PROMACTA (eltrombopag olamine 75 mg) Dailymed
Generic: eltrombopag olamine
IMPRINT: GS NX3 25
SHAPE: round
COLOR: orange
All Imprints
eltrombopag olamine 25 mg - gs nx3 25 round orange
eltrombopag olamine 50 mg - gs ufu 50 round blue
eltrombopag olamine 75 mg - gs ffs 75 round pink
Boxed Warning
Warning: Risk For Hepatic Decompensation In Patients With Chronic Hepatitis C
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Recent Major Changes Section
Indications and Usage, Treatment of Thrombocytopenia in Patients with Chronic ITP (1.1 )
08/2015
Indications and Usage, Treatment of Severe Aplastic Anemia (1.3 )
08/2014
Dosage and Administration, Chronic Immune (Idiopathic) Thrombocytopenia (2.1 )
08/2015
Dosage and Administration, Severe Aplastic Anemia (2.3 )
08/2014
Dosage and Administration, Administration (2.4 )
08/2015
Warning: Risk For Hepatic Decompensation In Patients With Chronic Hepatitis C
In patients with chronic hepatitis C, PROMACTA® in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions (5.1)].
WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C
See full prescribing information for complete boxed warning.
In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation. (5.1 )
1 Indications And Usage
PROMACTA is a thrombopoietin receptor agonist indicated for the treatment of:
• thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. (1.1 )• thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. (1.2 )• patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. (1.3 )
Limitations of Use:
• PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. (1.4 )• PROMACTA 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. (1.4 )• Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. (1.4 )1.1 Treatment of Thrombocytopenia in Patients with Chronic ITP
PROMACTA is indicated for the treatment of thrombocytopenia in adult andpediatric patients 1Â years and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
1.2 Treatment of Thrombocytopenia in Patients with Hepatitis C Infection
PROMACTA is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.
1.3 Treatment of Severe Aplastic Anemia
PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
1.4 Limitations of Use
• PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.• PROMACTA 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.• Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
2 Dosage And Administration
• Take on an empty stomach (1 hour before or 2 hours after a meal). (2.4 )• Chronic ITP: Initiate PROMACTA at 50 mg once daily for most adult and pediatric patients 6 years and older and at 25 mg once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 109/L. Do not exceed 75 mg per day. (2.1 ,8.6 ,8.8 )• Chronic Hepatitis C-associated Thrombocytopenia: Initiate PROMACTA at 25 mg 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. (2.2 )• Severe Aplastic Anemia: Initiate PROMACTA at 50 mg once daily for most patients. Reduce initial dose in patients with hepatic impairment or patients of East Asian ancestry. Adjust to maintain platelet count greater than 50 x 109/L. Do not exceed 150 mg per day. (2.3 ,8.6 ,8.8 )2.1 Chronic Immune (Idiopathic) Thrombocytopenia
Use the lowest dose of PROMACTA to achieve and maintain a platelet count greater than or equal to 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 [see Warnings and Precautions (5.3)]. In clinical trials, platelet counts generally increased within 1 to 2Â weeks after starting PROMACTA and decreased within 1 to 2Â weeks after discontinuing PROMACTA [see Clinical Studies (14.1)].
Initial Dose Regimen:Â Adult and Pediatric Patients 6Â Years and Older with ITP: Initiate PROMACTA at a dose of 50Â mg once daily, except in patients who are of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C).
For patients of East Asian ancestry with ITP, initiate PROMACTA at a reduced dose of 25Â mg once daily [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].
For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate PROMACTA at a reduced dose of 25Â mg once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
For patients of East Asian ancestry with ITP and hepatic impairment (Child-Pugh Class A, B, C), consider initiating PROMACTA at a reduced dose of 12.5Â mg once daily [see Clinical Pharmacology (12.3)].
Pediatric Patients with ITP Aged 1 to 5Â Years: Initiate PROMACTA at a dose of 25Â mg once daily [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].
Monitoring and Dose Adjustment: After initiating PROMACTA, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 109/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 PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 1. During therapy with PROMACTA, assess CBCs with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter.
When switching between the oral suspension and tablet, assess platelet counts weekly for 2Â weeks, and then follow standard monthly monitoring.
Table 1. Dose Adjustments of PROMACTA in Patients with Chronic Immune (Idiopathic) Thrombocytopenia
Platelet Count Result
Dose Adjustment or Response
<50 x 109/L following at least 2Â weeks of PROMACTA
Increase daily dose by 25Â mg to a maximum of 75Â 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 25Â mg. Wait 2Â weeks to assess the effects of this and any subsequent dose adjustments.
For patients taking 25Â mg once daily, decrease the dose to 12.5Â mg once daily.
>400 x 109/L
Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly.
Once the platelet count is <150 x 109/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 12.5Â mg.
>400 x 109/L after 2Â weeks of therapy at lowest dose of PROMACTA
Discontinue PROMACTA.
In patients with ITP and hepatic impairment (Child-Pugh Class A, B, C), after initiating PROMACTA or after any subsequent dosing increase, wait 3Â 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 PROMACTA. Do not administer more than one dose of PROMACTA within any 24-hour period.
Discontinuation: Discontinue PROMACTA if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4Â weeks of therapy with PROMACTA at the maximum daily dose of 75Â mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of PROMACTA [see Warnings and Precautions (5.2)]. Obtain CBCs with differentials, including platelet counts, weekly for at least 4Â weeks following discontinuation of PROMACTA.
2.2 Chronic Hepatitis C-associated Thrombocytopenia
Use the lowest dose of PROMACTA to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use PROMACTA to normalize platelet counts [see Warnings and Precautions (5.3)]. In clinical trials, platelet counts generally began to rise within the first week of treatment with PROMACTA [see Clinical Studies (14.2)].
Initial Dose Regimen: Initiate PROMACTA at a dose of 25Â mg once daily.
Monitoring and Dose Adjustment: Adjust the dose of PROMACTA 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 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 clinical hematology and liver tests regularly throughout therapy with PROMACTA.
For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information.
Table 2. Dose Adjustments of PROMACTA in Adults with Thrombocytopenia due to Chronic Hepatitis C
Platelet Count Result
Dose Adjustment or Response
<50 x 109/L following at least 2Â weeks of PROMACTA
Increase daily dose by 25Â mg to a maximum of 100Â mg/day.
≥200 x 109/L to ≤400 x 109/L at any time
Decrease the daily dose by 25Â mg.
Wait 2Â weeks to assess the effects of this and any subsequent dose adjustments.
>400 x 109/L
Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly.
Once the platelet count is <150 x 109/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 12.5Â mg.
>400 x 109/L after 2Â weeks of therapy at lowest dose of PROMACTA
Discontinue PROMACTA.
Discontinuation: 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.
PROMACTA 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 PROMACTA [see Warnings and Precautions (5.2)].
2.3 Severe Aplastic Anemia
Use the lowest dose of PROMACTA to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150Â mg, and may take up to 16Â weeks after starting PROMACTA [see Clinical Studies (14.3)].
Initial Dose Regimen: Initiate PROMACTA at a dose of 50Â mg once daily.
For patients with severe aplastic anemia of East Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate PROMACTA at a reduced dose of 25Â mg once daily [see Use in Specific Populations (8.6, 8.8), Clinical Pharmacology (12.3)].
