Alvaiz

Treatment ofThrombocytopenia in Patients with Persistent or Chronic Immune Thrombocytopenia

ALVAIZ® (eltrombopag tablets) are indicated for the treatment of thrombocytopenia in adult and pediatric patients 6 years and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. ALVAIZ 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

ALVAIZ is indicated for the treatment of thrombocytopenia in adult patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. ALVAIZ 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 SevereAplastic Anemia

ALVAIZ is indicated for the treatment of adult patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.

Limitations of Use

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

Important DosageInformation

• 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 [see Dosage and Administration ].

Recommended Dosage for Persistent or Chronic ImmuneThrombocytopenia

Use the lowest dose of ALVAIZ 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 ALVAIZ to normalize platelet counts [see Warnings and Precautions ]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting ALVAIZ and decreased within 1 to 2 weeks after discontinuing ALVAIZ [see Clinical Studies ].

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 once daily [see Use in Specific Populations , Clinical Pharmacology ].

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 once daily [see Use in Specific Populations , Clinical Pharmacology ].

For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh Class A, B, C), consider initiating ALVAIZ at a reduced dose of 9 mg once daily [see Clinical Pharmacology ].

Monitoring and Dose Adjustment: After initiating ALVAIZ, 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 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.

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 also necessitate discontinuation of ALVAIZ [see Warnings and Precautions ]. Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of ALVAIZ.

Recommended Dosage for Chronic HepatitisC-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. Dose adjustments are based upon the platelet count response. Do not use ALVAIZ to normalize platelet counts [see Warnings and Precautions ]. In clinical trials, platelet counts generally began to rise within the first week of treatment with ALVAIZ [see Clinical Studies ].

Initial Dose Regimen: Initiate ALVAIZ at a dose of 18 mg orally once daily.

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 regularly throughout therapy with ALVAIZ.

For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information.

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.

ALVAIZ 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 ALVAIZ [see Warnings and Precautions ].

RecommendedDosage for Refractory Severe Aplastic Anemia

Use the lowest dose of ALVAIZ to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 108 mg, and may take up to 16 weeks after starting ALVAIZ [see Clinical Studies ].

Initial Dose Regimen: Initiate ALVAIZ at a dose of 36 mg orally once daily.

For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate ALVAIZ at a reduced dose of 18 mg once daily [see Use in Specific Populations , Clinical Pharmacology ].

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 109/L as necessary. Do not exceed a dose of 108 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 3.

For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of ALVAIZ may be reduced by 50% [see Clinical Studies ]. If counts remain stable after 8 weeks at the reduced dose, then discontinue ALVAIZ and monitor blood counts. If platelet counts drop to less than 30 x 109/L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 109/L, ALVAIZ may be reinitiated at the previous effective dose.

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 [see Adverse Reactions ]. Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of ALVAIZ [see Warnings and Precautions ].

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 [see Drug Interactions , Clinical Pharmacology ].

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

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 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

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.

In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis 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). 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.

In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at 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), 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.

Lactation

Risk Summary

There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment.

 Females and Males of Reproductive Potential

Contraception

Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using ALVAIZ during treatment and for at least 7 days after stopping treatment with ALVAIZ.

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 [see Adverse Reactions , Clinical Studies ]. The pharmacokinetics of eltrombopag have been established in 130 pediatric patients 6 years and older with ITP dosed once daily [see Clinical Pharmacology ]. See Dosage and Administration for dosing recommendations for pediatric patients 6 years and older.

The safety and effectiveness of ALVAIZ have not been established in pediatric patients less than 6 years of age with persistent or chronic ITP. Pediatric patients must be able to swallow ALVAIZ tablets whole [see Dosage and Administration ].

The safety and effectiveness in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established.

Geriatric Use

Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Hepatic Impairment

Patients with Persistent or Chronic ITP and Severe Aplastic Anemia

Reduce the initial dose of eltrombopag in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh Class A, B, C) [see Dosage and Administration , Warnings and Precautions , Clinical Pharmacology ].

In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate [see Dosage and Administration , Clinical Pharmacology ].

Patients with Chronic Hepatitis C

No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology ].

Ethnicity

Reduce the initial dose of ALVAIZ for patients of East- /Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or adults with severe aplastic anemia [see Dosage and Administration , Clinical Pharmacology ]. No reduction in the initial dose of ALVAIZ is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology ].