Prescription Drug Information: PROMACTA (Page 2 of 7)

2.4 Administration

Administration of Tablets and Oral Suspension: Take PROMACTA without a meal or with a meal low in calcium (≤ 50 mg). Take PROMACTA at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

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

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 30 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, including the recommended duration of use of each oral dosing syringe, see Instructions for Use.

3 DOSAGE FORMS AND STRENGTHS

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.

For Oral Suspension

  • 12.5-mg packet —– contains a reddish-brown to yellow powder for reconstitution.
  • 25-mg packet —– contains a reddish-brown to yellow powder for reconstitution.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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 3.5 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 may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1)]. One patient (< 1%) with ITP treated with PROMACTA in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with PROMACTA in clinical trials experienced drug-induced liver injury.

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

Measure serum ALT, AST, and bilirubin prior to initiation of PROMACTA, every 2 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 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) 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.

First-Line Treatment of Severe Aplastic Anemia

Measure ALT, AST, and bilirubin prior to initiation of PROMACTA, every other day while hospitalized for h-ATG therapy, and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6.

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

A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either PROMACTA (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received PROMACTA or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the PROMACTA arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the PROMACTA arm). The incidence of progression to AML was 12% (21/179) in the PROMACTA arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the PROMACTA arm).

5.4 Thrombotic/Thromboembolic Complications

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 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).

In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 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 75 mg of PROMACTA once daily for 2 weeks in preparation for invasive procedures.

5.5 Cataracts

In the three controlled clinical trials in adults with persistent or 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 11% 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 clinically significant 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)]
  • Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions (5.3)]
  • Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.4)]
  • Cataracts [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Persistent or Chronic Immune Thrombocytopenia:Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4)]. The data described below reflect exposure of PROMACTA to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1)]. PROMACTA was administered to 330 patients for at least 6 months and 218 patients for at least 1 year.

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

Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.a Includes PTs of Urinary tract infection, Cystitis, Urinary tract infection bacterial, and Bacteriuria.

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

Urinary tract infectiona

5

4

Increased ALT

5

3

Myalgia

5

2

Oropharyngeal pain

4

3

Increased AST

4

2

Pharyngitis

4

2

Back pain

3

2

Influenza

3

2

Paresthesia

3

2

Rash

3

2

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

Among 302 patients with persistent or 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 9 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 9. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Adverse Reaction

PROMACTA 50 mg

n = 302

(%)

Headache

10

ALT increased

5

AST increased

5

Cataract

5

Fatigue

5

Blood bilirubin increased

4

Nausea

4

Hyperbilirubinemia

3

Diarrhea

3

In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for 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. Seventeen of the patients treated with PROMACTA in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of PROMACTA in one patient. In the extension persistent or chronic ITP trial, six additional patients had PROMACTA discontinued due to liver test abnormalities (less than or equal to Grade 3).

In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with PROMACTA and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with PROMACTA. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use.

The safety of PROMACTA was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 PROMACTA-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of PROMACTA-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of PROMACTA-treated patients versus 0% of placebo-treated patients.

In a placebo-controlled trial of PROMACTA in patients with chronic liver disease and 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 (5.4)].

Pediatric Patients: The data described below reflect median exposure to PROMACTA of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials.

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

Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for PROMACTA Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.a Includes adverse reactions or laboratory abnormalities > 3 x ULN.

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

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

In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with PROMACTA. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis.

Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received PROMACTA. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving PROMACTA compared with placebo).

Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C
a Includes PTs of Insomnia, Initial insomnia, and Poor quality sleep.

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

Insomniaa

16

15

Asthenia

16

13

Cough

15

12

Pruritus

15

13

Chills

14

9

Myalgia

12

10

Alopecia

10

6

Peripheral edema

10

5

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

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 1.5 x ULN was reported in 76% and 50% of patients receiving PROMACTA and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for PROMACTA and placebo, respectively.

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

The safety of PROMACTA was also assessed in all patients treated with PROMACTA in the two controlled trials, including patients who initially received PROMACTA in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 PROMACTA-treated patients). Hepatic failure was reported in 0.8% of PROMACTA-treated patients and 0.4% of placebo-treated patients.

Severe Aplastic Anemia:

First-Line Treatment of Severe Aplastic Anemia

The safety of PROMACTA was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, PROMACTA was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies (14.3)]. Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of PROMACTA, h-ATG, and cyclosporine at the recommended dose and schedule.

In this cohort, PROMACTA was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to PROMACTA in this cohort was 183 days with 70% of patients exposed for > 24 weeks.

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

Table 12. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Adverse Reaction

PROMACTAn = 92(%)

ALT increased

29

AST increased

17

Blood bilirubin increased

17

Rash

8

Skin discoloration, including hyperpigmentation

5

In the PROMACTA D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13).

New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the PROMACTA D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively.

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

Pediatric Patients

A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the PROMACTA D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with PROMACTA were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%).

Cytogenetic Abnormalities

In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the PROMACTA D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with PROMACTA.

Refractory Severe Aplastic Anemia

In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received PROMACTA. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache.

Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia

Adverse Reaction

PROMACTA

n = 43

(%)

Nausea

33

Fatigue

28

Cough

23

Diarrhea

21

Headache

21

Pain in extremity

19

Pyrexia

14

Dizziness

14

Oropharyngeal pain

14

Abdominal pain

12

Muscle spasms

12

Transaminases increased

12

Arthralgia

12

Rhinorrhea

12

Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients.

In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients.

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.

RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.

Medication Sections

Medication Information by RSS

As a leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. RxDrugLabels.com provides the full prescription-only subset of the FDA's repository. Medication information provided here is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.