ph-99991075
print Print Back Back

Thrombopoietin Receptor Agonists Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-99991075

Nplate is listed for information purpose only and is not targeted in the program.

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.

Thrombopoietin Receptor Agonists Prior Authorization with Quantity Limit

TARGET AGENT(S)

Doptelet® (avatrombopag)

Mulpleta® (lusutrombopag)

Nplate® (romiplostim)

Promacta® (eltrombopag)

Tavalisse™ (fostamatinib disodium)

Brand (generic)

GPI

Multisource Code

Quantity Limit (per day or as listed)

Doptelet (avatrombopag) oral tablet

   20 mg tablet

82405010200320

M, N, O, or Y

2 tablets

Mulpleta (lusutrombopag) oral tablet

   3 mg tablet

82405045000320

M, N, O, or Y

7 tablets/ 7 days

Nplate (romiplostim) subcutaneous injection

125 mcg single-use vial

82405060002110

M, N, O, or Y

Max 10 mcg/kg/week

250 mcg single-use vial

82405060002120

M, N, O, or Y

Max 10 mcg/kg/week

500 mcg single-use vial

82405060002130

M, N, O, or Y

Max 10 mcg/kg/week

Promacta (eltrombopag) oral suspension

12.5 mg packet for suspension

82405030103030

M, N, O, or Y

1 pack

25 mg powder for suspension

82405030103020

M, N, O, or Y

1 pack

Promacta (eltrombopag) oral tablet

12.5 mg tablet

82405030100310

M, N, O, or Y

1 tablet

25 mg tablet

82405030100320

M, N, O, or Y

1 tablet

50 mg tablet

82405030100330

M, N, O, or Y

2 tablets

75 mg tablet

82405030100340

M, N, O, or Y

2 tablets

Tavalisse (fostamatinib disodium hexahydrate)

100 mg tablet

85756040100310

M, N, O, or Y

2 tablets

150 mg tablet

85756040100320

M, N, O, or Y

2 tablets

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL

Initial Evaluation

Target Agent(s) will be approved when the ALL of the following are met:

  1. ONE of the following:
        1. The requested agent is Doptelet AND ONE of the following:
  1. The patient has a diagnosis of chronic (defined as lasting for at least 12 months) immune (idiopathic) thrombocytopenia (ITP) AND ALL of the following:
              1. ONE of the following:
  1. The patient has a platelet count ≤ 30 X 109/L

OR

  1. The patient has a platelet count > 30 X 109/L but < 50 X 109/L AND has symptomatic bleeding and/or an increased risk for bleeding

AND

  1. ONE of the following:
    1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP

OR

    1. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP

OR

    1. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP

OR

    1. The patient has tried and had an inadequate response to another thrombopoietin receptor agonist (e.g., Mulpleta, Nplate, Promacta, Tavalisse)

OR

    1. The patient has tried and had an inadequate response to immunoglobulins (IVIg or Anti-D)

OR

    1. The patient has had an inadequate response to a splenectomy

OR

    1. The patient has tried and had an inadequate response to rituximab

OR

  1. The patient has a diagnosis of thrombocytopenia and has chronic liver disease AND ALL of the following:
              1. The patient has a platelet count < 50 X 109/L

AND

              1. The patient is scheduled to undergo a procedure with an associated risk of bleeding (e.g., gastrointestinal endoscopy, liver biopsy, bronchoscopy, dental procedure)

AND

  1. The patient would require a platelet transfusion unless platelet counts are clinically increased from baseline

OR

  1. The patient has another FDA approved indication for the requested agent

OR

  1. The requested agent is Mulpleta (lusutrombopag) AND ONE of the following:
            1. The patient has a diagnosis of thrombocytopenia and has chronic liver disease AND BOTH of the following:
              1. The patient is scheduled to undergo a procedure with an associated risk of bleeding (e.g., gastrointestinal endoscopy, liver biopsy, bronchoscopy, dental procedure)

AND

              1. The patient would require a platelet transfusion unless platelet counts are clinically increased from baseline

OR

      1. The patient has another FDA approved indication for the requested agent

OR

  1. The requested agent is Nplate (romiplostim) AND ONE of the following:
            1. The patient has a diagnosis of hematopoietic syndrome of acute radiation syndrome (HS-ARS)

OR

            1. The patient has a diagnosis of immune (idiopathic) thrombocytopenia (ITP) AND ALL of the following:
  1. ONE of the following:
          1. The patient is between the ages of 1 and 17 years old AND the diagnosis has lasted for at least 6 months

OR

    1. The patient is 18 years old or over

AND

  1. ONE of the following:
          1. The patient has a platelet count ≤ 30 X 109/L

OR 

          1. The patient has a platelet count > 30 X 109/L but < 50 x 109/L AND has symptomatic bleeding and/or an increased risk for bleeding

AND

  1. ONE of the following:
    1. The patient has had an inadequate response to ONE corticosteroid used for the treatment of ITP

OR

    1. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP

OR

    1. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP

OR

    1. The patient has tried and had an inadequate response to immunoglobulins (IVIg or anti-D)

OR

    1. The patient has had an inadequate response to a splenectomy

OR

    1. The patient has tried and had an inadequate response to rituximab

OR

  1. The patient has another FDA approved indication for the requested agent

OR

  1. The requested agent is Promacta (eltrombopag) AND ONE of the following:
            1. The patient has a diagnosis of hepatitis C associated thrombocytopenia AND ONE of the following:
              1. The intent of therapy with the requested agent is to increase platelet counts sufficiently to initiate pegylated interferon therapy AND the patient’s platelet count is < 75 x 109/L

OR

              1. The patient is on concurrent therapy with a pegylated interferon and ribavirin AND is at risk for discontinuing hepatitis C therapy due to thrombocytopenia

OR

            1. The patient has a diagnosis of severe aplastic anemia AND ALL of the following:
              1. The patient has at least 2 of the following blood criteria:
  1. Neutrophils less than 0.5 X 109/L
  2. Platelets less than 20 X 109/L
  3. Reticulocytes less than 1% corrected [percentage of actual hematocrit (Hct) to normal Hct] or reticulocyte count < 20 X 109/L

AND

              1. The patient has 1 of the following marrow criteria:
  1. Severe hypocellularity: < 25%

OR

  1. Moderate hypocellularity, 25-50% with hematopoietic cells representing less than 30% of residual cells

AND

              1. ONE of the following:
    1.  BOTH of the following:
      1. The patient will use the requested agent as first-line treatment

AND

      1. The patient will use the requested agent in combination with standard immunosuppressive therapy [i.e. antithymocyte globulin (ATG) AND cyclosporine]

OR

    1. ONE of the following:
      1. The patient has tried and had an inadequate response to BOTH antithymocyte globulin (ATG) AND cyclosporine therapy

OR

      1. The patient has an intolerance or hypersensitivity to BOTH ATG AND cyclosporine

OR

      1. The patient has an FDA labeled contraindication to BOTH ATG AND cyclosporine

OR

  1. The patient has a diagnosis of chronic (defined as lasting for at least 12 months) immune (idiopathic) thrombocytopenia (ITP) AND BOTH of the following:
  1. ONE of the following:
          1. The patient has a platelet count ≤ 30 x 109/L

OR

          1. The patient has a platelet count > 30 x 109/L but < 50 x 109/L AND has symptomatic bleeding and/or an increased risk for bleeding

AND

  1. ONE of the following:
  1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP

OR

  1. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP  

OR

  1. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP

OR

  1. The patient has tried and had an inadequate response to immunoglobulins (IVIg or anti-D)

OR

  1. The patient has had an inadequate response to a splenectomy

OR

  1. The patient has tried and had an inadequate response to rituximab

OR

  1. The patient has another FDA approved indication for the requested agent

OR

  1. The requested agent is Tavalisse (fostamatinib disodium hexahydrate) AND ONE of the following:
  1. The patient has a diagnosis of chronic (defined as lasting for at least 12 months) immune (idiopathic) thrombocytopenia (ITP) AND ALL of the following:
      1. ONE of the following;
          1. The patient has a platelet count ≤ 30 X 109/L

OR

    1. The patient has a platelet count > 30 X 109/L but < 50 x 109/L AND has symptomatic bleeding and/or an increased risk for bleeding

AND

        1. ONE of the following:
          1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP

OR

  1. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP

OR

  1. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP

OR

  1. The patient has tried and had an inadequate response to another thrombopoietin receptor agonist (e.g., Mulpleta, Nplate, Promacta, Tavalisse)

OR

  1. The patient has tried and had an inadequate response to immunoglobulins (IVIg or Anti-D)

OR

  1. The patient has had an inadequate response to a splenectomy

OR

  1. The patient has tried and had an inadequate response to rituximab

OR

  1. The patient has another FDA approved indication for the requested agent

AND

  1. ONE of the following:
                1. The patient’s age is within FDA labeling for the requested indication for the requested agent

OR

                1. The prescriber has provided information in support of using the requested agent for the patient’s age

AND

  1. ONE of the following:
  1. The requested agent is Nplate AND the patient has a diagnosis of hematopoietic syndrome of acute radiation syndrome (HS-ARS)

OR

  1. The patient will NOT use the requested agent in combination with another thrombopoietin receptor agonist agent included in this program

AND

  1. The patient does NOT have any FDA labeled contraindications to the requested agent

AND

  1. ONE of the following:
  1. The requested quantity (dose) does NOT exceed the program quantity limit

OR

  1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

AND

      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication

AND

      1. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the limit

OR

  1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

AND

      1. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication

AND

      1. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Initial Lengths of Approval:

Doptelet

ITP

6 months

Thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure

1 month

Another FDA approved indication

6 months

Mulpleta

Thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure

1 month

Another FDA approved indication

6 months

Promacta

ITP

2 months

Thrombocytopenia in Hep C

3 months

First-Line therapy in severe aplastic anemia

6 months

All other severe aplastic anemia

4 months

Another FDA approved indication

6 months

Nplate

HS-ARS

1 time

ITP

4 months

Another FDA approved indication

6 months

Tavalisse

ITP

4 months

Another FDA approved indication

6 months

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

            1.  