Monitoring and Dose Adjustment: Adjust the dose of PROMACTA in 50-mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 109/L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 3.
Table 3. Dose Adjustments of PROMACTA in Patients with Severe Aplastic Anemia
Platelet Count Result
Dose Adjustment or Response
<50 x 109/L following at least 2Â weeks of PROMACTA
Increase daily dose by 50Â mg to a maximum of 150Â mg/day.
For patients taking 25Â mg once daily, increase the dose to 50Â mg daily before increasing the dose amount by 50Â mg.
≥200 x 109/L to ≤400 x 109/L at any time
Decrease the daily dose by 50Â mg. Wait 2Â weeks to assess the effects of this and any subsequent dose adjustments.
>400 x 109/L
Stop PROMACTA for 1Â week.
Once the platelet count is <150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
>400 x 109/L after 2Â weeks of therapy at lowest dose of PROMACTA
Discontinue PROMACTA.
For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of PROMACTA may be reduced by 50% [see Clinical Studies (14.3)]. If counts remain stable after 8 weeks at the reduced dose, then discontinue PROMACTA and monitor blood counts. If platelet counts drop to less than 30 x 109/L, hemoglobin to less than 9 g/dL, or ANC to less than 0.5 x 109/L, PROMACTA may be reinitiated at the previous effective dose.
Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with PROMACTA, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of PROMACTA [see Adverse Reactions (6.1)]. Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of PROMACTA [see Warnings and Precautions (5.2)].
2.4 Administration
Preparation of the Oral Suspension: Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration of PROMACTA for oral suspension.
Administer the oral suspension immediately after preparation. Discard any suspension not administered within 30Â minutes after preparation.
Prepare the suspension with water only. NOTE: Do not use hot water to prepare the suspension.
For details on preparation and administration of the suspension, see Instructions for Use.
Administration of Tablets and Oral Suspension:Take PROMACTA on an empty stomach (1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)].
Take PROMACTA at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium-fortified juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Do not crush tablets and mix with food or liquids.
Prepare the oral suspension with water only.
3 Dosage Forms And Strengths
• Tablets: 12.5 mg, 25 mg, 50 mg, 75 mg, and 100 mg (3 )• For oral suspension: 25 mg (3 )3.1 Tablets
• 12.5-mg tablets — round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid.• 25-mg tablets — round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid.• 50-mg tablets — round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid.• 75-mg tablets — round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid.• 100-mg tablets — round, biconvex, green, film-coated tablets debossed with GS 1L5. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 100 mg of eltrombopag free acid.3.2 For Oral Suspension
25-mg packet — contains a reddish-brown to yellow powder for reconstitution.
4 Contraindications
None.
None. (4 )
5 Warnings And Precautions
• Hepatotoxicity: Monitor liver function before and during therapy. (5.2 )• Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving PROMACTA. Monitor platelet counts regularly. (5.3 )5.1 Hepatic Decompensation in Patients with Chronic Hepatitis C
In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with PROMACTA plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5Â g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with PROMACTA plus antivirals. Discontinue PROMACTA if antiviral therapy is discontinued.
5.2 Hepatotoxicity
PROMACTA can cause liver enzyme elevations [see Adverse Reactions (6.1)]. Measure serum ALT, AST, and bilirubin prior to initiation of PROMACTA, every 2Â weeks during the dose adjustment phase, and monthly following establishment of a stable dose. PROMACTA inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue PROMACTA if ALT levels increase to greater than or equal to 3Â x ULN in patients with normal liver function or greater than or equal to 3Â x baseline in patients with pre-treatment elevations in transaminases and are:
• progressively increasing, or• persistent for greater than or equal to 4 weeks, or• accompanied by increased direct bilirubin, or• accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
If the potential benefit for reinitiating treatment with PROMACTA is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing PROMACTA and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if PROMACTA is reinitiated. If liver test abnormalities persist, worsen or recur, then permanently discontinue PROMACTA.
5.3 Thrombotic/Thromboembolic Complications
In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with PROMACTA experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with PROMACTA versus less than 1% for placebo).
Thrombotic/thromboembolic complications may result from increases in platelet counts with PROMACTA. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts.
Consider the potential for an increased risk of thromboembolism when administering PROMACTA to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use PROMACTA in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration (2.1, 2.2, 2.3)].
In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (NÂ =Â 292), the risk of thrombotic events was increased in patients treated with 75Â mg of PROMACTA once daily. Seven thrombotic complications (six patients) were reported in the group that received PROMACTA and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received PROMACTA were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received PROMACTA experienced a thrombotic complication within 30 days of completing treatment with PROMACTA and at a platelet count above 200 x 109/L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75Â mg of PROMACTA once daily for 2Â weeks in preparation for invasive procedures.
5.4 Cataracts
In the three controlled clinical trials in adults with chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of PROMACTA daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 4% of patients who underwent ocular examination prior to therapy with PROMACTA. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with PROMACTA and 5% of patients treated with placebo.
Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2)]. Perform a baseline ocular examination prior to administration of PROMACTA and, during therapy with PROMACTA, regularly monitor patients for signs and symptoms of cataracts.
6 Adverse Reactions
The following serious adverse reactions associated with PROMACTA are described in other sections.
• Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1)]• Hepatotoxicity [see Warnings and Precautions (5.2)]• Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.3)]• Cataracts [see Warnings and Precautions (5.4)]
• In adult patients with ITP, the most common adverse reactions (greater than or equal to 5% and greater than placebo) were: nausea, diarrhea, upper respiratory tract infection, vomiting, increased ALT, myalgia, and urinary tract infection. (6.1 )• In pediatric patients age 1 year and older with ITP, the most common adverse reactions (greater than or equal to 10% and greater than placebo) were upper respiratory tract infection, and nasopharyngitis. (6.1 )• In patients with chronic hepatitis C-associated thrombocytopenia, the most common adverse reactions (greater than or equal to 10% and greater than placebo) were: anemia, pyrexia, fatigue, headache, nausea, diarrhea, decreased appetite, influenza-like illness, asthenia, insomnia, cough, pruritus, chills, myalgia, alopecia, and peripheral edema. (6.1 )• In patients with severe aplastic anemia, the most common adverse reactions (greater than or equal to 20%) were: nausea, fatigue, cough, diarrhea, and headache. (6.1 )
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 orwww.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.
Chronic Immune (Idiopathic) Thrombocytopenia:Â Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.3)]. The data described below reflect exposure of PROMACTA to 446 patients with chronic ITP aged 18 to 85 years, of whom 65% were female, across the ITP clinical development program including three placebo-controlled trials. PROMACTA was administered to 277 patients for at least 6Â months and 202 patients for at least 1Â year.
Table 4 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the three placebo-controlled trials, with a higher incidence in PROMACTA versus placebo.
Table 4. Adverse Reactions (≥3%) from Three Placebo-controlled Trials in Adults with Chronic Immune (Idiopathic) Thrombocytopenia
Adverse Reaction
PROMACTA 50 mg
n = 241
(%)
Placebo
n = 128
(%)
Nausea
9
3
Diarrhea
9
7
Upper respiratory tract infection
7
6
Vomiting
6
<1
Increased ALT
5
3
Myalgia
5
2
Urinary tract infection
5
3
Oropharyngeal pain
4
3
Increased AST
4
2
Pharyngitis
4
2
Back pain
3
2
Influenza
3
2
Paresthesia
3
2
Rash
3
2
In the three controlled clinical chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with PROMACTA and in no patients who received placebo.
