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Eltrombopag

Pronunciation

(el TROM boe pag)

Index Terms

  • Eltrombopag Olamine
  • Revolade
  • SB-497115
  • SB-497115-GR

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Promacta: 12.5 mg

Promacta: 25 mg [contains fd&c yellow #6 aluminum lake]

Promacta: 50 mg [contains fd&c blue #2 aluminum lake]

Promacta: 75 mg

Brand Names: U.S.

  • Promacta

Pharmacologic Category

  • Colony Stimulating Factor
  • Hematopoietic Agent
  • Thrombopoietic Agent

Pharmacology

Thrombopoietin (TPO) nonpeptide agonist which increases platelet counts by binding to and activating the human TPO receptor. Activates intracellular signal transduction pathways to increase proliferation and differentiation of marrow progenitor cells. Does not induce platelet aggregation or activation.

Metabolism

Extensive hepatic metabolism; via CYP 1A2, 2C8 oxidation and UGT 1A1, 1A3 glucuronidation

Excretion

Feces (~59%, 20% as unchanged drug, 21% glutathione-related conjugates); urine (31%, 20% glucuronide of the phenylpyrazole moiety)

Onset of Action

Platelet count increase: Within 1 to 2 weeks; Peak platelet count increase: 14 to 16 days

Time to Peak

2 to 6 hours

Duration of Action

Platelets return to baseline: 1 to 2 weeks after last dose

Half-Life Elimination

~21 to 32 hours in healthy individuals; ~26 to 35 hours in patients with ITP

Protein Binding

>99%

Special Populations: Renal Function Impairment

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.

Special Populations: Hepatic Function Impairment

The AUC was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) and approximately twofold higher in patients with moderate-to-severe hepatic impairment (Child-Pugh class B and class C, respectively) when compared to patients with normal hepatic function. Following repeat doses of eltrombopag in thrombocytopenic patients with chronic liver disease, the AUC increased 87% to 110% in patients with mild hepatic impairment, and 141% to 240% in patients with moderate hepatic impairment. Half-life was prolonged 3- and 4-fold in mild and moderate hepatic impairment in thrombocytopenic patients with chronic liver disease, respectively. AUC increased with increasing Child-Pugh score in chronic hepatitis C patients; patients with chronic hepatitis C and mild impairment had ~100% to 144% higher plasma AUC than healthy subjects.

Special Populations: Children

Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC(0-τ) values compared with non-East Asian patients.

Special Populations: Race

Drug exposure is 50% to 55% higher in some East Asian subjects of Chinese, Japanese, Korean, or Taiwanese ancestry with ITP compared with non-East Asian subjects, who were predominantly white. An ~40% higher systemic exposure in healthy black subjects was found in at least 1 study.

Use: Labeled Indications

Aplastic anemia, severe: Treatment of severe aplastic anemia in patients who have had an insufficient response to immunosuppressive therapy.

Chronic hepatitis C infection-associated thrombocytopenia: Treatment of thrombocytopenia in patients with chronic hepatitis C (CHC) to allow the initiation and maintenance of interferon-based therapy.

Chronic immune (idiopathic) thrombocytopenia: Treatment of thrombocytopenia in adult and pediatric patients ≥1 year of age (US labeling) or adult patients (Canadian labeling) with chronic immune (idiopathic) thrombocytopenia (ITP) who have had insufficient response to corticosteroids, immune globulin, or splenectomy.

Limitations of use: For ITP, use eltrombopag only if the degree of thrombocytopenia and clinical condition increase the risk for bleeding. For chronic hepatitis C (CHC), use eltrombopag only if the degree of thrombocytopenia prevents initiation of or limits the ability to maintain interferon-based therapy. For CHC, safety and efficacy have not been established when used in combination with direct-acting antiviral agents without interferon for treatment of CHC infection.

Contraindications

US labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to eltrombopag or any component of the formulation; severe hepatic impairment (Child-Pugh class C)

Dosing: Adult

Note: Do not use eltrombopag to normalize platelet counts.