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process. Note: Doptelet and Mulpleta for thrombocytopenia with chronic liver disease AND Nplate for hematopoietic syndrome of acute radiation syndrome (HS-ARS) should always be reviewed under initial criteria

AND

  1. ONE of the following:
    1. The patient has a diagnosis of immune (idiopathic) thrombocytopenia (ITP) AND ONE of the following:
  1. The patient’s platelet count is ≥ 50 x 109/L

OR

  1. The patient’s platelet count has increased sufficiently to avoid clinically significant bleeding

OR

    1. The patient has the diagnosis of hepatitis C associated thrombocytopenia AND BOTH of the following:
  1. ONE of the following:
        1. The patient will be initiating hepatitis C therapy with pegylated interferon and ribavirin

OR

  1. The patient will be maintaining hepatitis C therapy with pegylated interferon and ribavirin

AND

  1. ONE of the following:
  1. The patient’s platelet count is ≥ 90 x 109/L

OR

  1. The patient’s platelet count has increased sufficiently to initiate or maintain pegylated interferon based therapy for the treatment of hepatitis C

OR

    1. The patient has the diagnosis of severe aplastic anemia AND ONE of the following:
  1. BOTH of the following:
        1. The patient will use the requested agent in combination with standard immunosuppressive therapy (i.e., antithymocyte globulin (ATG) and cyclosporine) for the first-line treatment of severe aplastic anemia

AND

  1. The patient has had a response by 6 months defined as meeting TWO of the following values on 2 consecutive serial blood count measurements at least 1 week apart:
        1. An absolute neutrophil count (ANC) greater than 500/mcL

OR

        1. Platelet count greater than 20 x 109/L

OR

        1. Reticulocyte count greater than 60,000/mcL

OR

      1. The patient is will NOT use the requested agent in combination with standard immunosuppressive therapy AND has had a hematological response by week 16 defined as ONE of the following:
              1. Platelet count increased at least 20 x 109/L above baseline

OR

              1. Stable platelet counts with transfusion independence for a minimum of 8 weeks

OR

  1. Hemoglobin increased by greater than 1.5 g/dL

OR

  1. Reduction in greater than or equal to 4 units of Red Blood Cell (RBC) transfusions for 8 consecutive weeks

OR

  1. An Absolute Neutrophil Count (ANC) increase of 100%

OR

  1. An Absolute Neutrophil Count (ANC) increase greater than 0.5 x 109/L

OR

    1. The patient has another FDA approved indication for the requested agent AND has shown clinical improvement (i.e., decreased symptom severity and/or frequency)

AND

  1. The patient will NOT use the requested agent in combination with another thrombopoietin receptor agonist agent included in this program

AND

  1. The patient does NOT have any FDA labeled contraindications to the requested agent

AND

  1. ONE of the following:
  1. The requested quantity (dose) does NOT exceed the program quantity limit

OR

  1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

AND

      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication

AND

      1. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the limit

OR

  1. ALL of the following:
            1. The requested quantity (dose) is greater than the program quantity limit

AND

            1. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication

AND

            1. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Renewal Lengths of approval: 

ITP

12 months

Severe aplastic anemia

12 months

Another FDA approved indication for the requested agent

12 months

Thrombocytopenia in hepatitis C

6 months

FDA APPROVED INDICATIONS AND DOSAGE1-5

Agent(s)

Indication(s)

Dosage

Doptelet® (avatrombopag)

Tablet

Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure

● Treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous therapy

Patients with chronic liver disease:

Platelet count less than 40 X 109/L:

60 mg (3 tablets) orally once daily for 5 days

Platelet count 40 to less than 50 X 109/L:

40 mg (2 tablets) orally once daily for 5 days

Chronic immune thrombocytopenia:

Begin Doptelet at a starting dose of 20 mg daily. After initiating therapy with Doptelet, assess platelet counts weekly until a stable platelet count of 50 X 109/L has been achieved, and then obtain platelet counts monthly thereafter. Dose adjustments are based on platelet counts (see prescribing information for information). Do not exceed a daily dose of 40 mg (2 tablets)

Mulpleta® (lusutrombopag)

Tablet

Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure

Patients with chronic liver disease:

3 mg (1 tablet) orally once daily for 7 days

Nplate® (romiplostim)

Injection for subcutaneous use

● Treatment of thrombocytopenia in adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy

● Treatment of thrombocytopenia in pediatric patients 1 year of age and older with ITP for at least 6 months, who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy

● Increase survival in adults and in pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [HS-ARS])

Limitations of Use:

  • Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than ITP

  • Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding
  • Nplate should not be used in an attempt to normalize platelet counts

ITP:

Initial dose of 1 mcg/kg once weekly as a subcutaneous injection.  Adjust weekly dose by increments of 1 mcg/kg to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding 

Do not exceed the maximum weekly dose of 10 mcg/kg

Do not dose if platelet count is > 400 x 109/L 

Discontinue romiplostim if platelet count does not increase after 4 weeks at the maximum dose. After platelet count has fallen to ≤ 200 x 109/L, resume romiplostim at a dose reduced by 1 mcg/kg

HS-ARS

10 mcg/kg administered once as a subcutaneous injection. Administer the dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy)

Administer Nplate regardless of whether a complete blood count (CBC) can be obtained

Promacta® (eltrombopag)

Tablet

Powder for oral suspension

● For the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune 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

● 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

● In combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia

● 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 syndrome (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 ITP:

 Initiate at 50 mg once daily for most adult and pediatric patients 6 years and older and at 25 mg once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 109/L. Do not exceed 75 mg per day. Discontinue Promacta for ITP if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum daily dose of 75 mg.

Chronic Hepatitis C-associated Thrombocytopenia:

Initiate at 25 mg once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg.

First-line therapy for severe aplastic anemia:

Patients 12 years and older:

150 mg once daily for 6 months

Pediatric patients 6 to 11 years:

75 mg once daily for 6 months

Pediatric patients 2 to 5 years:

2.5 mg/kg once daily for 6 months

Severe Aplastic Anemia after insufficient response to immunosuppressive therapy:

Initiate at 50 mg once daily for most patients. Reduce initial dose in patients with hepatic impairment or patients of East Asian ancestry. Adjust to maintain platelet count greater than 50 x 109/L. Do not exceed 150 mg per day.

Tavalisse™ (fostamatinib disodium hexahydrate)

Tablet

● Treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment

● 100 mg orally twice daily. After a month, if platelet count has not increased to at least 50 X 109/L, increase dose to 150 mg twice daily

CLINICAL RATIONALE

Immune (Idiopathic) Thrombocytopenia

Immune (idiopathic) thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a low platelet count resulting from platelet destruction and impaired platelet production. ITP can be an isolated primary condition, or it may be secondary to other conditions. The goal of all treatment strategies for ITP is to achieve a platelet count that is associated with adequate hemostasis, rather than a normal platelet count. Bleeding events are often unpredictable and patients with ITP, even in the setting of severe thrombocytopenia, may not exhibit bleeding beyond bruising and petechiae. However, more serious mucosal bleeding may occur, including menorrhagia, epistaxis, gastrointestinal hemorrhage, hematuria, or, rarely, intra-cranial hemorrhage. The decision as to whether a patient can be observed or requires further intervention is highly complex and varies based on comorbidities, medications, and age, which all impact the risk of bleeding. In addition, management approaches may vary based on disease duration, access to care, quality-of-life implications, and patient and provider preferences, among other factors. An International Working Group consensus panel defines ITP as newly diagnosed (diagnosis to 3 months), persistent (3-12 months from diagnosis), or chronic (lasting for more than 12 months).6

National Institute for Health and Care Excellence (NICE) guidelines issued in 2011 and updated in 2014 recommend romiplostim as an option for treating adults with chronic ITP who have had a splenectomy and whose condition is refractory to other treatments, or as second-line treatment in adults who have not had a splenectomy because surgery is contraindicated. These guidelines also state that romiplostim should only be recommended to patients if their condition is refractory to standard treatments and rescue therapies, or if they have severe disease with a high risk of bleeding requiring frequent courses of rescue therapies.7 

The American Society of Hematology (ASH) 2019 guidelines for immune thrombocytopenia separate treatments into adult and pediatric categories as well as initial vs secondary treatments in both groups.

In adults with newly diagnosed ITP and a platelet count of < 30 X 109/L who are asymptomatic or have minor mucocutaneous bleeding, ASH suggests corticosteroids rather than management with observation. There may be a subset of patients within this group for whom observation might be appropriate. This should include consideration of the severity of thrombocytopenia, additional comorbidities, use of anticoagulant or antiplatelet medications, need for upcoming procedures, and age of the patient.6

In adults with newly diagnosed ITP and a platelet count ≥ 30 X 109/L who are asymptomatic or have minor mucocutaneous bleeding, the ASH panel recommends against corticosteroids and in favor of management with observation. For patients with a platelet count at the lower end of this threshold, for those with additional comorbidities, anticoagulant or antiplatelet medications, or upcoming procedure, and for elderly (> 60 years old), treatment with corticosteroids may be appropriate.6