Among 299 patients with chronic ITP who received PROMACTA in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 5 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the extension trial.
Table 5. Treatment-related Adverse Reactions (≥3%) from Extension Trial in Adults with Chronic Immune (Idiopathic) Thrombocytopenia
Adverse Reaction
PROMACTA 50 mg
n = 299
(%)
Headache
10
Hyperbilirubinemia
6
ALT increased
6
Cataract
5
AST increased
4
Fatigue
4
Nausea
4
In the three controlled chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for PROMACTA and placebo, respectively. Four patients (1%) treated with PROMACTA and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the patients treated with PROMACTA in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in the extension trial. Six of these patients again experienced liver test abnormalities (predominantly Grade 1) resulting in discontinuation of PROMACTA in one patient. In the extension chronic ITP trial, one additional patient had PROMACTA discontinued due to liver test abnormalities (less than or equal to Grade 3).
In a placebo-controlled trial of PROMACTA in patients with chronic liver diseaseand thrombocytopenia not related to ITP, six patients treated with PROMACTA and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.3)].
Pediatric Patients: The data described below reflect median exposure to PROMACTA of 91Â days for 107Â pediatric patients (aged 1 to 17Â years) with chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials.
Table 6 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving PROMACTA) across the two placebo-controlled trials, with a higher incidence for PROMACTA versus placebo.
Table 6. Adverse Reactions (≥3%) with a Higher Incidence for PROMACTA versus Placebo from Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older with Chronic Immune (Idiopathic) Thrombocytopenia
PROMACTA
Placebo
n = 107
n = 50
Adverse Reaction
(%)
(%)
Upper respiratory tract infection
17
6
Nasopharyngitis
12
4
Cough
9
0
Diarrhea
9
2
Pyrexia
9
8
Rhinitis
9
6
Abdominal pain
8
4
Oropharyngeal pain
8
2
Toothache
6
0
ALT increaseda
6
0
Rash
5
2
AST increased
4
0
Rhinorrhea
4
0
 a Includes adverse reactions or laboratory abnormalities >3 x ULN.
Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received PROMACTA. Table 7 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving PROMACTA compared with placebo).
Table 7. Adverse Reactions (≥10% and Greater than Placebo) from Two Placebo-controlled Trials in Adults with Chronic Hepatitis C
Adverse Reaction
PROMACTA
+ 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
Asthenia
16
13
Insomnia
16
15
Cough
15
12
Pruritus
15
13
Chills
14
9
Myalgia
12
10
Alopecia
10
6
Peripheral edema
10
5
In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving PROMACTA compared with 3% for placebo. Total bilirubin greater than or equal to 1.5Â x ULN was reported in 76% and 50% of patients receiving PROMACTA and placebo, respectively. ALT or AST greater than or equal to 3Â x ULN was reported in 34% and 38% of patients for PROMACTA and placebo, respectively.
Severe Aplastic Anemia: In the single-arm, open-label trial, 43 patients with severe aplastic anemia received PROMACTA. Eleven patients (26%) were treated for greater than 6Â months and 7 patients (16%) were treated for greater than 1Â year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache.
Table 8. Adverse Reactions (≥10%) from One Open-label Trial in Adults with Severe Aplastic Anemia
Adverse Reaction
PROMACTA
(n = 43)
(%)
Nausea
33
Fatigue
28
Cough
23
Diarrhea
21
Headache
21
Pain in extremity
19
Dyspnea
14
Pyrexia
14
Dizziness
14
Oropharyngeal pain
14
Febrile neutropenia
14
Abdominal pain
12
Ecchymosis
12
Muscle spasms
12
Transaminases increased
12
Arthralgia
12
Rhinorrhea
12
In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of PROMACTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
Vascular Disorders: Thrombotic microangiopathy with acute renal failure.
7 Drug Interactions
In vitro, CYP1A2, CYP2C8, UGT1A1, and UGT1A3 are involved in the metabolism of eltrombopag. In vitro, eltrombopag inhibits the following metabolic or transporter systems: CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, OATP1B1, and breast cancer resistance protein (BCRP) [see Clinical Pharmacology (12.3)].
Take PROMACTA 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. (2.4 ,7.1 )
7.1 Polyvalent Cations (Chelation)
Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. In a clinical trial, administration of PROMACTA with a polyvalent cation-containing antacid decreased plasma eltrombopag systemic exposure by approximately 70% [see Clinical Pharmacology (12.3)].
Take PROMACTA at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of PROMACTA due to chelation [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
7.2 Transporters
Coadministration of PROMACTA with the OATP1B1 and BCRP substrate, rosuvastatin, to healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103% [see Clinical Pharmacology (12.3)].
Use caution when concomitantly administering PROMACTA and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or BCRP (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with PROMACTA, a dose reduction of rosuvastatin by 50% was recommended.
7.3 Protease Inhibitors
HIV Protease Inhibitors: In a drug interaction trial, coadministration of PROMACTA with lopinavir/ritonavir (LPV/RTV) decreased plasma eltrombopag exposure by 17% [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended when PROMACTA is coadministered with LPV/RTV. Drug interactions with other HIV protease inhibitors have not been evaluated.
Hepatitis C Virus (HCV) Protease Inhibitors: Coadministration of PROMACTA with either boceprevir or telaprevir did not affect eltrombopag or protease inhibitor exposure significantly [see Clinical Pharmacology (12.3)]. No dose adjustments are recommended. Drug interactions with other HCV protease inhibitors have not been evaluated.
7.4 Peginterferon alfa-2a/b Therapy
Coadministration of peginterferon alfa-2a (PEGASYS®) or -2b (PEGINTRON®) did not affect eltrombopag exposure in two randomized, double-blind, placebo-controlled trials with adult patients with chronic hepatitis C [see Clinical Pharmacology (12.3)].
8 Use In Specific Populations
• Pregnancy: Based on animal data, PROMACTA may cause fetal harm. (8.1 )• Nursing Mothers: A decision should be made to discontinue PROMACTA or nursing, taking into account the importance of PROMACTA to the mother. (8.3 )8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of eltrombopag use in pregnancy. In animal reproduction and developmental toxicity studies, there was evidence of embryolethality and reduced fetal weights at maternally toxic doses. PROMACTA should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60Â mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75Â mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.
Eltrombopag was administered orally to pregnant rats at 10, 20, or 60Â mg/kg/day (0.8, 2, and 6Â times, respectively, the human clinical exposure based on AUC in patients with ITP at 75Â mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â 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.
Pregnant rabbits were treated with oral eltrombopag doses of 30, 80, or 150Â mg/kg/day (0.04, 0.3, and 0.5Â times, respectively, the human clinical exposure based on AUC in patients with ITP at 75Â 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 100Â mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.
In a pre- and post-natal developmental toxicity study in pregnant rats (F0), no adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20Â mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75Â mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â 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.