Chronic immune (idiopathic) thrombocytopenia (ITP): Oral: Note: Use the lowest dose to achieve and maintain platelet count ≥50,000/mm3 as needed to reduce the risk of bleeding. Discontinue if platelet count does not respond to a level that avoids clinically important bleeding after 4 weeks at the maximum daily dose of 75 mg.

Initial: 50 mg once daily (25 mg once daily for patients of East-Asian ethnicity [eg, Chinese, Japanese, Korean, Taiwanese]); dose should be titrated based on platelet response. Maximum dose: 75 mg once daily.

Dosage adjustment based on platelet response (US labeling):

Platelet count <50,000/mm3 (≥2 weeks after treatment initiation or a dose increase): Increase daily dose by 25 mg (if taking 12.5 mg once daily, increase dose to 25 mg once daily prior to increasing the dose amount by 25 mg daily); maximum: 75 mg once daily

Platelet count ≥200,000/mm3 and ≤400,000/mm3 (at any time): Reduce daily dose by 25 mg (if taking 25 mg once daily, decrease dose to 12.5 mg once daily); reassess in 2 weeks

Platelet count >400,000/mm3: Withhold dose; assess platelet count twice weekly; when platelet count <150,000/mm3, resume with the daily dose reduced by 25 mg (if taking 25 mg once daily, resume with 12.5 mg once daily)

Platelet count >400,000/mm3 after 2 weeks at the lowest dose: Discontinue treatment

Dosage adjustment based on platelet response (Canadian labeling):

Platelet count <50,000/mm3 (≥2 weeks after treatment initiation or a dose increase): Increase daily dose by 25 mg; maximum: 75 mg once daily

Platelet count ≥200,000/mm3 and ≤300,000/mm3 (at any time): Reduce daily dose by 25 mg; reassess in 2 weeks

Platelet count >300,000/mm3: Withhold dose; assess platelet count twice weekly; when platelet count <150,000/mm3, resume with the daily dose reduced by 25 mg

Platelet count >300,000/mm3 after 2 weeks at the lowest dose: Discontinue treatment

Chronic hepatitis C-associated thrombocytopenia: Oral: Note: Use the lowest dose to achieve the target platelet count necessary to initiate antiviral therapy (peginterferon and ribavirin) or to avoid dose reductions of peginterferon during antiviral therapy. Discontinue when antiviral therapy is stopped.

Initial: 25 mg once daily; dose should be titrated based on platelet response. Maximum dose: 100 mg once daily

Dosage adjustment based on platelet response (US labeling):

Platelet count <50,000/mm3 (after at least 2 weeks): Increase daily dose by 25 mg every 2 weeks; maximum dose: 100 mg once daily

Platelet count ≥200,000/mm3 and ≤400,000/mm3 (at any time): Reduce daily dose by 25 mg; reassess in 2 weeks

Platelet count >400,000/mm3: Withhold dose; assess platelet count twice weekly; when platelet count <150,000/mm3, resume with the daily dose reduced by 25 mg (if taking 25 mg once daily, resume with 12.5 mg once daily)

Platelet count >400,000/mm3 after 2 weeks at the lowest dose: Discontinue treatment

Dosage adjustment based on platelet response (Canadian labeling):

Platelet count <50,000/mm3 (after at least 2 weeks): Increase daily dose by 25 mg every 2 weeks; maximum dose: 100 mg once daily

Platelet count ≥150,000/mm3 and ≤200,000/mm3: Reduce daily dose by 25 mg; reassess in 2 weeks

Platelet count >200,000/mm3: Withhold dose; assess platelet count twice weekly; when platelet count <150,000/mm3, resume with the daily dose reduced by 25 mg (if taking 25 mg once daily, consider resuming with 25 mg every other day)

Platelet count >200,000/mm3 after 2 weeks at the lowest dose: Discontinue treatment

Severe aplastic anemia: Oral: Note: Use the lowest dose to achieve and maintain hematologic response. Hematologic response may take up to 16 weeks and requires dose titration. Discontinue therapy if hematologic response is not achieved after 16 weeks of treatment, for excessive platelet responses or for liver function abnormalities. Consider discontinuing if new cytogenetic abnormalities are observed.