In adult patients with ITP for ≥ 3 months who are corticosteroid dependent or do not have a response to corticosteroids, the ASH panel suggests treatment with a thrombopoietin receptor agonist (the guidelines suggest either eltrombopag or romiplostim but also acknowledge no therapies available after 2017 were included in these guidelines), rituximab, or a splenectomy. The panel suggests use of a thrombopoietin receptor agonist over rituximab or a splenectomy and rituximab over a splenectomy. Each of these second-line treatments may be effective therapy and therefore the choice of treatment should be individualized based on duration of ITP, frequency of bleeding episodes requiring hospitalization or rescue medication, comorbidities, age of patient, medication adherence, medical and social support networks, patient values and preferences, cost, and availability.6

In children with newly diagnosed ITP who have non-life-threatening mucosal bleeding and/or diminished health related quality of life (HRQoL), the panel suggests corticosteroids over IVIG or anti-D immunoglobulin but does suggest that IVIG or anti-D immunoglobulin could be used in certain situations.6

In children with ITP who have non-life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment the ASH panel suggests the use of thrombopoietin receptor agonists over rituximab or splenectomy and rituximab over splenectomy.6

Given the impact of corticosteroids on mental health, the treating prescriber should assess HRQoL (e.g., depression, fatigue, mental status) while patients are receiving corticosteroids. Based on clinical experience, the ASH panel agreed there was likely trivial benefit in continuing corticosteroids in adults beyond 6 weeks. For the majority of patients, a trial of 6 weeks of corticosteroids should determine whether a patient is going to enter remission or will require additional therapy. For patients who require additional therapy, consideration of alternative therapy is preferred over ongoing exposure to corticosteroids. In children the ASH panel advises against courses of corticosteroids longer than 7 days.6

Recommendations from the 2011 ASH guidelines that were not prioritized to be addressed, discussed or updated by the 2019 guideline panel were as follows:6

  • First-line treatment of adult ITP:
  • IVIG with corticosteroids can be used when a more rapid increase in platelet count is required
  • Either IVIG or anti-D (in appropriate patients) be used as a first-line treatment if corticosteroids are contraindicated

 

Chronic Hepatitis C associated thrombocytopenia11

A number of studies have suggested an association between hepatitis C virus (HCV) infection and immune thrombocytopenia (ITP) and/or autoimmune hemolytic anemia, either as a consequence of interferon therapy or in the setting of chronic infection without therapy. One of the largest studies included 120,691 United States veterans with chronic HCV who were matched with 454,905 controls. HCV was associated with ITP in both treated and untreated patients (hazard ratio 1.8).

Severe Aplastic Anemia

The British Journal of Haematology guidelines for the diagnosis and management of adult aplastic anaemia define severe aplastic anemia as:10

At least 2 of the following blood criteria:

  • Neutrophils less than 0.5 X 109/L
  • Platelets less than 20 X 109/L
  • Reticulocytes less than 1% corrected (percentage of actual hematocrit [Hct] to normal Hct) or reticulocyte count <20 X 109/L

AND

1 of the following marrow criteria:

  • Severe hypocellularity: <25%
  • Moderate hypocellularity, 25-50% with hematopoietic cells representing less than 30% of residual cells

The standard treatment for aplastic anemia is immunosuppressive therapy with horse antithymocyte globulin (ATG) and cyclosporine, and hematologic responses are observed in about two thirds of patients. Patients with disease that is refractory to immunosuppression and those who have a relapse after treatment may undergo allogeneic hematopoietic stem-cell transplantation (HSCT). However, 20 to 40% of patients without a suitable donor for HSCT continue to have severe cytopenias and are at risk for life-threatening hemorrhage due to thrombocytopenia and severe infections due to neutropenia. No standard therapies are available for patients who have aplastic anemia that is refractory to immunosuppression and are ineligible for HSCT, other than transfusions and treatment of infections. More than 40% of patients with disease that is refractory to immunosuppression die from bleeding or infection within 5 years after diagnosis. Although readministration of immunosuppressive therapy has been effective as salvage therapy in some patients, intensification of the regimen with more potent agents, such as rabbit ATG, sirolimus, or mycophenolate, has not improved the response rate.8,9

Thrombocytopenia in liver disease12

Patients with acute and chronic liver disease frequently acquire unique changes in hemodynamic and hemostatic pathways that may result in life-threatening bleeding and thrombosis. Additionally, activation of hemostatic pathways may play a role in disease progression through prechymal extinction, or organ atrophy, recruitment of inflammatory cells and activation of stellate cells.

Traditional coagulation measures, including pro-thrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), and bleeding time (BT) do not measure bleeding risk in cirrhosis. In addition, platelet count alone provides an incomplete guide to bleeding risk in cirrhosis. However, values below 50,000/µL may be associated with a higher risk of bleeding.

