Promacta

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.
• 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.

For Oral Suspension

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

Storage And Handling

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 0078-0684-15.
• 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 0078-0685-15.
• 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 0078-0686-15.
• 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 0078-0687-15.
• The 100-mg tablets are round, biconvex, green, film-coated tablets debossed with GS 1L5 and are available in bottles of 30: NDC 0078-0688-15. 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). Do not remove desiccant if present. Dispense in original bottle.

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 0078-0697-61) contains 30 packets: NDC 0078-0697-19.

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). 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). Throw away (discard) the mixture if not used within 30 minutes.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: Oct 2017

Treatment Of Thrombocytopenia In Patients With Chronic ITP

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

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. 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.

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.

Limitations Of Use

• PROMACTA is not indicated for the treatment of patients with myelodysplastic syndromes (MDS).
• Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.

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. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting PROMACTA and decreased within 1 to 2 weeks after discontinuing PROMACTA.

Initial Dose Regimen

Adult and Pediatric Patients 6 Years and Older with ITP

Initiate PROMACTA at a dose of 50 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 25 mg once daily.

For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate PROMACTA at a reduced dose of 25 mg once daily.

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 12.5 mg once daily.

Pediatric Patients with ITP Aged 1 to 5 Years

Initiate PROMACTA at a dose of 25 mg once daily.

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 2 weeks, and then follow standard monthly monitoring.

Table 1. Dose Adjustments of PROMACTA in Patients with Chronic Immune (Idiopathic) Thrombocytopenia

In patients with ITP and hepatic impairment (Child-Pugh Class A, B, C), after initiating PROMACTA or after any subsequent dosing increase, wait 3 weeks before increasing the dose.

Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with 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 4 weeks of therapy with PROMACTA at the maximum daily dose of 75 mg.

Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of PROMACTA. Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of PROMACTA.

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

Initial Dose Regimen

Initiate PROMACTA at a dose of 25 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

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.

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 150 mg, and may take up to 16 weeks after starting PROMACTA.

Initial Dose Regimen

Initiate PROMACTA at a dose of 50 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 25 mg once daily.

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

For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of PROMACTA may be reduced by 50%. 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

f no hematologic response has occurred after 16 weeks of therapy with PROMACTA, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of PROMACTA. Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of PROMACTA.

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 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, 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). 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.

Do not crush tablets and mix with food or liquids.

Prepare the oral suspension with water only.

None.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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.

Hepatotoxicity

PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity. 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.

Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory values occurred approximately three months after initiation of PROMACTA. In all cases, the event resolved following PROMACTA discontinuation.

Increased Risk Of Death And Progression Of Myelodysplastic Syndromes (MDS) To Acute Myeloid Leukemia (AML)

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 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).

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.

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.

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

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:

Risks

Hepatotoxicity

• 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 PROMACTA with 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)

Risk of Bleeding Upon PROMACTA Discontinuation

• Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing PROMACTA, particularly if PROMACTA is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with PROMACTA, they should continue to avoid situations or medications that may increase the risk for bleeding.

Thrombotic/Thromboembolic Complications

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

Cataracts

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

Drug Interactions

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

Administration Of 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 .
• 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.

The following are registered trademarks of their respective owners: PEGASYS/Hoffmann-La Roche Inc.; PEGINTRON/Schering Corporation.

Nonclinical Toxicology

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 75 mg/kg/day or in rats at doses up to 40 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 100 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 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 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 100 mg/day).

Use In Specific Populations

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 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.

Eltrombopag was administered orally to pregnant rats at 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed.

Pregnant rabbits were treated with oral eltrombopag doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.

In a pre-and post-natal developmental toxicity study in pregnant rats (F0), no adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.

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.

Pediatric Use

The safety and efficacy of PROMACTA in pediatric patients 1 year and older with chronic ITP were evaluated in two double-blind, placebo-controlled trials. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily. See DOSAGE AND ADMINISTRATION for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of 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.

Geriatric Use

Of the 106 patients in two randomized clinical trials of PROMACTA 50 mg in chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. In the two randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while fewer than 1% were 75 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.

Hepatic Impairment

Hepatic impairment influences the exposure of PROMACTA.

Reduce the initial dose of PROMACTA in patients with chronic ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia who also have hepatic impairment (Child-Pugh Class A, B, C). No dosage adjustment is necessary for patients with chronic hepatitis C and hepatic impairment.

Renal Impairment

No adjustment in the initial dose of PROMACTA is needed for patients with renal impairment. Closely monitor patients with impaired renal function when administering PROMACTA.

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. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C.

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 AUC0INF 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 75 mg once daily was administered for 7 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-INF 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-INF 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-INF or Cmax to a significant extent.

Cyclosporine

In a drug interaction trial, coadministration of a single dose of PROMACTA 50 mg with a single dose of an OATP and BCRP inhibitor cyclosporine 200 mg in healthy adult subjects decreased plasma eltrombopag AUC0-INF by 18% (90% CI: 8%, 28%) and Cmax by 25% (90% CI: 15%, 35%). In the same clinical trial, coadministration of a single dose of PROMACTA 50 mg with a single dose of cyclosporine 600 mg in healthy adult subjects decreased plasma eltrombopag AUC0-INF by 24% (90% CI: 14%, 32%) and Cmax by 39% (90% CI: 30%, 47%).

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

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 BCRP.

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 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.

Eltrombopag was administered orally to pregnant rats at 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed.

Pregnant rabbits were treated with oral eltrombopag doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.

In a pre-and post-natal developmental toxicity study in pregnant rats (F0), no adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.

The following serious adverse reactions associated with PROMACTA are described in other sections.

• Hepatic Decompensation in Patients with Chronic Hepatitis C
• Hepatotoxicity
• Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia
• Thrombotic/Thromboembolic Complications
• Cataracts

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

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. The data described below reflect exposure of PROMACTA to patients with chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial. PROMACTA was administered to 330 patients for at least 6 months and 218 patients for at least 1 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

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 302 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

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. 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 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 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.

In clinical trials in patients with chronic ITP, one patient treated with PROMACTA (<1%) experienced drug-induced liver injury.

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.

Pediatric Patients

The data described below reflect median exposure to PROMACTA of 91 days for 107 pediatric patients (aged 1 to 17 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

In the two controlled clinical 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 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

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.

In clinical trials in patients with chronic hepatitis C, 11 patients treated with PROMACTA (1%) experienced drug-induced liver injury.

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 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 8. Adverse Reactions (≥10%) from One Open-label Trial in Adults with Severe Aplastic Anemia

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

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.

Skin and Subcutaneous Tissue Disorders: Skin discoloration including hyperpigmentation and skin yellowing.

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.

Absorption

Eltrombopag is absorbed with a peak concentration occurring 2 to 6 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-INF 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-INF 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-INF 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-INF 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-INF 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 Pglycoprotein (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 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.