Initial: 50 mg once daily (25 mg once daily for patients of East-Asian ethnicity); dose should be titrated based on platelet response. Maximum dose: 150 mg once daily.

Dosage adjustment based on platelet response (US labeling):

Platelet count <50,000/mm3 (≥2 weeks after treatment initiation or a dose increase): Increase daily dose by 50 mg (if taking 25 mg once daily, increase dose to 50 mg once daily prior to increasing the dose amount by 50 mg daily); maximum: 150 mg once daily

Platelet count ≥200,000/mm3 and ≤400,000/mm3 (at any time): Reduce daily dose by 50 mg; reassess in 2 weeks

Platelet count >400,000/mm3: Withhold dose for 1 week; when platelet count <150,000/mm3, resume with the daily dose reduced by 50 mg

Platelet count >400,000/mm3 after 2 weeks at the lowest dose: Discontinue treatment

Dosage adjustment based on platelet response (Canadian labeling):

Platelet count <50,000/mm3 (≥2 weeks after treatment initiation or a dose increase): Increase daily dose by 50 mg (if taking 25 mg once daily, increase dose to 50 mg once daily prior to increasing the dose amount by 50 mg daily); maximum: 150 mg once daily

Platelet count ≥200,000/mm3 and ≤300,000/mm3 (at any time): Reduce daily dose by 50 mg (if taking 50 mg once daily, reduce daily dose by 25 mg); reassess in 2 weeks

Platelet count >300,000/mm3: Withhold dose for at least 1 week; when platelet count <150,000/mm3, resume with the daily dose reduced by 50 mg

Platelet count >300,000/mm3 after 2 weeks at the lowest dose: Discontinue treatment

For patients who achieve tri-lineage response, including transfusion independence, lasting 8 weeks, may reduce the dose by 50%. If counts remain stable after 8 weeks at the reduced dose, discontinue and monitor blood counts. If platelets counts drop to <30,000/mm3, hemoglobin to <9 g/dL, or ANC to <500/mm3, may reinitiate at the prior effective dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Do not use eltrombopag to normalize platelet counts.

Chronic immune (idiopathic) thrombocytopenia (ITP): Note: Use the lowest dose to achieve and maintain platelet count ≥50,000/mm3 as needed to reduce the risk of bleeding. Discontinue if platelet count does not respond to a level that avoids clinically important bleeding after 4 weeks at the maximum daily dose of 75 mg.

Children 1 to 5 years: Oral: Initial: 25 mg once daily; dose should be titrated based on platelet response (no dosage adjustment required for patients of East Asian ancestry). Maximum dose: 75 mg once daily.

Children ≥6 years and Adolescents: Oral: Refer to adult dosing

Dosing: Renal Impairment

US labeling: No dosage adjustment is necessary.

Canadian labeling:

Mild to moderate impairment (CrCl ≥30 mL/minute): No dosage adjustment is necessary. Use with caution and monitor closely.

Severe impairment (CrCl <30 mL/minute): Use is generally not recommended.

Dosing: Hepatic Impairment

Adjustment for hepatic impairment prior to initiating treatment:

Chronic ITP: Note: In patients with ITP and hepatic impairment, wait 3 weeks (instead of 2 weeks) after therapy initiation or subsequent dosage changes prior to increasing dose.

US labeling:

Mild, moderate, or severe impairment (Child-Pugh classes A, B, or C): Initial: 25 mg once daily

Patients of East-Asian ethnicity with hepatic impairment (Child-Pugh classes A, B, or C): Initial: Consider 12.5 mg once daily

Canadian labeling:

Mild or moderate impairment (Child-Pugh classes A or B): Initial: 25 mg once daily

Severe impairment (Child-Pugh class C): Use is contraindicated

Chronic hepatitis C-associated thrombocytopenia:

US labeling: Initial: No dosage adjustment is necessary

Canadian labeling:

Mild or moderate impairment (Child-Pugh classes A or B): Initial: No dosage adjustment is necessary

