Promacta For Oral Suspension

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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
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  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Promacta For Oral Suspension Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Eltrombopag (as olamine) 12.5mg, 25mg; per pkt; pwd for reconstitution; contains mannitol.

    Pharmacological Class

    Thrombopoietin receptor agonist.

    See Also

    How Supplied

    Tabs 12.5mg, 25mg, 75mg—30; 50mg—14, 30; Oral susp kit—1 (30 pkts w. supplies)

    How Supplied

    Promacta 12.5 mg for Oral Suspension is a reddish-brown to yellow powder in unit-dose packets, co-packaged in a kit with a 40-cc reconstitution vessel, a threaded closure with syringe-port capability, and 30 single-use oral dosing syringes. Each kit contains 30 packets.

    Promacta 25 mg for Oral Suspension is a reddish-brown to yellow powder in unit-dose packets, co-packaged in a kit with a 40-cc reconstitution vessel, a threaded closure with syringe-port capability, and 30 single-use oral dosing syringes. Each kit contains 30 packets.

    Storage

    Promacta for Oral Suspension: 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). Following reconstitution, the product should be administered immediately but may be stored for a maximum period of 30 minutes between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Throw away (discard) the mixture if not used within 30 minutes.  

    Manufacturer

    Novartis Pharmaceuticals Corp

    Generic Availability

    NO

    Mechanism of Action

    Eltrombopag is a small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation from bone marrow progenitor cells.

    Promacta For Oral Suspension Indications

    Indications

    First-line treatment of severe aplastic anemia in patients ≥2yrs, in combination with standard immunosuppressive therapy. Severe aplastic anemia in adults who have had insufficient response to immunosuppressive therapy.

    Limitations of Use

    Not indicated for the treatment of myelodysplastic syndromes (MDS).

    Promacta For Oral Suspension Dosage and Administration

    Adult

    Take without a meal or with a meal low in calcium (≤50mg). First-line treatment: if baseline ALT/AST levels >6×ULN, do not initiate until baseline transaminases <5×ULN. ≥12yrs: initially 150mg once daily for 6 months. Hepatic impairment or East-/Southeast-Asian ancestry: reduce initial dose by 50%. Refractory: initially 50mg once daily. Hepatic impairment or East-/Southeast-Asian ancestry: initially 25mg once daily. Titrate dose by 50mg increments every 2 weeks as needed to maintain platelet count ≥50×109/L; max 150mg daily. Monitoring, dose adjustment, and discontinuation: see full labeling.

    Adult

    First-Line Severe Aplastic Anemia

    • Initiate concurrently with standard immunosuppressive therapy.

    • Initial Dose Regimen:

      • Pediatric patients 2 to 5 years: 2.5 mg/kg once daily for 6 months.

      • Pediatric patients 6 to 11 years: 75 mg once daily for 6 months.

      • Patients 12 years and older: 150 mg once daily for 6 months.

      • For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with hepatic impairment: decrease initial dose by 50%.

      • If baseline AST or ALT levels are > 6 x ULN: do not initiate until levels are < 5 x ULN.

    • Recommended Initial Promacta Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Hepatic Impairment (Child-Pugh Class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia:

      • Pediatric patients 2 to 5 years: 1.25 mg/kg once daily for 6 months.

      • Pediatric patients 6 to 11 years: 37.5 mg once daily for 6 months.

      • Patients 12 years and older: 75 mg once daily for 6 months.

    • Monitoring and Dose Adjustment:

      • Monitor hematology and liver tests regularly throughout therapy and modify the dosage regimen based on platelet counts.

    • Dose Adjustments of Promacta for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia:
      • > 200 x 109/L to ≤ 400 x 109/L: Decrease daily dose by 25 mg every 2 weeks to lowest dose to maintain platelet count ≥ 50 x 109/L. For patients <12 years of age: decrease daily dose by 12.5 mg.
      • > 400 x 109/L: Discontinue for 1 week. When platelet count is < 200 x109/L, reinitiate at a daily dose reduced by 25 mg (or 12.5 mg in patients <12 years of age).

    • Recommended Dose Modifications for Promacta for ALT or AST Elevations and Thromboembolic Events:

      • Increase in ALT or AST > 6 x ULN: Discontinue. When ALT or AST is < 5 x ULN, reinitiate at the same dose.