8.3 Nursing Mothers
It is not known whether eltrombopag is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PROMACTA, a decision should be made whether to discontinue nursing or to discontinue PROMACTA taking into account the importance of PROMACTA to the mother.
8.4 Pediatric Use
The safety and efficacy of PROMACTA in pediatric patients 1Â year and older with chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.2), Clinical Studies (14.2)]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3)]. See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1Â year and older. The safety and efficacy of PROMACTA in pediatric patients younger than 1 year with ITP have not yet been established.
The safety and efficacy of PROMACTA in pediatric patients with thrombocytopenia associated with chronic hepatitis C and severe aplastic anemia have not been established.
8.5 Geriatric Use
Of the 106 patients in two randomized clinical trials of PROMACTA 50 mg in chronic ITP, 22% were 65Â years of age and over, while 9% were 75Â years of age and over. In the two randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia, 7% were 65Â years of age and over, while fewer than 1% were 75Â years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients in the placebo-controlled trials, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
Hepatic impairment influences the exposure of PROMACTA [see Clinical Pharmacology (12.3)].
Reduce the initial dose of PROMACTA in patients with chronic ITP (adults and pediatric patients 6 years and older only) or severe aplastic anemia who also have hepatic impairment (Child-Pugh Class A, B, C) [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.2)]. No dosage adjustment is necessary for patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No adjustment in the initial dose of PROMACTA is needed for patients with renal impairment [see Clinical Pharmacology (12.3)]. Closely monitor patients with impaired renal function when administering PROMACTA.
8.8 Ethnicity
Patients of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) exhibit higher eltrombopag exposures. A reduction in the initial dose of PROMACTA is recommended for patients of East Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration (2.1, 2.3)]. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C [see Clinical Pharmacology (12.3)].
10 Overdosage
In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications.
In one report, a subject who ingested 5,000 mg of PROMACTA had a platelet count increase to a maximum of 929 x 109/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 PROMACTA in accordance with dosing and administration recommendations [see Dosage and Administration (2.1, 2.2)].
11 Description
PROMACTA (eltrombopag) tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production.
Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C25H22N4O4•2(C2H7NO). The molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free acid. Eltrombopag olamine has the following structural formula:
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Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.
PROMACTA (eltrombopag) tablets contain eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of eltrombopag free acid. The inactive ingredients of PROMACTA tablets are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: hypromellose (12.5-mg, 25-mg, 50-mg, and 75-mg tablets) or polyvinyl alcohol and talc (100-mg tablet), polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5-mg tablet), FD&C Yellow No. 6 aluminum lake (25-mg tablet), FD&C Blue No. 2 aluminum lake (50-mg tablet), Iron Oxide Red and Iron Oxide Black (75-mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100-mg tablet).
PROMACTA (eltrombopag) for oral suspension packets contain a reddish-brown to yellow powder which produces a reddish-brown suspension when reconstituted with water. Each 25-mg packet delivers eltrombopag olamine equivalent to 25Â mg of eltrombopag free acid. The inactive ingredients of PROMACTA for oral suspension are mannitol, sucralose, and xanthan gum.
12 Clinical Pharmacology
12.1 Mechanism of Action
Eltrombopag is an orally bioavailable, 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.
12.3 Pharmacokinetics
Absorption: Eltrombopag is absorbed with a peak concentration occurring 2 to 6Â hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%.
An open-label, randomized, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
In a second trial, administration of a single 25-mg dose of eltrombopag for oral suspension to adults with a high-calcium, moderate-fat, moderate-calorie meal reduced plasma eltrombopag AUC0-∞ by 75% (90% CI: 71%, 88%) and Cmax by 79% (90% CI: 76%, 82%). Administration of a single 25-mg dose of eltrombopag for oral suspension 2 hours after the high-calcium meal reduced plasma eltrombopag AUC0-∞ by 47% (90% CI: 40%, 53%) and Cmax by 48% (90% CI: 40%, 54%). Administration of a single 25-mg dose of eltrombopag for oral suspension 2 hours before the high-calcium meal reduced plasma eltrombopag AUC0-∞ by 20% (90% CI: 9%, 29%) and Cmax by 14% (90% CI: 2%, 25%).
In a relative bioavailability trial in adults, the eltrombopag for oral suspension delivered 22% higher plasma AUC0-∞ than the tablet formulation.
Distribution: 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.
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 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. The plasma elimination half-life of eltrombopag is approximately 21 to 32Â hours in healthy subjects and 26 to 35Â hours in patients with ITP.
Drug Interactions: Polyvalent Cation-containing Antacids: In a clinical trial, coadministration of 75 mg of PROMACTA with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) to 26 healthy adult subjects decreased plasma eltrombopag AUC0-∞ and Cmax by approximately 70%. The contribution of sodium alginate to this interaction is not known.
Cytochrome P450 Enzymes (CYPs): In a clinical trial, PROMACTA 75Â mg once daily was administered for 7Â days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this trial.
Rosuvastatin: In a clinical trial, coadministration of 75 mg of PROMACTA once daily for 5 days with a single 10-mg dose of the OATP1B1 and BCRP substrate, rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%.
Protease Inhibitors: HIV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg twice daily with a single dose of PROMACTA 100 mg to 40 healthy adult subjects decreased plasma eltrombopag AUC0-∞ by 17%.
HCV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose telaprevir 750 mg every 8 hours or boceprevir 800 mg every 8 hours with a single dose of PROMACTA 200 mg to healthy adult subjects did not alter plasma telaprevir, boceprevir, or eltrombopag AUC0-∞ or Cmax to a significant extent.
Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin: The pharmacokinetics of eltrombopag in both the presence and absence of pegylated interferon alfa-2a and -2b therapy were evaluated using a population pharmacokinetic analysis in 635 patients with chronic hepatitis C. The population PK model estimates of clearance indicate no significant difference in eltrombopag clearance in the presence of pegylated interferon alfa plus ribavirin therapy.
In vitro Studies: Eltrombopag is an inhibitor of CYP2C8 and CYP2C9 in vitro. Eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 in vitro. Eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and BCRP in vitro.
Specific Populations:Â Ethnicity: Based on two population PK analyses of eltrombopag concentrations in patients with ITP or chronic hepatitis C, East Asian (i.e., Japanese, Chinese, Taiwanese, Korean) subjects exhibited 50% to 55% higher eltrombopag plasma concentrations compared with non-East Asian subjects [see Dosage and Administration (2.1, 2.3)].
An approximately 40% higher systemic eltrombopag exposure in healthy African-American subjects was noted in at least one clinical pharmacology trial. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.
Hepatic Impairment: In a pharmacokinetic trial, the disposition of a single 50-mg dose of PROMACTA in patients with mild, moderate, and severe hepatic impairment was compared with subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC0-∞ was approximately 2-fold higher in patients with moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C). The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein binding effects.
Chronic Liver Disease: A population PK analysis in thrombocytopenic patients with chronic liver disease following repeat doses of eltrombopag demonstrated that mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC(0-Ï„) and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC(0-Ï„) 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. This clinical trial did not evaluate protein-binding effects.
Chronic Hepatitis C: A population PK analysis in 28 healthy adults and 635 patients with chronic hepatitis C demonstrated that patients with chronic hepatitis C treated with PROMACTA had higher plasma AUC(0-Ï„) values as compared with healthy subjects, and AUC(0-Ï„) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-Ï„) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects.