Severe impairment (Child-Pugh class C): Use is contraindicated

Severe aplastic anemia:

US labeling: Mild, moderate, or severe impairment (Child-Pugh classes A, B, or C): Initial: 25 mg once daily

Canadian labeling:

Mild or moderate impairment (Child-Pugh classes A or B): Initial: 25 mg once daily

Severe impairment (Child-Pugh class C): Use is contraindicated

Adjustment for hepatic impairment during treatment:

ALT levels ≥3 times the upper limit of normal (ULN) in patients with normal hepatic function or ≥3 times baseline in those with preexisting transaminase elevations and which are progressive, persistent (≥4 weeks), accompanied by increased direct bilirubin, or accompanied by clinical signs of liver injury or evidence of hepatic decompensation: Discontinue treatment. Hepatotoxicity may recur with re-treatment after therapy interruption, but if determined to be clinically beneficial, may cautiously resume treatment; monitor ALT weekly during dosage titration; permanently discontinue if liver function test elevations persist, worsen, or recur.

Reconstitution

The oral suspension must be reconstituted with cool or cold water only (do not use hot water). Fill the provided oral syringe with 20 mL of drinking water and empty into the mixing bottle. Add the appropriate eltrombopag dose to the mixing bottle; gently and slowly shake the bottle for at least 20 seconds to mix. If not used immediately, suspension may be stored for up to 30 minutes at room temperature; discard any solution if not used within 30 minutes. Following administration, discard suspension remaining in bottle in trash (do not dispose of in drain); clean supplies by removing plunger from oral syringe, rinse bottle, lid, syringe, and plunger under running water and air-dry (bottle may stain, this is normal); wash hands with soap and water. If powder or suspension spills during preparation or administration, consider wearing disposable gloves during spill clean-up to avoid staining skin.

Administration

Administer on an empty stomach, 1 hour before or 2 hours after a meal. Swallow tablets whole; do not crush and mix with food or liquids. Prepare the suspension with cool or cold water only (do not use hot water); discard any suspension not administered within 30 minutes after reconstitution. If powder or suspension spills during preparation or administration, consider wearing disposable gloves during spill clean-up to avoid staining skin. Do not administer concurrently with antacids, foods high in calcium, or minerals (eg, iron, calcium, aluminum, magnesium, selenium, zinc); administer eltrombopag at least 2 hours before and 4 hours after. Do not administer more than one dose within 24 hours.

Dietary Considerations

Food, especially dairy products, may decrease the absorption of eltrombopag; allow at least 4 hours between dosing of eltrombopag and polyvalent cation intake (eg, dairy products, calcium-rich foods, multivitamins with minerals).

Storage

Oral suspension: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Once reconstituted (if not used immediately), the suspension may be stored for a maximum of 30 minutes between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Discard the mixture if not used within 30 minutes.

Tablets: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). If present, do not remove desiccant. Dispense in original bottle.

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any aluminum-containing product. Consider therapy modification

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

BCRP/ABCG2 Substrates: Eltrombopag may increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Calcium Salts: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any calcium-containing product. Consider therapy modification

CycloSPORINE (Systemic): May decrease the serum concentration of Eltrombopag. Monitor therapy

Deferiprone: UGT1A6 Inhibitors may increase the serum concentration of Deferiprone. Monitor therapy

Eluxadoline: Eltrombopag may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with eltrombopag and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Iron Salts: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any iron-containing product. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any magnesium-containing product. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any multivitamin containing polyvalent cations. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any multivitamin containing polyvalent cations. Consider therapy modification

OATP1B1/SLCO1B1 Substrates: Eltrombopag may increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Rosuvastatin: Eltrombopag may increase the serum concentration of Rosuvastatin. Management: Consideration a preventive 50% reduction in rosuvastatin adult dose when starting this combination; Canadian labeling recommends limiting rosuvastatin to a maximum of 20 mg/day. Consider therapy modification

Selenium: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any selenium-containing product. Consider therapy modification

Sucralfate: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of sucralfate. Consider therapy modification

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Consider therapy modification

Zinc Salts: May decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any zinc-containing product. Consider therapy modification

Adverse Reactions

Adverse reactions and incidences reported are associated with adults unless otherwise indicated.