      • Increase in ALT or AST > 6 x ULN after reinitiating Promacta: Discontinue and monitor ALT or AST at least every 3 to 4 days. When ALT or AST is < 5 x ULN, reinitiate at a daily dose reduced by 25 mg vs previous dose.

      • If ALT or AST returns to > 6 x ULN on the reduced dose: Reduce daily dose by 25 mg until ALT or AST is < 5 x ULN. In patients < 12 years of age - reduce daily dose by ≥15% to the nearest dose.

      • Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction): Discontinue but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.

    • The total duration of treatment is 6 months.

     

    Refractory Severe Aplastic Anemia

    • Use lowest dose to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count response. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after initiating.

    • Initial Dose Regimen: 

      • Initially 50 mg once daily.

      • For patients of East-/Southeast-Asian ancestry with ITP or for patients with ITP and hepatic impairment (Child-Pugh Class A, B, C): Initially 25 mg once daily.

    • Monitoring and Dose Adjustment:

      • Adjust dose of Promacta in 50 mg increments every 2 weeks as needed to achieve target platelet count ≥ 50 x 109/L as necessary. Do not exceed 150 mg daily.

      • Monitor hematology and liver tests regularly throughout and modify dosage regimen based on platelet counts.

    • Dose Adjustments of Promacta in Patients With Refractory Severe Aplastic Anemia:

      • < 50 x 109/L after at least 2 weeks: Increase daily dose by 50 mg to a maximum of 150 mg/day. If taking 25 mg once daily - increase the dose to 50 mg before increasing the dose by 50 mg.

      • ≥ 200 x 109/L to ≤ 400 x 109/L at any time: Decrease daily dose by 50 mg. Wait 2 weeks to assess and any subsequent dose adjustments. 

      • > 400 x 109/L: Interrupt Promacta for 1 week. When platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 50 mg.

      • > 400 x 109/L after 2 weeks of therapy at lowest dose of Promacta: Discontinue treatment.

      • For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: may reduce dose by 50%. 

      • If counts remain stable after 8 weeks at reduced dose: discontinue and monitor blood counts.

      • If platelet counts < 30 x 109/L, hemoglobin < 9 g/dL, or ANC < 05 x 109/L: may reinitiate Promacta at the previous transfusion dose.

    • Discontinuation: Discontinue if no hematologic response after 16 weeks of therapy. Consider discontinuing if new cytogenetic abnormalities are observed. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. 

    Children

    <2yrs: not established. Take without a meal or with a meal low in calcium (≤50mg). If baseline ALT/AST levels >6×ULN, do not initiate until baseline transaminases <5×ULN. First-line treatment (2–5yrs): initially 2.5mg/kg once daily; (6–11yrs): initially 75mg once daily. Treat for 6 months. Hepatic impairment or East-/Southeast-Asian ancestry: reduce initial dose by 50%. Monitoring, dose adjustment, and discontinuation: see full labeling.

    Children

    First-Line Severe Aplastic Anemia

    • Initiate concurrently with standard immunosuppressive therapy.

    • Initial Dose Regimen:

      • Pediatric patients 2 to 5 years: 2.5 mg/kg once daily for 6 months.

      • Pediatric patients 6 to 11 years: 75 mg once daily for 6 months.

      • Patients 12 years and older: 150 mg once daily for 6 months.

      • For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with hepatic impairment: decrease initial dose by 50%.

      • If baseline AST or ALT levels are > 6 x ULN: do not initiate until levels are < 5 x ULN.

    • Recommended Initial Promacta Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Hepatic Impairment (Child-Pugh Class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia:

      • Pediatric patients 2 to 5 years: 1.25 mg/kg once daily for 6 months.

      • Pediatric patients 6 to 11 years: 37.5 mg once daily for 6 months.

      • Patients 12 years and older: 75 mg once daily for 6 months.

    • Monitoring and Dose Adjustment:

      • Monitor hematology and liver tests regularly throughout therapy and modify the dosage regimen based on platelet counts.

    • Dose Adjustments of Promacta for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia:
      • > 200 x 109/L to ≤ 400 x 109/L: Decrease daily dose by 25 mg every 2 weeks to lowest dose to maintain platelet count ≥ 50 x 109/L. For patients <12 years of age: decrease daily dose by 12.5 mg.
      • > 400 x 109/L: Discontinue for 1 week. When platelet count is < 200 x109/L, reinitiate at a daily dose reduced by 25 mg (or 12.5 mg in patients <12 years of age).