Renal Impairment: The disposition of a single 50-mg dose of PROMACTA in patients with mild (creatinine clearance [CrCl] of 50 to 80 mL/min), moderate (CrCl of 30 to 49 mL/min), and severe (CrCl less than 30 mL/min) renal impairment was compared with subjects with normal renal function. Average total plasma eltrombopag AUC0-∞ was 32% to 36% lower in subjects with mild to moderate renal impairment and 60% lower in subjects with severe renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.
Pediatric Patients: The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1Â 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 Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC(0-Ï„) values as compared with non-East Asian patients.
Plasma eltrombopag AUC(0-Ï„) and Cmax in pediatric patients aged 12 to 17Â years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 9.
Table 9. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients with ITP (Normalized to a Once-daily 50-mg Dose)
Cmax b
AUC(0-Ï„) b
Age
(mcg/mL)
(mcg.h/mL)
Adults (n = 108)
7.03
101
(6.44, 7.68)
(91.4, 113)
12 to 17 years (n = 62)
6.80
103
(6.17, 7.50)
(91.1, 116)
6 to 11 years (n = 68)
10.3
153
(9.42, 11.2)
(137, 170)
1 to 5 years (n = 38)
11.6
162
(10.4, 12.9)
(139, 187)
 a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates.12.6 Assessment of Risk of QT/QTc Prolongation
There is no indication of a QT/QTc prolonging effect of PROMACTA at doses up to 150Â mg daily for 5Â days. The effects of PROMACTA at doses up to 150Â mg daily for 5Â days (supratherapeutic doses) on the QT/QTc interval were evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg, single oral dose) crossover trial in healthy adult subjects. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans.
Eltrombopag was not carcinogenic in mice at doses up to 75Â mg/kg/day or in rats at doses up to 40Â mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).
Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on Cmax in patients with chronic hepatitis C at 100Â mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency).
Eltrombopag did not affect female fertility in rats at doses up to 20Â mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75Â mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40Â mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â mg/day).
13.2 Animal Pharmacology and/or Toxicology
Eltrombopag is phototoxic in vitro. There was no evidence of in vivo cutaneous or ocular phototoxicity in rodents.
Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75Â mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â mg/day, cataracts were observed in mice after 6 weeks and in rats after 28Â weeks of dosing. At greater than or equal to 4Â times the human clinical exposure based on AUC in patients with ITP at 75Â mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â mg/day, cataracts were observed in mice after 13Â weeks and in rats after 39Â weeks of dosing [see Warnings and Precautions (5.4)].
Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150Â mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100Â mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.
14 Clinical Studies
14.1 Chronic ITP
Adults: The efficacy and safety of PROMACTA in adult patients with chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial.
Trials 1 and 2: In Trials 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 109/L were randomized to receive either PROMACTA or placebo daily for up to 6Â weeks, followed by 6Â weeks off therapy. During the trials, PROMACTA or placebo was discontinued if the platelet count exceeded 200 x 109/L.
The median age of the patients was 50Â years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109/L) were similar among all treatment groups.
Trial 1 randomized 114 patients (2:1) to PROMACTA 50Â mg or placebo. Trial 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of PROMACTA, 30Â mg, 50Â mg, or 75Â mg each administered daily.
The efficacy of PROMACTA in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 109/L to greater than or equal to 50 x 109/L at any time during the treatment period (Table 10).
Table 10. Trials 1 and 2 Platelet Count Response (≥50 x 109/L) Rates in Adults with Chronic Immune (Idiopathic) Thrombocytopenia
Trial
PROMACTA
50 mg Daily
Placebo
1
43/73 (59%)a
6/37 (16%)
2
19/27 (70%)a
3/27 (11%)
a P value <0.001 for PROMACTA versus placebo.
The platelet count response to PROMACTA was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of PROMACTA and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of PROMACTA, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 109/L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of PROMACTA was 42 days in Trial 1 and 43 days in Trial 2.
Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with PROMACTA. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with PROMACTA.
Trial 3: In this trial, 197 patients were randomized (2:1) to receive either PROMACTA 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of PROMACTA could be adjusted based on individual platelet counts. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with PROMACTA for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated.
The median ages of the patients treated with PROMACTA and placebo were 47Â years and 52.5Â years, respectively. Approximately half of the patients treated with PROMACTA and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to15 x 109/L (50% and 48%, respectively). A similar percentage of patients treated with PROMACTA and placebo (37% and 34%, respectively) had a prior splenectomy.
The efficacy of PROMACTA in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for patients receiving PROMACTA relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with PROMACTA, compared with 10% of patients treated with placebo (splenectomized patients: PROMACTA 51%, placebo 8%; non-splenectomized patients: PROMACTA 66%, placebo 11%). The proportion of responders in the group of patients treated with PROMACTA was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with PROMACTA were significantly more likely to achieve a platelet count between 50 x 109/L and 400 x 109/L during the entire 6-month treatment period compared with those patients treated with placebo.
Outcomes of treatment are presented in Table 11 for all patients enrolled in the trial.
Table 11. Outcomes of Treatment from Trial 3 in Adults with Chronic Immune (Idiopathic) Thrombocytopenia
Outcome
PROMACTA
NÂ =Â 135
Placebo
NÂ =Â 62
Mean number of weeks with platelet counts ≥50 x 109/L
11.3
2.4
Requiring rescue therapy, n (%)
24 (18)
25 (40)
Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with PROMACTA and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial.
Extension Trial: Patients who completed any prior clinical trial with PROMACTA were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. PROMACTA was administered to 299 patients; 249 completed 6Â months, 210 patients completed 12 months, and 138 patients completed 24Â months of therapy. The median baseline platelet count was 19 x 109/L prior to administration of PROMACTA.
Pediatric Patients: The efficacy and safety of PROMACTA in pediatric patients 1 year and older with chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of PROMACTA was reduced if the platelet count exceeded 200 x 109/L and interrupted and reduced if it exceeded 400 x 109/L.
Trial 4: Patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109/L (n = 92) were stratified by age and randomized (2:1) to PROMACTA (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East Asian patients aged 6 to 17 years regardless of weight.The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East Asian patients) administered as oral suspension.
The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive PROMACTA.
The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 109/L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with PROMACTA and 90% in the group treated with placebo. Four patients in the group treated with PROMACTA had undergone splenectomy.
The efficacy of PROMACTA in this trial was evaluated by the proportion of subjects on PROMACTA achieving platelet counts ≥50 x 109/L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 12).
Table 12. Trial 4 Platelet Count Response (≥50 x 109/L without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older with Chronic Immune (Idiopathic) Thrombocytopenia
Age Cohort
PROMACTA
Placebo
Overall
26/63 (41%)a
1/29 (3%)
 12 to 17 years
10/24 (42%)
1/10 (10%)
 6 to 11 years
11/25 (44%)
0/13 (0%)
 1 to 5 years
5/14 (36%)
0/6 (0%)
a P value = <0.001 for PROMACTA versus placebo.
More pediatric patients treated with PROMACTA (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 109/L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (98% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥50 x 109/L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting PROMACTA.
Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy.