>10%:

Central nervous system: Fatigue (ITP: 4%; chronic hepatitis C: 28%; aplastic anemia: 28%), headache (ITP: 10%; chronic hepatitis C: 21%; aplastic anemia 21%), insomnia (chronic hepatitis C: 16%), chills (chronic hepatitis C: 14%), dizziness (aplastic anemia: 14%)

Dermatologic: Pruritus (chronic hepatitis C: 15%), ecchymosis (aplastic anemia: 12%)

Gastrointestinal: Nausea (ITP: 4% to 9%; chronic hepatitis C: 19%; aplastic anemia 33%), diarrhea (aplastic anemia: 21%; chronic hepatitis C: 19%; ITP: 9%; children: 9%), appetite decreased (chronic hepatitis C: 18%), abdominal pain (aplastic anemia 12%; children: 8%)

Hematologic & oncologic: Anemia (chronic hepatitis C: 40%), febrile neutropenia (aplastic anemia: 14%)

Hepatic: Hyperbilirubinemia (total bilirubin ≥1.5 x ULN: 76%; ITP and chronic hepatitis C: 6% to 8%), increased serum transaminases (aplastic anemia: 12%), abnormal hepatic function (ITP: 11%), increased serum ALT (children: 6%; ITP: 5% to 6%), increased serum AST (ITP: 4%; children: 4%)

Neuromuscular & skeletal: Limb pain (aplastic anemia: 19%), weakness (chronic hepatitis C: 16%), arthralgia (aplastic anemia: 12%), muscle spasm (aplastic anemia: 12%), myalgia (ITP and chronic hepatitis C: 5% to 12%)

Respiratory: Cough (aplastic anemia: 23%; chronic hepatitis C: 15%; children: 9%), flu-like syndrome (chronic hepatitis C: 18%), upper respiratory infection (children: 17%; ITP: 7%), dyspnea (aplastic anemia: 14%), oropharyngeal pain (aplastic anemia: 14%; children: 8%; ITP: 4%), nasopharyngitis (children: 12%), rhinorrhea (aplastic anemia: 12%, children: 4%)

Miscellaneous: Fever (chronic hepatitis C: 30%; aplastic anemia: 14%; children: 9%)

1% to 10%:

Cardiovascular: Peripheral edema (chronic hepatitis C: 10%), thrombosis (chronic hepatitis C: 3%)

Dermatologic: Alopecia (ITP: 2%; chronic hepatitis C: 10%), skin rash (children: 5%; ITP: 3%)

Gastrointestinal: Toothache (children: 6%), vomiting (ITP: 6%), xerostomia (ITP: 2%)

Genitourinary: Urinary tract infection (ITP: 5%)

Hematologic & oncologic: Thrombocytopenia (chronic hepatitis C: 3%)

Hepatic: Alkaline phosphatase increased (ITP: 2%)

Infection: Influenza (ITP: 3%)

Neuromuscular & skeletal: Back pain (ITP: 3%), paresthesia (ITP: 3%), musculoskeletal pain (ITP: 2%)

Ophthalmic: Cataract (ITP and chronic hepatitis C: 4% to 8%)

Respiratory: Rhinitis (children: 9%), pharyngitis (ITP: 4%)

<1% (Limited to important or life-threatening): Deep vein thrombosis, dysgeusia, dyspepsia, facial swelling, fecal discoloration, hemorrhage, hypokalemia, increased hemoglobin, increased serum albumin, increased serum creatinine, increased serum total protein, lesion (hepatic), malignant neoplasm (rectosigmoid), oropharyngeal blistering, ostealgia, portal vein thrombosis, pulmonary embolism, retinal hemorrhage, sinus tachycardia, superficial thrombophlebitis, tachycardia, thrombotic microangiopathy (with acute renal failure)

ALERT: U.S. Boxed Warning

Hepatic decompensation:

In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow reticulin (Canadian labeling): May increase the risk for bone marrow reticulin formation or progression. 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).