    • Recommended Dose Modifications for Promacta for ALT or AST Elevations and Thromboembolic Events:

      • Increase in ALT or AST > 6 x ULN: Discontinue. When ALT or AST is < 5 x ULN, reinitiate at the same dose.

      • Increase in ALT or AST > 6 x ULN after reinitiating Promacta: Discontinue and monitor ALT or AST at least every 3 to 4 days. When ALT or AST is < 5 x ULN, reinitiate at a daily dose reduced by 25 mg vs previous dose.

      • If ALT or AST returns to > 6 x ULN on the reduced dose: Reduce daily dose by 25 mg until ALT or AST is < 5 x ULN. In patients < 12 years of age - reduce daily dose by ≥15% to the nearest dose.

      • Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction): Discontinue but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.

    • The total duration of treatment is 6 months.

     

    Refractory Severe Aplastic Anemia

    • Use lowest dose to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count response. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after initiating.

    • Initial Dose Regimen: 

      • Initially 50 mg once daily.

      • For patients of East-/Southeast-Asian ancestry with ITP or for patients with ITP and hepatic impairment (Child-Pugh Class A, B, C): Initially 25 mg once daily.

    • Monitoring and Dose Adjustment:

      • Adjust dose of Promacta in 50 mg increments every 2 weeks as needed to achieve target platelet count ≥ 50 x 109/L as necessary. Do not exceed 150 mg daily.

      • Monitor hematology and liver tests regularly throughout and modify dosage regimen based on platelet counts.

    • Dose Adjustments of Promacta in Patients With Refractory Severe Aplastic Anemia:

      • < 50 x 109/L after at least 2 weeks: Increase daily dose by 50 mg to a maximum of 150 mg/day. If taking 25 mg once daily - increase the dose to 50 mg before increasing the dose by 50 mg.

      • ≥ 200 x 109/L to ≤ 400 x 109/L at any time: Decrease daily dose by 50 mg. Wait 2 weeks to assess and any subsequent dose adjustments. 

      • > 400 x 109/L: Interrupt Promacta for 1 week. When platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 50 mg.

      • > 400 x 109/L after 2 weeks of therapy at lowest dose of Promacta: Discontinue treatment.

      • For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: may reduce dose by 50%. 

      • If counts remain stable after 8 weeks at reduced dose: discontinue and monitor blood counts.

      • If platelet counts < 30 x 109/L, hemoglobin < 9 g/dL, or ANC < 05 x 109/L: may reinitiate Promacta at the previous transfusion dose.

    • Discontinuation: Discontinue if no hematologic response after 16 weeks of therapy. Consider discontinuing if new cytogenetic abnormalities are observed. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. 

    Hepatic Impairment

    See Adults Dosage and Children Dosage.

    Administration

    Administration of Tablets and Oral Suspension:

    • Take without a meal or with a meal low in calcium (≤ 50 mg). Take at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc.

    • Do not split, chew, or crush tablets and mix with food or liquids. 

    Preparation of the Oral Suspension:

    • Administer the oral suspension immediately after preparation. Discard any suspension not administered within 30 minutes after preparation.

    • Prepare the suspension with water only. NOTE: Do not use hot water to prepare the suspension.

    Promacta For Oral Suspension Contraindications

    Not Applicable

    Promacta For Oral Suspension Boxed Warnings

    Boxed Warning

    Risk for hepatic decompensation in patients with chronic hepatitis C. Risk of hepatotoxicity.

    Boxed Warning

    Risk for Hepatic Decompensation in Patients With Chronic Hepatitis C and Risk of Hepatotoxicity

    • The concomitant use of Promacta in combination with interferon and ribavirin in patients with chronic hepatitis C may increase the risk of hepatic decompensation.