Trial 5: Patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109/L (n = 67) were stratified by age and randomized (2:1) to PROMACTA (n = 45) or placebo (n = 22). The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East Asian patients) administered as oral suspension.
The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive PROMACTA.
The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 109/L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with PROMACTA and 86% in the group treated with placebo. Five patients in the group treated with PROMACTA had undergone splenectomy.
The efficacy of PROMACTA in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 109/L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 13). Platelet response to PROMACTA was consistent across the age cohorts.
Table 13. Trial 5 Platelet Count Response (≥50 x 109/L without Rescue) Rates in Pediatric Patients 1 Year and Older with Chronic Immune (Idiopathic) Thrombocytopenia
PROMACTA
Placebo
Overall
28/45 (62%)a
7/22 (32%)
 12 to 17 years
10/16 (62%)
0/8 (0%)
 6 to 11 years
12/19 (63%)
3/9 (33%)
 1 to 5 years
6/10 (60%)
4/5 (80%)
a P value = 0.011 for PROMACTA versus placebo.
Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]).
Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy.
14.2 Chronic Hepatitis C-associated Thrombocytopenia
The efficacy and safety of PROMACTA for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. Trial 1 utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and Trial 2 utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 109/L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6 with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh Class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 109/L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label PROMACTA to increase the platelet count to a threshold of greater than or equal to 90 x 109/L for Trial 1 and greater than or equal to 100 x 109/L for Trial 2. PROMACTA was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label PROMACTA was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of PROMACTA at the end of the pre-treatment phase or to placebo. PROMACTA was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks.
The efficacy of PROMACTA for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24Â weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 109/L was approximately 2Â weeks. Ninety-five percent of patients were able to initiate antiviral therapy.
In both trials, a significantly greater proportion of patients treated with PROMACTA achieved SVR (see Table 14). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 109/L versus greater than or equal to 50 x 109/L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for PROMACTA versus 8% (20/239) for placebo.
Table 14. Trials 1 and 2 Sustained Virologic Response in Adults with Chronic Hepatitis C
Trial 1a
Trial 2b
Pre-antiviral Treatment Phase
N = 715
N = 805
% Patients who achieved target platelet counts and initiated antiviral therapyc
95%
94%
Antiviral Treatment Phase
PROMACTA
N = 450
%
Placebo
N = 232
%
PROMACTA
N = 506
%
Placebo
N = 253
%
Overall SVRd
23
14
19
13
 HCV Genotype 2,3
35
24
34
25
 HCV Genotype 1,4,6
18
10
13
7
 a PROMACTA given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b PROMACTA given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥90 x 10 9 /L for Trial 1 and ≥100 x 10 9 /L for Trial 2. d P value <0.05 for PROMACTA versus placebo.
The majority of patients treated with PROMACTA (76%) maintained a platelet count greater than or equal to 50Â x 109/L compared with 19% for placebo. A greater proportion of patients on PROMACTA did not require any antiviral dose reduction as compared with placebo (45% versus 27%).
14.3 Severe Aplastic Anemia
PROMACTA was studied in a single-arm, single-center, open-label trial 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. PROMACTA was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of PROMACTA in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. 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 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. Patients who responded continued therapy in an extension phase of the trial.
The treated population had median age of 45 years (range: 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 109/L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 109/L, and absolute reticulocyte count was 24.3 x 109/L. Eighty-six percent of patients were RBC transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.
Table 15 presents the efficacy results.
Table 15. Hematologic Response in Patients with Severe Aplastic Anemia
Outcome
PROMACTA
N = 43
Response ratea, n (%)
 95% CI (%)
17 (40)
(25, 56)
Median of duration of response in months (95%CI)
NRb (3.0, NRb)
 a Includes single- and multi-lineage. b NR = Not reached due to few events (relapsed).
In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096Â days with a median of 200Â days, and the RBC transfusion-free period ranged from 15 to 1,082Â days with a median of 208Â days.
In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with PROMACTA and maintained the response (median follow up: 8.1Â months, range: 7.2 to 10.6Â months).
16 How Supplied/storage And Handling
16.1 Tablets
• The 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: NDC 0007-4643-13.• The 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: NDC 0007-4640-13.• The 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 30: NDC 0007-4641-13.• The 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: NDC 0007-4642-13.• The 100-mg tablets are round, biconvex, green, film-coated tablets debossed with GS 1L5 and are available in bottles of 30: NDC 0007-4646-13. This product contains a desiccant.
Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccant if present. Dispense in original bottle.
16.2 For Oral Suspension
The 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, an oral dosing syringe, and a threaded closure with syringe-port capability.
Each kit (NDC 0007-4515-27) contains 30 packets: NDC 0007-4515-01.
Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Following reconstitution, the product should be administered immediately but may be stored for a maximum period 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) [see USP Controlled Room Temperature]. Throw away (discard) the mixture if not used within 30 minutes.
17 Patient Counseling Information
Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Prior to treatment, patients should fully understand and be informed of the following risks and considerations for PROMACTA:
• For patients with chronic ITP, therapy with PROMACTA is administered to achieve and maintain a platelet count greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding.• For patients with chronic hepatitis C, therapy with PROMACTA is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.• Therapy with PROMACTA 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 alfa interferon therapy.• Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.
• 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 (abdomen)• 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 too much PROMACTA may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.• Advise patients that during therapy with PROMACTA, they should continue to avoid situations or medications that may increase the risk for bleeding.• Advise patients to have a baseline ocular examination prior to administration of PROMACTA and be monitored for signs and symptoms of cataracts during therapy.• Advise patients to take PROMACTA at least 2 hours before or 4 hours after foods, mineral supplements, and antacids which contain polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.• Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration.• Inform patients or caregivers how many packets to administer to get the full dose.
PROMACTA is a registered trademark of the GSK group of companies. The following are registered trademarks of their respective owners: PEGASYS/Hoffmann-La Roche Inc.; PEGINTRON/Schering Corporation.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2015, the GSK group of companies. All rights reserved.
PRM:11PI
Spl Medguide Section
 MEDICATION GUIDE
 PROMACTA®(pro-MAC-ta)
 PROMACTA®(pro-MAC-ta)
 (eltrombopag)
 (eltrombopag)
 tablets
 for oral suspension
 Read this Medication Guide before you start taking PROMACTA and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.
 What is the most important information I should know about PROMACTA? PROMACTA can cause serious side effects, including: Liver problems. If you have chronic hepatitis C virus, and take PROMACTA with interferon and ribavirin treatment, PROMACTA may increase your risk of liver problems. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
• yellowing of the skin or the whites of the eyes (jaundice)• unusual darkening of the urine• unusual tiredness• right upper stomach area (abdomen) pain• confusion• swelling of the stomach area (abdomen) See “What are the possible side effects of PROMACTA?†for other side effects of PROMACTA.
 What is PROMACTA? PROMACTA is a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to chronic immune (idiopathic) thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. PROMACTA is also used to treat patients with:• low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon.• severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. PROMACTA is used to try to raise platelet counts in order to lower your risk for bleeding. PROMACTA is not used to make platelet counts normal. PROMACTA is for treatment of certain people with low platelet counts caused by chronic ITP, chronic HCV, or SAA, not low platelet counts caused by other conditions or diseases. It is not known if PROMACTA is safe and effective when used with other antiviral medicines that are approved to treat chronic hepatitis C. It is not known if PROMACTA is safe and effective in children with chronic hepatitis C or severe aplastic anemia or in children younger than 1 year with ITP.