• Cataract formation: 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).

• Hepatotoxicity: Liver enzyme elevations may occur; obtain ALT, AST, and bilirubin prior to treatment initiation, every 2 weeks during adjustment phase, then monthly (after stable dose established). 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. Discontinue treatment for ALT levels ≥3 times the upper limit of normal (ULN) in patients with normal hepatic function, or ≥3 times baseline in those with preexisting transaminase elevations and which are progressive, 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 recur 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 test abnormalities persist, worsen, or recur with rechallenge.

• Malignancy/tumorigenicity (Canadian labeling): Stimulation of cell surface thrombopoietin (TPO) receptors may increase the risk for hematologic malignancies.

• Thromboembolism: Thromboembolism (venous or arterial) 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.

Disease-related concerns:

• Chronic hepatitis C infection: [US Boxed Warning]: 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.

• Hepatic impairment: Clearance may be reduced in patients with hepatic impairment; use with caution; reduced starting doses are recommended in patients with ITP (except children 1 to 5 years) and severe aplastic anemia who have hepatic impairment (no initial dose reductions are necessary in patients with chronic hepatitis C-related thrombocytopenia). The Canadian labeling contraindicates use in patients with severe impairment.

• Renal impairment: Use with caution with renal impairment (any degree) and monitor closely; initial dosage adjustment is not necessary.

Concurrent drug therapy issues:

• Antacids/calcium/cation mineral supplements: May reduce eltrombopag levels; take eltrombopag at least 2 hours before and 4 hours after antacids, minerals (eg, iron, calcium, aluminum, magnesium, selenium, zinc), or foods high in calcium.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• East-Asian ethnicity (eg, Chinese, Japanese, Korean, Taiwanese): May have greater drug exposure (compared to non-East Asians); therapy should be initiated with lower starting doses in ITP and severe aplastic anemia patients.

Other warnings/precautions:

• Appropriate use: 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 immune 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 prevents the initiation and maintenance of interferon-based 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 aplastic anemia: Use the lowest dose to achieve and maintain hematologic response. Discontinue if no hematologic response has occurred after 16 weeks of therapy, excessive platelet count responses or important liver test abnormalities. Consider discontinuation if new cytogenetic abnormalities are observed.

Monitoring Parameters

Thrombocytopenia due to CHC and chronic ITP: Liver function tests, including ALT, AST, and bilirubin (baseline, every 2 weeks during dosage titration, then monthly; evaluate abnormal liver function tests within 3 to 5 days; monitor weekly until abnormalities resolve, stabilize, or return to baseline or if re-treating [not recommended] after therapy interruption for hepatotoxicity); bilirubin fractionation (for elevated bilirubin); CBC with differential and platelet count (weekly at initiation and during dosage titration, then monthly when stable; after cessation, monitor weekly for ≥4 weeks; when switching between the oral suspension and tablet, monitor platelet counts weekly for 2 weeks, then monthly when stable); peripheral blood smear (baseline and monthly when stable), bone marrow biopsy with staining for fibrosis (if peripheral blood smear reveals abnormality); ophthalmic exam (baseline and during treatment)

Severe aplastic anemia: CBC with differential and platelets (regularly throughout therapy), liver function tests (regularly throughout therapy); ophthalmic exam (baseline and during treatment)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. A Promacta pregnancy registry has been established to monitor outcomes of women exposed to eltrombopag during pregnancy (1-888-825-5249).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, insomnia, itching, lack of appetite, flu-like symptoms, cough, muscle pain, joint pain, rhinorrhea, rhinitis, sneezing, back pain, dizziness, pharyngitis, tooth pain, muscle spasms, or alopecia. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), loss of strength and energy, severe abdominal pain, angina, shortness of breath, coughing up blood, vision changes, eye pain, severe eye irritation, burning or numbness feeling, severe nausea, vomiting, severe diarrhea, bruising, bleeding, mouth sores, dysuria, polyuria, illogical thinking, swelling of arm or leg, chills, or abdominal edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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