    • May increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

    Promacta For Oral Suspension Warnings/Precautions

    Warnings/Precautions

    Increased risk of hepatic decompensation in patients with chronic hepatitis C in combination with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Increased risk of severe hepatotoxicity; monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (for first-line treatment of aplastic anemia, monitor at baseline, every other day while hospitalized, and every 2 weeks during therapy; see full labeling); discontinue if ALT ≥3×ULN in those with normal liver function or ≥3× baseline (or >5×ULN, whichever is lower) in those with pre-treatment transaminase elevations and are progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or symptoms/evidence of hepatic injury/decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of death and progression of MDS to acute myeloid leukemia (AML). Increased risk of thromboembolism in those with risk factors (eg, Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease); do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Asian ancestry. Advise females of reproductive potential to use effective contraception during and for ≥7 days after stopping treatment. Pregnancy. Nursing mothers: not recommended.

    Warnings/Precautions

    Hepatic Decompensation in Patients With Chronic Hepatitis C

    • The concomitant use of Promacta in combination with interferon and ribavirin in patients with chronic hepatitis C may increase the risk of hepatic decompensation.

    • Discontinue if antiviral therapy is discontinued.

    Hepatotoxicity

    • May increase the risk of severe and potentially life-threatening hepatotoxicity. 

    • Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia:

      • Measure serum ALT, AST, and bilirubin prior to initiation, every 2 weeks during the dose adjustment phase, and monthly after establishing a stable dose. If bilirubin is elevated, perform fractionation.

      • Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized.

      • Discontinue if ALT levels increase to ≥ 3 x ULN in patients with normal liver function.

      • Discontinue if ALT levels  increase to ≥ 3 x baseline (or > 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing; or persistent for ≥ 4 weeks; or accompanied by increased direct bilirubin; or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.

      • If the potential benefit for reinitiating Promacta outweighs the risk for hepatotoxicity, then consider cautiously reintroducing Promacta and measure serum liver tests weekly during the dose adjustment phase. Permanently discontinue Promacta if liver test abnormalities persist, worsen, or recur.

    • First-Line Treatment of Severe Aplastic Anemia:

      • Measure ALT, AST, and bilirubin prior to initiation, every other day while hospitalized for hATG therapy, and then every 2 weeks during treatment. 

      • During treatment, manage increases in ALT or AST levels (see Adults and Children Dosage).

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

    • A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either Promacta (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML).

    • The incidence of death (overall survival) was 32% (57/179) in the Promacta arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the Promacta arm).

    • The incidence of progression to AML was 12% (21/179) in the Promacta arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the Promacta arm).

    Thrombotic/Thromboembolic Complications 

    • Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. 

    • Consider the risk of thromboembolism when administering to patients with known risk factors (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease).

    • Do not use to normalize platelet counts to minimize the risk for thrombotic/thromboembolic complications.

    Cataracts

    • Perform a baseline ocular examination prior to administration of Promacta and, during therapy with Promacta, regularly monitor patients for signs and symptoms of cataracts.

    Pregnancy Considerations

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

    Nursing Mother Considerations

    No data is available regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum.

    Breastfeeding is not recommended during treatment due to the potential for serious adverse reactions.

     

    Pediatric Considerations

    The safety and efficacy of Promacta 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.

    Geriatric Considerations

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

    Hepatic Impairment Considerations

    Patients With Persistent or Chronic ITP and Severe Aplastic Anemia

    • Reduce the initial dose of Promacta in patients with persistent or chronic ITP (patients aged ≥6 years) or refractory severe aplastic anemia who also have hpeatic impairment (see Adults and Children Dosage).

    • Reduce the initial dose of Promacta in patients with hepatic impairment who initiates Promacta for the first-lnie treatment of severe aplastic anemia.

    Patients With Chronic Hepatitis C

    • No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment. 

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Contraception: Advise sexually-active females of reproductive potential to use effective contraception (methods that result in <1% pregnancy rates) during and for at least 7 days after stopping treatment.

    Ethnicity

    • For patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia: reduce the initial dose. 

    Promacta For Oral Suspension Pharmacokinetics

    Absorption

    Eltrombopag is absorbed with a peak concentration occurring 2 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 AUC0-INF by ~59% and Cmax by 65% and delayed Tmax 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. 

    Distribution

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

    Metabolism

    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. 

    Elimination

    The plasma elimination half-life of eltrombopag is ~21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.

    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 ~20% of the dose; unchanged eltrombopag is not detectable in urine.  

    Promacta For Oral Suspension Interactions

    Interactions

    Potentiates substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Separate dosing by at least 2hrs before or 4hrs after food/drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2).

    Promacta For Oral Suspension Adverse Reactions

    Adverse Reactions

    Anemia, nausea, pyrexia, increased ALT, cough, fatigue, headache, diarrhea; hepatotoxicity, thrombotic/thromboembolic complications, cataracts.

    Promacta For Oral Suspension Clinical Trials

    Clinical Trials

    First-Line Treatment of Severe Aplastic Anemia  

    In a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]), the concomitant use of Promacta with h-ATG and cyclosporine was evaluated in 153 patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. All patients received Promacta in 3 sequential cohorts and an extension of the third cohort. 

    The starting dose of Promacta for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians).  

    • Cohort 1 (n=30): Promacta on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine

    • Cohort 2 (n = 31): Promacta on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine  

    • Cohort 3 + Extension cohort [Promacta  D1-M6 cohort] (n = 92): Promacta on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) 

    The efficacy of Promacta in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 109 /L and hemoglobin > 10 g/dL.

    The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. 

    Pediatric Patients: There were 34 patients 2 to 16 years of age who enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months.

     

    Refractory Severe Aplastic Anemia 

    The approval was based on data from a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) that evaluated Promacta in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109 /L. Patients received an initial dose of 50 mg once daily for 2 weeks then increased over 2-week periods up to a maximum dose of 150 mg once daily. 

    The efficacy was evaluated by the hematologic response after 12 weeks. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109 /L. Promacta was discontinued after 16 weeks if no hematologic response was observed.

    Results showed that 40% (n=17/43) of patients achieved hematologic response. Among the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days. 

    Promacta For Oral Suspension Note

    Not Applicable

    Promacta For Oral Suspension Patient Counseling

    Patient Counseling

    Hepatotoxicity

    • May be associated with hepatobiliary laboratory abnormalities.

    • Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving Promacta with alfa interferon therapy.

    • Advise patients that they should report any of signs and symptoms of liver problems to their healthcare provider right away (e.g., yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, unusual tiredness, right upper stomach area pain, confusion, swelling of the stomach area)

    Risk of Bleeding Upon Promacta Discontinuation

    • Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing Promacta, particularly if Promacta is discontinued while the patient is on anticoagulants or antiplatelet agents. 

    • Advise patients that during therapy with Promacta, they should continue to avoid situations or medications that may increase the risk for bleeding.

    Thrombotic/Thromboembolic Complications

    • Advise patients that too much Promacta may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.

    Cataracts

    • Advise to have a baseline ocular examination prior to administration of Promacta and be monitored for signs and symptoms of cataracts during therapy.

    Drug Interactions

    • Advise patients to take Promacta at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc.

    Lactation

    • Advise women not to breastfeed during treatment with Promacta.

    Promacta For Oral Suspension Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Eltrombopag (as olamine) 12.5mg, 25mg; per pkt; pwd for reconstitution; contains mannitol.

    Pharmacological Class

    Thrombopoietin receptor agonist.

    See Also

    How Supplied

    Tabs 12.5mg, 25mg, 75mg—30; 50mg—14, 30; Oral susp kit—1 (30 pkts w. supplies)

    How Supplied

    Promacta 12.5 mg tablets are round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side and are available in bottles of 30.

    Promacta 25 mg tablets are round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side and are available in bottles of 30.

    Promacta 50 mg tablets are round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side and are available in bottles of 14 and 30. 

    Promacta 75 mg tablets are round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side and are available in bottles of 30.

    Storage

    Promacta Tablets: 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).

    Manufacturer

    Novartis Pharmaceuticals Corp

    Generic Availability

    NO

    Mechanism of Action

    Eltrombopag is a small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation from bone marrow progenitor cells.

    Promacta For Oral Suspension Indications

    Indications

    Thrombocytopenia in adult and pediatric patients ≥1year with persistent or chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Should be used only in ITP patients whose degree of thrombocytopenia and clinical condition increase the risk of bleeding. Thrombocytopenia in adults with chronic hepatitis C to allow initiation and maintenance of interferon-based therapy. Should be used only in chronic hepatitis C patients whose degree of thrombocytopenia prevents starting or limiting ability to maintain interferon-based therapy.

    Limitations of Use

    Not indicated for the treatment of myelodysplastic syndromes (MDS). Safety and efficacy not established in combination with direct-acting antiviral agents without interferon for chronic hepatitis C infection.

    Promacta For Oral Suspension Dosage and Administration

    Adults and Children

    Take without a meal or with a meal low in calcium (≤50mg). ITP: <1yr: not established; 1–5yrs: initially 25mg once daily; ≥6yrs: initially 50mg once daily. Hepatic impairment or East-/Southeast-Asian ancestry: initially 25mg once daily. East-/Southeast-Asian ancestry with hepatic impairment: consider initiating at 12.5mg once daily. Titrate to maintain platelet count ≥50×109/L; max 75mg once daily. Chronic hepatitis C-associated thrombocytopenia: initially 25mg once daily. Titrate dose by 25mg increments every 2 weeks as needed to achieve target platelet counts; max 100mg/day. Monitoring, dose adjustment, and discontinuation: see full labeling.

    Adults and Children

    Use the lowest dose to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding.

    Dose adjustments are based upon the platelet count response. Do not use Promacta to normalize platelet counts. 

     

    Persistent or Chronic Immune Thrombocytopenia (ITP)

    • Initial Dose Regimen: 

      • Adult and Pediatric Patients 6 Years and Older with ITP: Initially 50 mg 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 or for patients with ITP and hepatic impairment (Child-Pugh Class A, B, C): Initially 25 mg once daily.

      • For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment: consider initiating at a reduced dose of 12.5 mg once daily.

      • Pediatric Patients with ITP Aged 1 to 5 Years: Initially 25 mg once daily.

    • Monitoring and Dose Adjustment:

      • After initiating, adjust dose to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Do not exceed 75 mg daily.

      • Monitor hematology and liver tests regularly throughout therapy and modify the dosage regimen based on platelet counts.

      • During treatment, assess CBC with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter.

      • If switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, then monthly thereafter.

    • Dose Adjustments of Promacta in Patients With Persistent or Chronic Immune Thrombocytopenia:

      • < 50 x 109/L after at least 2 weeks: Increase daily dose by 25 mg to a maximum of 75 mg/day. If taking 12.5 mg once daily - increase the dose to 25 mg before increasing the dose by 25 mg.

      • ≥ 200 x 109/L to ≤ 400 x 109/L at any time: Decrease daily dose by 25 mg. Wait 2 weeks to assess and any subsequent dose adjustments. If taking 25 mg once daily - decrease the dose to 12.5 mg once daily.

      • > 400 x 109/L: Interrupt Promacta; increase frequency of platelet monitoring to twice weekly. When platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. If taking 25 mg once daily, reinitiate at a daily dose of 12.5 mg.

      • > 400 x 109/L after 2 weeks of therapy at lowest dose of Promacta: Discontinue treatment.

      • In patients with ITP and hepatic impairment: after initiating or any subsequent dose increases, wait 3 weeks before increasing dose.

      • Do not administer more than one dose within any 24-hour period.

    • Discontinuation: Discontinue Promacta if platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum daily dose of 75 mg. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. Following discontinuation, obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks.

     

    Chronic Hepatitis C-Associated Thrombocytopenia

    • Initial Dose Regimen: Initially 25 mg once daily.

    • Monitoring and Dose Adjustment: 

      • Adjust dose of Promacta in 25 mg increments every 2 weeks as needed to achieve target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy.

      • During antiviral therapy, adjust dose of Promacta to avoid dose reductions of peginterferon.

      • Monitor 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 hematology and liver tests regularly throughout therapy

    • Dose Adjustments of Promacta in Adults With Thrombocytopenia Due to Chronic Hepatitis C:

      • < 50 x 109/L after at least 2 weeks: Increase daily dose by 25 mg to a maximum of 100 mg/day.

      • ≥ 200 x 109/L to ≤ 400 x 109/L at any time: Decrease daily dose by 25 mg. Wait 2 weeks to assess and any subsequent dose adjustments.

      • > 400 x 109/L: Interrupt Promacta; increase frequency of platelet monitoring to twice weekly. When platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. If taking 25 mg once daily, reinitiate at a daily dose of 12.5 mg.

      • > 400 x 109/L after 2 weeks of therapy at lowest dose of Promacta: Discontinue treatment.

    • Discontinuation: Discontinue Promacta when antiviral therapy is discontinued. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. 

    Hepatic Impairment

    See Adults and Children Dosage.

    Administration

    Administration of Tablets and Oral Suspension:

    • Take without a meal or with a meal low in calcium (≤ 50 mg). Take at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc.

    • Do not split, chew, or crush tablets and mix with food or liquids. 

    Preparation of the Oral Suspension:

    • Administer the oral suspension immediately after preparation. Discard any suspension not administered within 30 minutes after preparation.

    • Prepare the suspension with water only. NOTE: Do not use hot water to prepare the suspension.

    Promacta For Oral Suspension Contraindications

    Not Applicable

    Promacta For Oral Suspension Boxed Warnings

    Boxed Warning

    Risk for hepatic decompensation in patients with chronic hepatitis C. Risk of hepatotoxicity.

    Boxed Warning

    Risk for Hepatic Decompensation in Patients With Chronic Hepatitis C and Risk of Hepatotoxicity

    • The concomitant use of Promacta in combination with interferon and ribavirin in patients with chronic hepatitis C may increase the risk of hepatic decompensation.

    • May increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

    Promacta For Oral Suspension Warnings/Precautions

    Warnings/Precautions

    Increased risk of hepatic decompensation in patients with chronic hepatitis C in combination with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Increased risk of severe hepatotoxicity; monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (for first-line treatment of aplastic anemia, monitor at baseline, every other day while hospitalized, and every 2 weeks during therapy; see full labeling); discontinue if ALT ≥3×ULN in those with normal liver function or ≥3× baseline (or >5×ULN, whichever is lower) in those with pre-treatment transaminase elevations and are progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or symptoms/evidence of hepatic injury/decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of death and progression of MDS to acute myeloid leukemia (AML). Increased risk of thromboembolism in those with risk factors (eg, Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease); do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Asian ancestry. Advise females of reproductive potential to use effective contraception during and for ≥7 days after stopping treatment. Pregnancy. Nursing mothers: not recommended.

    Warnings/Precautions

    Hepatic Decompensation in Patients With Chronic Hepatitis C

    • The concomitant use of Promacta in combination with interferon and ribavirin in patients with chronic hepatitis C may increase the risk of hepatic decompensation.

    • Discontinue if antiviral therapy is discontinued.

    Hepatotoxicity

    • May increase the risk of severe and potentially life-threatening hepatotoxicity. 

    • Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia:

      • Measure serum ALT, AST, and bilirubin prior to initiation, every 2 weeks during the dose adjustment phase, and monthly after establishing a stable dose. If bilirubin is elevated, perform fractionation.

      • Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized.

      • Discontinue if ALT levels increase to ≥ 3 x ULN in patients with normal liver function.

      • Discontinue if ALT levels  increase to ≥ 3 x baseline (or > 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing; or persistent for ≥ 4 weeks; or accompanied by increased direct bilirubin; or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.

      • If the potential benefit for reinitiating Promacta outweighs the risk for hepatotoxicity, then consider cautiously reintroducing Promacta and measure serum liver tests weekly during the dose adjustment phase. Permanently discontinue Promacta if liver test abnormalities persist, worsen, or recur.

    • First-Line Treatment of Severe Aplastic Anemia:

      • Measure ALT, AST, and bilirubin prior to initiation, every other day while hospitalized for hATG therapy, and then every 2 weeks during treatment. 

      • During treatment, manage increases in ALT or AST levels (see Adults and Children Dosage).

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

    • A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either Promacta (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML).

    • The incidence of death (overall survival) was 32% (57/179) in the Promacta arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the Promacta arm).

    • The incidence of progression to AML was 12% (21/179) in the Promacta arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the Promacta arm).

    Thrombotic/Thromboembolic Complications 

    • Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. 

    • Consider the risk of thromboembolism when administering to patients with known risk factors (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease).

    • Do not use to normalize platelet counts to minimize the risk for thrombotic/thromboembolic complications.

    Cataracts

    • Perform a baseline ocular examination prior to administration of Promacta and, during therapy with Promacta, regularly monitor patients for signs and symptoms of cataracts.

    Pregnancy Considerations

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

    Nursing Mother Considerations

    No data is available regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum.

    Breastfeeding is not recommended during treatment due to the potential for serious adverse reactions.

     

    Pediatric Considerations

    The safety and efficacy of Promacta 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.

    Geriatric Considerations

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

    Hepatic Impairment Considerations

    Patients With Persistent or Chronic ITP and Severe Aplastic Anemia

    • Reduce the initial dose of Promacta in patients with persistent or chronic ITP (patients aged ≥6 years) or refractory severe aplastic anemia who also have hpeatic impairment (see Adults and Children Dosage).

    • Reduce the initial dose of Promacta in patients with hepatic impairment who initiates Promacta for the first-lnie treatment of severe aplastic anemia.

    Patients With Chronic Hepatitis C

    • No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment. 

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Contraception: Advise sexually-active females of reproductive potential to use effective contraception (methods that result in <1% pregnancy rates) during and for at least 7 days after stopping treatment.

    Ethnicity

    • For patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia: reduce the initial dose. 

    Promacta For Oral Suspension Pharmacokinetics

    Absorption

    Eltrombopag is absorbed with a peak concentration occurring 2 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 AUC0-INF by ~59% and Cmax by 65% and delayed Tmax 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. 

    Distribution

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

    Metabolism

    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. 

    Elimination

    The plasma elimination half-life of eltrombopag is ~21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.

    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 ~20% of the dose; unchanged eltrombopag is not detectable in urine.  

    Promacta For Oral Suspension Interactions

    Interactions

    Potentiates substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Separate dosing by at least 2hrs before or 4hrs after food/drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2).

    Promacta For Oral Suspension Adverse Reactions

    Adverse Reactions

    Anemia, nausea, pyrexia, increased ALT, cough, fatigue, headache, diarrhea; hepatotoxicity, thrombotic/thromboembolic complications, cataracts.

    Promacta For Oral Suspension Clinical Trials

    Clinical Trials

    First-Line Treatment of Severe Aplastic Anemia  

    In a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]), the concomitant use of Promacta with h-ATG and cyclosporine was evaluated in 153 patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. All patients received Promacta in 3 sequential cohorts and an extension of the third cohort. 

    The starting dose of Promacta for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians).  

    • Cohort 1 (n=30): Promacta on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine

    • Cohort 2 (n = 31): Promacta on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine  

    • Cohort 3 + Extension cohort [Promacta  D1-M6 cohort] (n = 92): Promacta on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) 

    The efficacy of Promacta in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 109 /L and hemoglobin > 10 g/dL.

    The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. 

    Pediatric Patients: There were 34 patients 2 to 16 years of age who enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months.

     

    Refractory Severe Aplastic Anemia 

    The approval was based on data from a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) that evaluated Promacta in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109 /L. Patients received an initial dose of 50 mg once daily for 2 weeks then increased over 2-week periods up to a maximum dose of 150 mg once daily. 

    The efficacy was evaluated by the hematologic response after 12 weeks. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109 /L. Promacta was discontinued after 16 weeks if no hematologic response was observed.

    Results showed that 40% (n=17/43) of patients achieved hematologic response. Among the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days. 

    Promacta For Oral Suspension Note

    Not Applicable

    Promacta For Oral Suspension Patient Counseling

    Patient Counseling

    Hepatotoxicity

    • May be associated with hepatobiliary laboratory abnormalities.

    • Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving Promacta with alfa interferon therapy.

    • Advise patients that they should report any of signs and symptoms of liver problems to their healthcare provider right away (e.g., yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, unusual tiredness, right upper stomach area pain, confusion, swelling of the stomach area)

    Risk of Bleeding Upon Promacta Discontinuation

    • Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing Promacta, particularly if Promacta is discontinued while the patient is on anticoagulants or antiplatelet agents. 

    • Advise patients that during therapy with Promacta, they should continue to avoid situations or medications that may increase the risk for bleeding.

    Thrombotic/Thromboembolic Complications

    • Advise patients that too much Promacta may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.

    Cataracts

    • Advise to have a baseline ocular examination prior to administration of Promacta and be monitored for signs and symptoms of cataracts during therapy.

    Drug Interactions

    • Advise patients to take Promacta at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc.

    Lactation

    • Advise women not to breastfeed during treatment with Promacta.

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