 What should I tell my healthcare provider before taking PROMACTA? Before you take PROMACTA, tell your healthcare provider if you:• have liver or kidney problems• have or had a blood clot• have a history of cataracts• have had surgery to remove your spleen (splenectomy)• have bleeding problems• are Asian and you are of Chinese, Japanese, Taiwanese, or Korean ancestry. You may need a lower dose of PROMACTA.• have any other medical conditions• are pregnant or plan to become pregnant. It is not known if PROMACTA will harm an unborn baby.• are breastfeeding or plan to breastfeed. It is not known if PROMACTA passes into your breast milk. You and your healthcare provider should decide whether you will take PROMACTA or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PROMACTA may affect the way certain medicines work. Certain other medicines may affect the way PROMACTA works. Especially tell your healthcare provider if you take:• certain medicines used to treat high cholesterol, called “statinsâ€.• a blood thinner medicine. Certain medicines may keep PROMACTA from working correctly. Take PROMACTA at least 2 hours before or 4 hours after taking these products:• antacid medicine used to treat stomach ulcers or heartburn• multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is uled above. Know the medicines you take. Keep a ul of them and show it to your healthcare provider and pharmacist when you get a new medicine.
 How should I take PROMACTA?• Take PROMACTA exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of PROMACTA tablets or PROMACTA oral suspension that is right for you.• If your healthcare provider prescribes PROMACTA oral suspension, see “Instructions for Use†that comes with your medicine for instructions on how to prepare and take your dose.• Do not stop taking PROMACTA without talking with your healthcare provider first. Do not change your dose or schedule for taking PROMACTA unless your healthcare provider tells you to change it.• Take PROMACTA on an empty stomach, either 1 hour before or 2 hours after eating food.• Take PROMACTA at least 2 hours before or 4 hours after eating dairy products and calcium-fortified juices.• Take PROMACTA tablets whole. Do not crush PROMACTA tablets and mix with food or liquids. If you miss a dose of PROMACTA, wait and take your next scheduled dose. Do not take more than one dose of PROMACTA in one day.• If you take too much PROMACTA, you may have a higher risk of serious side effects. Call your healthcare provider right away.• Your healthcare provider will check your platelet count during your treatment with PROMACTA and change your dose of PROMACTA as needed.• Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking PROMACTA.
 What should I avoid while taking PROMACTA? Avoid situations and medicines that may increase your risk of bleeding.
 What are the possible side effects of PROMACTA? PROMACTA may cause serious side effects, including:• See “What is the most important information I should know about PROMACTA?â€â€¢ Abnormal liver function tests. Your healthcare provider will order blood tests to check your liver before you start taking PROMACTA and during your treatment. In some cases treatment with PROMACTA may need to be stopped due to changes in your liver function tests.• High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with PROMACTA. Your risk of getting a blood clot may also be increased during treatment with PROMACTA if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop PROMACTA if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area. Tell your healthcare provider right away if you have stomach area pain that may be a symptom of this type of blood clot.• New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts have happened in people taking PROMACTA. Your healthcare provider will check your eyes before and during your treatment with PROMACTA. Tell your healthcare provider about any changes in your eyesight while taking PROMACTA.
 The most common side effects of PROMACTA in adults when used to treat chronic ITP are:• nausea• diarrhea• upper respiratory tract infection. Symptoms may include runny nose, stuffy nose, and sneezing• vomiting• muscle aches• urinary tract infection. Symptoms may include frequent or urgent need to urinate, low fever in some people, pain or burning with urination.• pain or swelling (inflammation) in your throat or mouth (oropharyngeal pain and pharyngitis)• abnormal liver function tests• back pain• â€fluâ€-like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches• skin tingling, itching, or burning• rash The most common side effects of PROMACTA in children 1 year and older when used to treat chronic ITP are:• upper respiratory tract infection. Symptoms may include runny nose, stuffy nose, and sneezing.• pain or swelling (inflammation) in your nose or throat (nasopharyngitis)• cough• diarrhea• fever• runny, stuffy nose (rhinitis)• stomach (abdominal) pain• pain or swelling (inflammation) in your throat or mouth (oropharyngeal pain)• toothache• rash• abnormal liver function tests The most common side effects when PROMACTA is used in combination with other medicines to treat chronic HCV are:• low red blood cell count (anemia)• fever• tiredness• headache• nausea• diarrhea• decreased appetite• “fluâ€-like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches• feeling weak• trouble sleeping• cough• itching• chills• muscle aches• hair loss• swelling in your ankles, feet, and legs The most common side effects when PROMACTA is used to treat severe aplastic anemia are:• nausea• feeling tired• cough• diarrhea• headache• pain in arms, legs, hands, or feet• shortness of breath• fever• dizziness• pain in the nose or throat• abdominal pain• bruising• muscle spasms• abnormal liver function tests• joint pain• runny nose Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PROMACTA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
 How should I store PROMACTA tablets and oral suspension? Tablets:• Store PROMACTA tablets at room temperature between 68°F to 77°F (20°C to 25°C).• Keep PROMACTA tightly closed in the bottle given to you.• The PROMACTA bottle may contain a desiccant pack to help keep your medicine dry. Do not remove the desiccant pack from the bottle. For oral suspension:• Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).• After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep PROMACTA and all medicines out of the reach of children.
 General information about the safe and effective use of PROMACTA Medicines are sometimes prescribed for purposes other than those uled in a Medication Guide. Do not use PROMACTA for a condition for which it was not prescribed. Do not give PROMACTA to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about PROMACTA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about PROMACTA that is written for health professionals. For more information about PROMACTA, go to www.PROMACTA.com or call 1-888-825-5249.
 What are the ingredients in PROMACTA? Tablets: Active ingredient: eltrombopag olamine. Inactive ingredients:• Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate.• Coating: hypromellose (12.5-mg, 25-mg, 50-mg, and 75-mg tablets) or polyvinyl alcohol and talc (100-mg tablet), polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5-mg tablet), and FD&C Yellow No. 6 aluminum lake (25-mg tablet), FD&C Blue No. 2 aluminum lake (50-mg tablet), Iron Oxide Red and Iron Oxide Black (75-mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100-mg tablet). For oral suspension: Active ingredient: eltrombopag olamine. Inactive ingredients: mannitol, sucralose, xanthan gum. PROMACTA is a registered trademark of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 ©2015, the GSK group of companies. All rights reserved. PRM:10MG
 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised August 2015INSTRUCTIONS FOR USE SECTION
INSTRUCTIONS FOR USE
PROMACTA®(pro-MAC-ta)
(eltrombopag)
for oral suspension
Read all the Instructions for Use and follow the steps below to mix and give a dose of PROMACTA for oral suspension.
