients.

Adjust to achieve target platelet count required to initiate antiviral therapy.

Do not exceed a daily dose of 100 mg.

• First-line Severe Aplastic Anemia: Initiate eltrombopag tablets orally once daily at 2.5 mg/kg (in pediatric patients aged to 5 years old), 75 mg (pediatric patients aged to 11 years old), or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy.

Reduce initial dose in patients of

East-/Southeast-Asian ancestry.

Modify dosage for toxicity or elevated platelet counts.

• Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets orally at 50 mg once daily.

Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry.

Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding.

Dose adjustments are based upon the platelet count response.

Do not use eltrombopag tablets to normalize platelet counts.

In clinical trials, platelet counts generally increased within to 2 weeks after starting eltrombopag tablets and decreased within to 2 weeks after discontinuing eltrombopag tablets.

Adult and Pediatric Patients 6 Years and Older with ITP: Initiate eltrombopag tablets at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C).

For patients of

East-/Southeast-Asian ancestry with ITP, initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily.

For patients with

ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily.

East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag tablets at a reduced dose of 12.5 mg orally once daily.

Aged to 5 Years: Initiate eltrombopag tablets at a dose of 25 mg orally once daily.

After initiating eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding.

Do not exceed a dose of 75 mg daily.

Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1.

During therapy with eltrombopag tablets, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved.

CBCs with differentials, including platelet counts, monthly thereafter.

When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring.

Table 1.

Dose Adjustments of Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.

For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets or after any subsequent dosing increase, wait 3 weeks before increasing the dose.

Modify the dosage regimen of concomitant

ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag tablets.

Do not administer more than one dose of eltrombopag tablets within any 24-hour period.

Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g.,transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag tablets.

CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.

In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag tablets.

Initiate eltrombopag tablets at a dose of 25 mg orally once daily.

Adjust the dose of eltrombopag tablets in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy.

Monitor platelet counts every week prior to starting antiviral therapy.

During antiviral therapy, adjust the dose of eltrombopag tablets to avoid dose reductions of peginterferon.

CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved.

Monitor platelet counts monthly thereafter.

Do not exceed a dose of 100 mg daily.

Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag tablets.

For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information.

Table 2.

Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.

The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility.

Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility.

Eltrombopag tablets should be discontinued when antiviral therapy is discontinued.

Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets. 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets concurrently with standard immunosuppressive therapy.

Initial Dose Regimen The recommended initial dose regimen is listed in Table 3.

Do not exceed the initial dose of eltrombopag tablets.

Table 3.

Recommended Initial Eltrombopag Tablets Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients to 11 years 75 mg orally once daily for 6 months Pediatric patients to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag tablets dose by 50% as listed in Table 4.

If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag tablets until transaminase levels are < 5 x ULN.

Determine the initial dose for these patients based on Table 3 or Table 4.

Table 4.

Recommended Initial Eltrombopag Tablets Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients to 11 years 37.5 mg orally once daily for 6 months Pediatric patients to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for Eltrombopag Tablets: Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets.

Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5.

Table 5.

Dose Adjustments of Eltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week.

Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets at a daily.

The 12.5 mg tablets are round, biconvex, white color, film-coated tablets debossed with ‘ZE1’on one side and plain on other side.

NDC 0054-0962-13: Bottle of The 25 mg tablets are round, biconvex, orange color, film-coated tablets debossed with ‘ZE2’ on one side and plain on other side.

NDC 0054-0963-13: Bottle of The 50 mg tablets are round, biconvex, blue color, film-coated tablets debossed with ‘ZE3’ on one side and plain on other side.

NDC 0054-0964-13: Bottle of The 75 mg tablets are round, biconvex, pink, film-coated tablets debossed with ‘ZE4’ on one side and plain on other side.

NDC 0054-0965-13: Bottle of 30 Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) .

Dispense in original bottle.

Available data from a small number of published case reports and postmarketing experience with eltrombopag tablets use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses.

These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).

Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.

In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).

Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity.

However, no evidence of major structural malformations was observed.

In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).

No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.

In a pre-and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20.

No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed 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 was detected in the plasma of offspring (F1).

The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.

Females and Males of Reproductive Potential 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 tablets during treatment and for at least 7 days after stopping treatment with eltrombopag tablets.

The safety and efficacy of eltrombopag tablets have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine).

Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established.

Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established.

The safety and efficacy of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials.

The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily.

See Dosage and

Administration for dosing recommendations for pediatric patients 1 year and older.

The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial.

A total of 26 pediatric patients (ages to < 17 years) were evaluated; 12 children (aged to < 12 years) and 14 adolescents (aged to < 17).

Administration for dosing recommendations for pediatric patients 2 years and older.

The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established.

In patients to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older.

Among the 12 patients who were to 11 years of age in the eltrombopag tablets D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month was 8% versus 46% in patients age to 16 years and 50% in patients 17 years of age and older.

Of the 106 patients in two randomized clinical trials of eltrombopag tablets 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over.

Of the 1439 patients in two randomized clinical trials of eltrombopag tablets in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over.

Of the 196 patients who received eltrombopag tablets for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients.