Alvaiz Drug Information

Important Dosage Information Eltrombopag is available for different indications and in different dosage forms and tablet strengths. ALVAIZ is not substitutable with other eltrombopag products on a milligram per milligram basis due to the observed bioavailability in studies conducted on ALVAIZ. Patients must be able to swallow ALVAIZ tablets whole.

Recommended Dosage for Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of ALVAIZ to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use ALVAIZ to normalize platelet counts.

Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP: Initiate ALVAIZ at a dose of 36 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate ALVAIZ at a reduced dose of 18 mg orally once daily. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate ALVAIZ at a reduced dose of 18 mg orally once daily.

Monitoring and Dose Adjustment: After initiating ALVAIZ, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 54 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with ALVAIZ and modify the dosage regimen of ALVAIZ based on platelet counts as outlined in Table 1.

During therapy with ALVAIZ, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. Table 1.

Dose Adjustments of ALVAIZ in Patients with Persistent or Chronic Immune Thrombocytopenia In patients with ITP and hepatic impairment (Child-Pugh Class A, B, C), after initiating ALVAIZ 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 ALVAIZ. Do not administer more than one dose of ALVAIZ within any 24-hour period.

Discontinuation: Discontinue ALVAIZ if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with ALVAIZ at the maximum daily dose of 54 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of ALVAIZ. Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of ALVAIZ.

Recommended Dosage for Chronic Hepatitis C-associated Thrombocytopenia Use the lowest dose of ALVAIZ to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. In clinical trials, platelet counts generally began to rise within the first week of treatment with ALVAIZ. Monitoring and Dose Adjustment: Adjust the dose of ALVAIZ in 18-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 ALVAIZ 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 72 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with ALVAIZ.

For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2. Dose Adjustments of ALVAIZ 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.

ALVAIZ should be discontinued when antiviral therapy is discontinued.

Recommended Dosage for Refractory Severe Aplastic Anemia Use the lowest dose of ALVAIZ to achieve and maintain a hematologic response. Hematologic response requires dose titration, generally up to 108 mg, and may take up to 16 weeks after starting ALVAIZ. Monitoring and Dose Adjustment: Adjust the dose of ALVAIZ in 36-mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary.

Do not exceed a dose of 108 mg daily. Table 3. Dose Adjustments of ALVAIZ in Patients with Refractory Severe Aplastic Anemia For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of ALVAIZ may be reduced by 50%.

If counts remain stable after 8 weeks at the reduced dose, then discontinue ALVAIZ and monitor blood counts. Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with ALVAIZ, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of ALVAIZ.

Administration Administration of Tablets: Take

ALVAIZ without a meal or with a meal low in calcium (≤ 50 mg). Take ALVAIZ 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. Swallow tablets whole.

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

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. The safety of ALVAIZ has been established based on adequate and well-controlled studies of eltrombopag olamine in adult and pediatric patients 6 years and older with persistent or chronic ITP, adult patients with chronic hepatitis C-associated thrombocytopenia, and adult patients with refractory severe aplastic anemia. Below is a display of the adverse reactions of eltrombopag olamine in these adequate and well-controlled studies.

Persistent or Chronic Immune Thrombocytopenia: Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications. The data described below reflect exposure of eltrombopag 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.

Table 4 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 4. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults with Persistent or Chronic Immune Thrombocytopenia 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 eltrombopag and in no patients who received placebo.

Among 302 patients with persistent or chronic ITP who received eltrombopag 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 eltrombopag) from the extension trial. Table 5.

Treatment-related Adverse Reactions (≥3%) From Extension Trial in Adults with Persistent or Chronic Immune Thrombocytopenia 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 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 eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities.

Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag 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 eltrombopag 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 eltrombopag.

Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients.

In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses. ALVAIZ is not indicated for pediatric patients <6 years of age with persistent or chronic ITP. 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 eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo.

Table 6. Adverse Reactions (≥ 3%) with a Higher Incidence for Eltrombopag Versus Placebo from Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older with Persistent or Chronic Immune Thrombocytopenia In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. 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 eltrombopag. Table 7 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 7.

Adverse Reactions (≥ 10% and Greater Than Placebo) from Two Placebo-controlled Trials in Adults with Chronic Hepatitis C was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag 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 eltrombopag and placebo, respectively.

ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag 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 eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 eltrombopag-treated patients).

Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia: Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. 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 Refractory Severe Aplastic 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of eltrombopag. 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. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing.

Polyvalent Cations (Chelation)

Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take ALVAIZ 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 ALVAIZ due to chelation.

Transporters

Use caution when concomitantly administering ALVAIZ and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38, valsartan) or breast cancer resistance protein (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 eltrombopag, a dose reduction of rosuvastatin by 50% was recommended.

Protease Inhibitors HIV Protease Inhibitors

No dose adjustment is recommended when ALVAIZ is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when ALVAIZ is coadministered with boceprevir or telaprevir.

Peginterferon Alfa-2a/b Therapy

No dose adjustments are recommended when ALVAIZ is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ).

Interference with Clinical Laboratory Tests Eltrombopag (ALVAIZ) is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing: Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient.

Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing: Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed.

Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking ALVAIZ. Re-testing using other methods may also help in determining the validity of the test results.

Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is respectively.

Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. 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.

No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. 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.

Pediatric Use The safety and effectiveness of ALVAIZ have been established in pediatric patients 6 years and older with persistent or chronic ITP. The safety and effectiveness of eltrombopag in pediatric patients 6 years and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The pharmacokinetics of eltrombopag have been established in 130 pediatric patients 6 years and older with ITP dosed once daily.

See Dosage and Administration for dosing recommendations for pediatric patients 6 years and older. Pediatric patients must be able to swallow ALVAIZ tablets whole. The safety and effectiveness in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established.

In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. 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 eltrombopag in accordance with dosing and administration recommendations. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.