Important:
• Do not take PROMACTA for oral suspension or give it to someone else until you have been shown how to properly give PROMACTA for oral suspension. Your healthcare provider or nurse will show you how to prepare and give a dose of PROMACTA for oral suspension properly.• PROMACTA for oral suspension must be mixed with cool or cold water only. Do not use hot water to prepare the oral suspension.• Give the dose of suspension right away after mixing with water. If medicine is not given within 30 minutes, you will have to mix a new dose. Throw away (discard) the unused mixture into the trash. Do not pour it down the drain.• Avoid letting the medicine touch your skin. If this happens, wash the affected area right away with soap and water. Call your doctor if you have a skin reaction or if you have any questions. If you spill any powder or liquid, follow the clean up instructions in Step 12.• Contact your doctor or pharmacist if you have any questions about how to mix or give PROMACTA to the child or if you damage or lose any of the supplies in your kit.• After you have used all 30 packets, throw all the remaining supplies (mixing bottle, lid with cap, and oral dosing syringe) away in the trash.
Each PROMACTA for oral suspension kit contains the following supplies:
30 packets of PROMACTA for oral suspension
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1 Reusable mixing bottle with lid and cap
1 Reusable 20-mL oral syringe
You will need the following to give a single dose of PROMACTA for oral suspension.
From the kit:
• prescribed number of packets• 1 reusable mixing bottle with lid and cap. NOTE: Due to its small size, the cap may pose a danger of choking to small children.• 1 reusable 20-mL oral dosing syringe
Not included in the kit:
• 1 clean glass or cup filled with drinking water• scissors to cut packet• paper towels or disposable cloth• gloves (optional)
How do I prepare a dose of PROMACTA for oral suspension?
Step 1. Make sure that the mixing bottle, cap, lid and oral syringe are dry before use. Remove the lid from the mixing bottle.
• Prepare a clean, flat work surface.• Wash and dry your hands before preparing the medicine.
Step 2. Fill the oral syringe with 20Â mL of drinking water from the glass or cup.
• Start with the plunger pushed all the way into the syringe.• Put the tip of the syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the syringe.
Step 3. Place the oral syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral syringe.
Step 4. Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose.
• 12.5-mg dose (1 packet) Note: See Step 9 for instructions on how to give a 12.5-mg dose.• 25-mg dose (1 packet)• 50-mg dose (2 packets)• 75-mg dose (3 packets)
Step 5. Add the prescribed number of packets to the mixing bottle.
• Tap the top of each packet to make sure the contents fall to the bottom.• Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle.• Make sure not to spill the powder outside the mixing bottle.
Step 6. Screw the lid tightly onto the bottle. Make sure the cap is pushed onto the lid.
Step 7. Gently and slowly shake the bottle back and forth for at least 20Â seconds to mix the water with the powder.
• To prevent the mixture from foaming, do not shake the bottle hard.
How should I give a dose of PROMACTA for oral suspension?
Step 8. Make sure the plunger is pushed all the way into the oral syringe. Pull cap off the mixing bottle lid and insert the syringe tip into the hole in the lid.
Step 9. Transfer the mixture into the oral syringe. The liquid will be dark brown in color.
• Turn the mixing bottle upside down along with the syringe.• Pull back the plunger:
• to the 10 mL mark on the syringe for a 12.5-mg dose only OR
• until all the medicine is in the syringe (25-mg, 50-mg, or 75-mg dose).
Step 10. Return the bottle to the upright position and remove the syringe from the bottle.
Step 11. Giving a dose of PROMACTA for oral suspension to a child.
• Place the tip of the oral syringe into the inside of the child’s cheek.• Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine.
How should I clean up?
Step 12. Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth.
• To avoid possibly staining your skin, consider using disposable gloves.• Throw away (discard) used paper towel and gloves in the trash.
Step 13. Clean the mixing supplies.
• Do not reuse any of the mixture remaining in the bottle.• Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain.• Remove the plunger from the oral syringe.• Rinse the mixing bottle, lid, syringe, and plunger under running water and air dry. The mixing bottle may become stained from the medicine. This is normal.• Wash hands with soap and water.
Keep PROMACTA and all medicines out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
PROMACTA is a registered trademark of the GSK group of companies.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2015, the GSK group of companies. All rights reserved.
Issued: August 2015
PRM:1IFU
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC 0007-4643-13
PROMACTA®
(eltrombopag) Tablets
12.5 mg*
30 Tablets
Rx only
*Each tablet contains eltrombopag olamine equivalent to 12.5 mg of eltrombopag free acid.
Federal Law requires dispensing of PROMACTA® with the Medication Guide provided with this bottle.
Store between 20o and 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59o to 86oF).
Do not use if printed safety seal under cap is broken or missing.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise directed by physicians or requested by purchaser.
GlaxoSmithKline, RTP, NC 27709
Made in Ireland
 10000000123247 Rev. 1/14![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC 0007-4640-13
PROMACTA®
(eltrombopag) Tablets
25 mg*
30 Tablets
Rx only
*Each tablet contains eltrombopag olamine equivalent to 25 mg of eltrombopag free acid.
Federal Law requires dispensing of PROMACTA® with the Medication Guide provided with this bottle.
Store between 20o and 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59o to 86oF).
Do not use if printed safety seal under cap is broken or missing.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise directed by physicians or requested by purchaser.
GlaxoSmithKline, RTP, NC 27709
Made in Ireland
 10000000123416 Rev. 1/14![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC 0007-4641-13
PROMACTA®
(eltrombopag) Tablets
50 mg*
30 Tablets
Rx only
*Each tablet contains eltrombopag olamine equivalent to 50 mg of eltrombopag free acid.
Federal Law requires dispensing of PROMACTA® with the Medication Guide provided with this bottle.
Store between 20o and 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59o to 86oF).
Do not use if printed safety seal under cap is broken or missing.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise directed by physicians or requested by purchaser.
GlaxoSmithKline, RTP, NC 27709
Made in Ireland
 10000000123417 Rev. 1/14![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC 0007-4642-13
PROMACTA®
(eltrombopag) Tablets
75 mg*
30 Tablets
Rx only
*Each tablet contains eltrombopag olamine equivalent to 75 mg of eltrombopag free acid.
Federal Law requires dispensing of PROMACTA® with the Medication Guide provided with this bottle.
Store between 20o and 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59o to 86oF).
Do not use if printed safety seal under cap is broken or missing.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise directed by physicians or requested by purchaser.
GlaxoSmithKline, RTP, NC 27709
Made in Ireland
 10000000123248 Rev. 1/14![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC 0007-4646-13
PROMACTA®
(eltrombopag) Tablets
100 mg*
30 Tablets
Rx only
*Each tablet contains eltrombopag olamine equivalent to 100 mg of eltrombopag free acid.
Federal Law requires dispensing of PROMACTA® with the Medication Guide provided with this bottle.
Store between 20o and 25oC (68o to77oF); excursions permitted to 15o to 30oC (59o to 86oF). Do not remove desiccant.
Do not use if printed safety seal under cap is broken or missing.
Dosage:
See accompanying prescribing information.
Important:
Use safety closures when dispensing this product unless otherwise directed by physicians or requested by purchaser.
GlaxoSmithKline, RTP, NC 27709
Made in Ireland
10000000123249 Rev. 1/14
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC 0007-4514-27
PROMACTA®
(eltrombopag) for Oral Suspension
25 mg
Rx Only
Federal Law requires dispensing of PROMACTA® with the Medication Guide provided with this package.
30 Packets
©2015, the GSK group of companies
 DEVCOMP-0003801 Rev. 8/2015![]()
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