Procedure-related bleeding is common in cirrhosis patients but estimates of incidence vary widely. For many years, the PT/INR served as a surrogate marker for estimating bleeding risk in cirrhosis. However, use of INR and arbitrary “cut-offs” as a clinical target is not recommended or supported by scientific evidence. Assessment of individual patient characteristics is also essential as clinical factors, such as acute kidney injury or infection may alter bleeding risk in certain clinical scenarios. In elective and planned settings, such as planned dental extractions or other invasive procedures with moderate or high risk, thrombopoietin receptor agonists are an alternative means to increase platelets prior to invasive procedures.

Hematopoietic syndrome of acute radiation syndrome

Acute radiation syndrome (ARS) (sometimes known as radiation toxicity or radiation sickness) refers to a spectrum of pathophysiological effects that are induced when high doses of ionizing radiation interact with the human body.13 The major cause of this syndrome is depletion of immature parenchymal stem cells in specific tissues. The required conditions for ARS are:14

  • The radiation dose must be large (i.e., greater than 0.7 Gray (Gy) or 70 rads)
  • Mild symptoms may be observed with doses as low as 0.3 Gy or 30 rads
  • The dose usually must be external (i.e., the source of radiation is outside of the patient’s body)
  • Radioactive materials deposited inside the body have produced some ARS effects only in extremely rare cases
  • The radiation must be penetrating (i.e., able to reach internal organs)
  • High energy X-rays, gamma rays, and neutrons are penetrating radiations
  • The entire body (or a significant portion of it) must have received the dose
  • Most radiation injuries are local, frequently involving the hands, and these local injuries seldom cause classical signs of ARS
  • The dose must have been delivered in a short time (usually a matter of minutes)
  • Fractionated doses are often used in radiation therapy. These are large total doses delivered in small daily amounts over a period of time. Fractionated doses are less effective at inducing ARS than a single dose of the same magnitude

The four classic ARS syndromes are hematopoietic syndrome, gastrointestinal (GI) syndrome, cardiovascular (CV) syndrome, and central nervous system (CNS) syndrome. Of the 4, the hematopoietic syndrome is the only one that may be reversed through medical intervention.13

The full syndrome of hematopoietic syndrome will usually occur with a dose between 0.7 and 10 Gy (70-1000 rads) though mild symptoms may occur as low as 0.3 Gy or 30 rads. The survival rate of patient with bone marrow syndrome decreases with increasing dose. The primary cause of death is the destruction of the bone marrow resulting in infection and hemorrhage.14

Efficacy

Doptelet1

Doptelet (avatrombopag) is a thrombopoietin receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets.

The efficacy of Doptelet for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was established in 2 identically-designed multicenter, randomized, double-blind, placebo-controlled trials (ADAPT-1 and ADAPT-2). In each study, patients were assigned to the low baseline platelet count cohort (<40 X 109L) or high baseline platelet count cohort (≥ 40 to < 50 X 109L) based on their platelet count at baseline.

In the ADAPT-1 trial 149 patients were treated with Doptelet and 82 patients were treated with placebo both once daily for 5 days. In the ADAPT-2 trial, 128 patients were treated with Doptelet and 76 patients were treated with placebo.  Across both baseline platelet count cohorts and the Doptelet and placebo treatment groups, patients underwent a broad spectrum of types of scheduled procedures that ranged from low to high bleeding risk.

The major efficacy outcome in both trials was the proportion of patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure. Additional secondary efficacy outcomes were the proportion of patients who achieved platelet counts of ≥ 50 X 109L on the day of procedure and the change in platelet count from baseline to procedure day.

Responders were defined as patients who did not require a platelet transfusion or any rescue procedure (whole blood transfusion, packed red blood cell transfusion, platelet transfusion, fresh frozen plasma or cryoprecipitate administration, Vitamin K, desmopressin, recombinant activated factor VII, aminocaproic acid, tranexamic acid, or surgical or interventional radiology performed to achieve hemostasis and control blood loss) for bleeding after randomization and up to 7 days following a scheduled procedure. In both baseline platelet count cohorts, patients in the Doptelet treatment groups had a greater proportion of responders than the corresponding placebo treatment groups that was both clinically meaningful and statistically significant.

The percentage of responders in the low baseline platelet count cohort and treatment group that responded in the ADAPT-1 trial was 66% in the Doptelet group and 23% in the placebo group (p-value <0.0001). In the Adapt-2 trial the percentage of responders was 69% in the Doptelet group and 35% in the placebo group (p-value 0.0006).

The percentage of responders in the high baseline platelet count cohort in ADAPT-1 trial was 88% in the Doptelet group and 38% in the placebo group (p-value <0.0001). In the ADAPT-2 trial the percentage of responders was 88% in the Doptelet group and 33% in the placebo group (p-value <0.0001).

Both trials also demonstrated a higher proportion of patients who achieved the target platelet count of ≥ 50 X 109L on the day of the procedure (a secondary efficacy endpoint) and a greater mean change in platelet counts from baseline to the day of the procedure (a secondary efficacy endpoint).

The efficacy of Doptelet in adult patients with chronic immune thrombocytopenia was evaluated in a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT01438840). Patients had received one or more chronic immune thrombocytopenia therapies and had an average platelet count of 30 X 109/L. The major efficacy outcome was the cumulative number of weeks in which the platelet count was ≥ 50 X 109/L during the 6-month treatment period in the 6-month treatment period in the absence of rescue therapy. Doptelet-treated patients had a longer duration of platelet counts ≥50 x109 /L in the absence of rescue therapy than those who received placebo (median 12.4 [0, 25] vs 0 [0, 2] weeks, respectively, p<0.0001. In addition, a larger proportion of patients in the Doptelet treatment group had platelet counts ≥ 50 X 109/L at Day 8 compared to placebo (21/32; 66% vs 0/17; 0.0%, respectively; p<0.0001).

Mulpleta2

Mulpleta (lusutrombopag) is an orally bioavailable TPO receptor agonist that interacts with the transmembrane domain of human TPO receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation.

The efficacy of Mulpleta for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was evaluated in 2 randomized, double-blind, placebo-controlled trial (L-PLUS 1 and L-PLUS 2). Patients with chronic liver disease who were undergoing an invasive procedure and had a platelet count less than 50 X 109/L were eligible to participate. Patients were randomized to receive 3 mg of Mulpleta or placebo once daily for up to 7 days.

In L-PLUS 1 the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure. In L-PLUS 2 the major efficacy outcome was the proportion of patients who required no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding (i.e., platelet preparations, other blood preparations, including red blood cells and plasma, volume expanders) from randomization through 7 days after the primary invasive procedure. In both the L-PLUS 1 and L-PLUS 2 trials, responders were defined as patients who had a platelet count of ≥ 50 X 109/L with an increase of ≥ 20 X 109/L from baseline.

In the L-PLUS 1 trial the percentage of patients not requiring platelet transfusion prior to invasive procedure was 78% in the Mulpleta arm and 13% in the placebo arm (95% CI, P-value <0.0001).  The percentage of patients that responded during the study was 76% in the Mulpleta arm and 6% in the placebo arm (95%CI, p-value <0.001).

In the L-Plus 2 trial the percentage of patients not requiring platelet transfusion prior to invasive procedure or rescue therapy for bleeding from randomization through 7 days after invasive procedure was 65% in the Mulpleta arm and 29% in the placebo arm (95% CI, P-value <0.0001).  The percentage of patients that responded during the study was 65% in the Mulpleta arm and 13% in the placebo arm (95%CI, p-value <0.001).

Nplate3

Nplate (romiplostim) is a thrombopoietin receptor agonist that increases platelet production through binding and activation of the thrombopoietin (TPO) receptor, similar in mechanism to endogenous TPO.

 

The safety and efficacy of Nplate were assessed in two double-blind, placebo-controlled clinical studies, in an open-label single-arm study, and in an open-label extension study. Efficacy in all studies was defined as maintaining a target platelet count ≥ 50 X 109/L.

The safety and efficacy of Nplate in pediatric patients 1 year and older with ITP for at least 6 months were assessed in two double-blind, placebo controlled clinical trials. The efficacy in both studies was defined as maintaining a target platelet count of ≥ 50 X 109/L.

Efficacy studies of Nplate could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval for this indication was based on efficacy studies conducted in animals, Nplate’s effect on platelet count in healthy human volunteers, and on data supporting Nplate’s effect on thrombocytopenia in patients with ITP and insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Promacta4

Promacta (eltrombopag) interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production.

Safety and efficacy of Promacta in adult patient with chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. Safety and efficacy of Promacta in pediatric patients 1 year and older with chronic ITP were evaluated in two double-blind, placebo-controlled trials. All of these trials showed clinically significant efficacy of Promacta vs placebo.

Safety and efficacy of Promacta was evaluated in 2 randomized, double-blind, placebo-controlled trials for eltrombopag in treating thrombocytopenia in patients with chronic hepatitis C. One trial used peginterferon alfa-2a (Pegasys); the other used peginterferon alfa-2b (Pegintron), both were in combination with ribavirin. Approximately 30% of patients had been previously treated with interferon and ribavirin.  Patients had to have platelet counts of <75 x109/L.  The trials consisted of 2 phases: a pre-antiviral treatment phase and an antiviral treatment phase.  Patients were allowed to be randomized for the antiviral treatment phase if they reached the platelet count threshold of ≥ 90 X 109/L (trial 1) and ≥100 x 109/L (trial 2). The maximum allowed time on open label eltrombopag was 9 weeks.  The primary efficacy endpoint for both studies was sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment.  The median time to achieve the target platelet count in study 1 was approximately 2 weeks with 95% of patients initiating antiviral therapy.

The safety of Promacta as first-line treatment of severe aplastic anemia was established based on 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. The efficacy of Promacta in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) >1,000/μL, platelet count > 100 X 109/L, and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/μL, platelet count > 20 X 109/L, or reticulocyte count > 60,000/μL. Overall response rate is defined as the number of partial responses plus complete responses. The overall response rate at month 6 was 79% (95% CI). The median duration of overall response was 70 months (95% CI). The median duration of complete response was 46 months (95% CI).

Promacta was studied in a single-arm, single-center, open-label trial in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count of less than or equal to 30 X 109/L. The efficacy was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 X 109/L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 X 109/L Promacta was discontinued after 16 weeks if no hematologic response was observed. The response rate was 40% (95% CI) and the median of duration of response was not reached due to few events.

Tavalisse5

Tavalisse (fostamatinib) is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase.

Tavalisse was studied in two placebo-controlled efficacy and safety studies (FIT-1 and FIT-2), and an open-label extension study (FIT-3).

A total of 150 patients with persistent or chronic immune thrombocytopenia, who had an insufficient response to previous treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries. For each study, patients were randomized to receive Tavalisse or placebo for 24 weeks. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in the open-label extension study. The efficacy of Tavalisse was based on stable platelet response (at least 50 X 109/L on at least 4 of the 6 visits between weeks 14 to 24).

The percent of patients who had a stable platelet response was 16-18% in the Tavalisse arms and 0-1% in the placebo arms.

The FIT-3 extension study enrolled 123 patients who completed 24 weeks of treatment in the FIT-1 and FIT-2 studies, or who did not respond to treatment any time after 12 weeks in these studies. Patients who were designated as responders in the FIT-1 and FIT-2 studies (defined as platelet count of at least 50 X 109/L) at the time of rollover continued in the extension study at their current trial dose and regimen. Patients who entered the extension study as non-responders (defined as platelet count less than 50 X 109/L) received Tavalisse 100 mg twice daily regardless of their dose and regimen in the prior study. Stable response in this study was prospectively defined as no 2 visits, at least 4 weeks apart, with a platelet count less than 50 X 109/L, without an intervening visit with a platelet count of at least 50 X 109/L (unrelated to rescue therapy), within a period of 12 weeks following initial achievement of the target platelet count.

Among the patients who achieved stable response in FIT-1, FIT-2, and FIT-3 trials, 18 patients maintained the platelet count of at least 50 X 109/L for 12 months or longer.

Safety1-5

  • All of the targeted agents have no FDA labeled contraindications

REFERENCES

  1. Doptelet prescribing information. Dova Pharmaceuticals, Inc. August 2020.
  2. Mulpleta prescribing information. Shionogi Inc. July 2018.
  3. Nplate prescribing information. Amgen. January 2021.
  4. Promacta prescribing information. Novartis. April 2020.
  5. Tavalisse prescribing information. Rigel Pharmaceuticals, Inc. April 2018.
  6. Neunert C, Terrell DR, Arnold DM, et al.  The American Society of Hematology 2019 guidelines for immune thrombocytopenia.  Blood 2019; volume 3 number 23: 3829-3866.
  7. National Institute for Health and Care Excellence (2014): Romiplostim for the treatment of chronic immune (idiopathic) thrombocytopenic purpura.
  8. Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia. N Engl J Med 2012; 367:11-19July 5, 2012DOI: 10.1056/NEJMoa1200931. http://www.nejm.org/doi/full/10.1056/NEJMoa1200931#t=articleTop.
  9. http://www.nejm.org/doi/full/10.1056/NEJMoa1103975. Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia.
  10. Killick SB, Brown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. British Journal of Haematology, 2016. 172, 187-207.
  11. Chiao EY, Engles EA,Kramer JR, et al. Risk of Immune Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia among 120,908 US veterans with Hepatitis C virus Infection. Arch Intern Med. 2009 Feb 23;169(4):357-363.
  12. Intagliata NM, Argo CK, Stein JG, et al. Concepts and controversies in Haemostasis and Thrombosis Associated with Liver Disease: Proceedings of the 7th International coagulation in Liver Disease conference. Thromb Haemost. 2018 Aug; 118(8): 1491-1506.
  13. Johns Hopkins Bloomberg School of Public Health. Center for Health Security. Clinicians’ Biosecurity News. Analysis of Advanced and Challenges in Clinical Biosecurity. April 2011.
  14. CDC Centers for Disease Control and Prevention. Radiation Emergencies. Acute Radiation Syndrome: A Fact Sheet for Clinicians. Accessed at: https://www.cdc.gov/nceh/radiation/emergencies/arsphysicianfactsheet.htm

 

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
 
The purpose of pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
 
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

ALBP_PS_Thrombopoietin_Receptor_Agonists_PAQL_ProgSum_AR0521