Effective Date

Date of Origin   

10-01-2024           

Alvaiz™

(eltrombopag)

Tablet

• 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 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 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 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

16

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 previous treatment

1

Mulpleta®

(lusutrombopag)

Tablet  

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

2

Nplate®

(romiplostim)

Subcutaneous injection 

• 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

3

Promacta®

(eltrombopag)

Tablet

Powder for oral suspension

• Treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or 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
• 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
• 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

4

Tavalisse®

(fostamatinib)

Tablet 

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

5

ITP

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)

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.(6)

In adults with newly diagnosed ITP and a platelet count of less than 30 X 10^9/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 greater than or equal to 30 X 10^9/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 (greater than 60 years old), treatment with corticosteroids may be appropriate.(6)

In adult patients with ITP for greater than or equal to 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) can be used as a first-line treatment if corticosteroids are contraindicated

HCV associated thrombocytopenia

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).(11)

Aplastic anemia

Aplastic anemia (AA) is a diagnosis of exclusion. There is no single test that can be used to consistently diagnose AA from the multiple of other causes of bone marrow failure and the diagnostic evaluation must assess for and exclude these alterative etiologies. At initial presentation many patients exhibit fatigue, weakness, pallor, and headaches due to anemia. Often patients have petechiae of the skin and mucous membranes, epistaxis, and/or gum bleeding related to severe thrombocytopenia. Fever and infections can also be seen in these patients as a result of low white blood cell counts and neutropenia. AA patients identified earlier in the course of the disease by abnormalities found on routine laboratory testing may not have any physical manifestations of their disease.(15)

AA is further classified clinically by the severity of the depression of the peripheral blood counts. Severe AA is defined by a decrease in blood counts involving greater than or equal to 2 hematopoietic lineages (i.e., absolute reticulocyte count <60 x 10^9/L, absolute neutrophil count <0.5 X 10^9/L, platelet count <20 x 10^9/L) and bone marrow hypocellularity (<25% of the normal cellularity). Very severe AA has an absolute neutrophil count <0.2 x 10^9/L and moderate AA is characterized by the depression of blood counts not fulfilling the definition of severe disease.(15)

The British Journal of Haematology guidelines for the diagnosis and management of adult aplastic anaemia define severe aplastic anemia as severe hypocellularity <25% (or moderate hypocellularity of 25-50% with hematopoietic cells representing <30% of residual cells) and at least 2 of the following blood criteria: neutrophils <0.5 X 10^9/L, platelets <20 X 10^9/L, absolute reticulocyte level of <20 X 10^9/L.(10)

The standard treatment for AA 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.(8) No standard therapies are available for patients who have AA 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)

Thrombocytopenia in liver disease

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.(12)

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.(12)

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.(12)

Hematopoietic syndrome of ARS

Acute radiation syndrome (ARS) (sometimes known as radiation toxicity or radiation sickness) is an acute illness caused by irradiation of the entire body (or most of the body) by a high dose of penetrating radiation in a very short period of time (usually a matter of minutes). The major cause of this syndrome is depletion of immature parenchymal stem cells in specific tissues. The three classic ARS syndromes are hematopoietic syndrome, gastrointestinal (GI) syndrome, and cardiovascular (CV)/central nervous system (CNS) syndrome. Of the 3, the hematopoietic syndrome is the only one that may be reversed through medical intervention preventing death. 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)

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

Efficacy

Doptelet(1)

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 (less than 40 X 10^9/L) or high baseline platelet count cohort (greater than or equal to 40 to less than 50 X 10^9/L) 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 greater than or equal to 50 X 10^9/L 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 less than 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 less than 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 less than 0.0001).

Both trials also demonstrated a higher proportion of patients who achieved the target platelet count of greater than or equal to 50 X 10^9/L 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 less than 30 X 10^9/L). The major efficacy outcome was the cumulative number of weeks in which the platelet count was greater than or equal to 50 X 10^9/L during the 6-month treatment period in the absence of rescue therapy. Doptelet-treated patients had a longer duration of platelet counts greater than or equal to 50 x10^9/L in the absence of rescue therapy than those who received placebo (median 12.4 [0, 25] vs 0 [0, 2] weeks, respectively, p less than 0.0001. In addition, a larger proportion of patients in the Doptelet treatment group had platelet counts greater than or equal to 50 X 10^9/L at Day 8 compared to placebo (21/32; 66% vs 0/17; 0.0%, respectively; p less than 0.0001).

Mulpleta(2)

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 10^9/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 greater than or equal to 50 X 10^9/L with an increase of greater than or equal to 20 X 10^9/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 less than 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 less than 0.0001).

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 less than 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 less than 0.0001).

Nplate(3)

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 greater than or equal to 50 X 10^9/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 greater than or equal to 50 X 10^9/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.

Promacta(4)

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 patients with persistent or 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 persistent or 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 less than 75 x10^9/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 greater than or equal to 90 X 10^9/L (trial 1) and greater than or equal to 100 x 10^9/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) greater than 1,000/microliter, platelet count greater than 100 X 10^9/L, and hemoglobin greater than 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 greater than 500/microliter, platelet count greater than 20 X 10^9/L, or reticulocyte count greater than 60,000/microliter. 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 10^9/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 10^9/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 10^9/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.

Alvaiz(16)

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

Safety and efficacy 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. These studies are listed under Promacta.

Tavalisse(5)

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 10^9/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 0-4% 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 10^9/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 10^9/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 10^9/L, without an intervening visit with a platelet count of at least 50 X 10^9/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 10^9/L for 12 months or longer.

Safety

All targeted agents have no FDA labeled contraindications of use.(1-5,16)

1

Doptelet prescribing information. AkaRx, Inc. July 2021.

2

Mulpleta prescribing information. Shionogi Inc. April 2020.

3

Nplate prescribing information. Amgen. February 2022.

4

Promacta prescribing information. Novartis. March 2023.

5

Tavalisse prescribing information. Rigel Pharmaceuticals, Inc. November 2020.

6

Neunert, C., Terrell, D. R., Arnold, D. M., Buchanan, G., Cines, D. B., Cooper, N., Cuker, A., Despotovic, J. M., George, J. N., Grace, R. F., Kühne, T., Kuter, D. J., Lim, W., McCrae, K. R., Pruitt, B., Shimanek, H., & Vesely, S. K. (2019). American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Advances, 3(23), 3829–3866. https://doi.org/10.1182/bloodadvances.2019000966

7

Reference no longer used

8

Olnes, M. J., Scheinberg, P., Calvo, K. R., Desmond, R., Tang, Y., Dumitriu, B., Parikh, A. R., Soto, S., Biancotto, A., Feng, X., Lozier, J., Wu, C. O., Young, N. S., & Dunbar, C. E. (2012). Eltrombopag and improved hematopoiesis in refractory aplastic anemia. New England Journal of Medicine, 367(1), 11–19. https://doi.org/10.1056/nejmoa1200931  

9

Reference no longer used 

10

Killick, S. B., Bown, N., Cavenagh, J., Dokal, I., Foukaneli, T., Hill, A., Hillmen, P., Ireland, R., Kulasekararaj, A., Mufti, G., Snowden, J. A., Samarasinghe, S., Wood, A., & Marsh, J. C. (2015). Guidelines for the diagnosis and management of adult aplastic anaemia. British Journal of Haematology, 172(2), 187–207. https://doi.org/10.1111/bjh.13853

11

Chiao, E. Y., Engels, E. A., Kramer, J. R., Pietz, K., Henderson, L., Giordano, T. P., & Landgren, O. (2009). Risk of Immune Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia Among 120 908 US Veterans with Hepatitis C Virus Infection. Archives of Internal Medicine, 169(4), 357–363. https://doi.org/10.1001/archinternmed.2008.576

12

Intagliata, N. M., Argo, C. K., Stine, J. G., Lisman, T., Caldwell, S. H., & Violi, F. (2018). Concepts and controversies in haemostasis and thrombosis associated with liver disease: Proceedings of the 7th international coagulation in liver disease conference. Thrombosis and Haemostasis, 118(08), 1491–1506. https://doi.org/10.1055/s-0038-1666861

13

Reference no longer used 

14

Centers for Disease Control and Prevention. (2018, April 4). Acute Radiation Syndrome: A Fact Sheet for Clinicians. Centers for Disease Control and Prevention. https://www.cdc.gov/nceh/radiation/emergencies/arsphysicianfactsheet.htm

15

DeZern, A. E., & Churpek, J. E. (2021). Approach to the diagnosis of aplastic anemia. Blood Advances, 5(12), 2660–2671. https://doi.org/10.1182/bloodadvances.2021004345

16

Alvaiz prescribing information. Teva Pharmaceuticals, Inc. February 2024.

Doptelet

avatrombopag maleate tab

20 MG

M ; N ; O ; Y

N

Alvaiz

eltrombopag choline tab

18 MG ; 36 MG ; 54 MG ; 9 MG

M ; N ; O ; Y

N

Promacta

eltrombopag olamine powder pack for susp

12.5 MG ; 25 MG

M ; N ; O ; Y

N

Promacta

eltrombopag olamine tab

12.5 MG ; 25 MG ; 50 MG ; 75 MG

M ; N ; O ; Y

N

Tavalisse

fostamatinib disodium tab

100 MG ; 150 MG

M ; N ; O ; Y

N

Mulpleta

lusutrombopag tab

3 MG

M ; N ; O ; Y

N

Alvaiz

eltrombopag choline tab

9 MG

30

Tablets

30

DAYS

Alvaiz

eltrombopag choline tab

18 MG

30

Tablets

30

DAYS

Alvaiz

eltrombopag choline tab

36 MG

60

Tablets

30

DAYS

Alvaiz

eltrombopag choline tab

54 MG

60

Tablets

30

DAYS

Doptelet

Avatrombopag Maleate Tab 20 MG (Base Equiv)

20 MG

60

Tablets

30

DAYS

Mulpleta

Lusutrombopag Tab 3 MG

3 MG

7

Tablets

7

DAYS

Promacta

Eltrombopag Olamine Powder Pack for Susp 12.5 MG (Base Eq)

12.5 MG

30

Packets

30

DAYS

Promacta

Eltrombopag Olamine Powder Pack for Susp 25 MG (Base Equiv)

25 MG

30

Packets

30

DAYS

Promacta

Eltrombopag Olamine Tab 12.5 MG (Base Equiv)

12.5 MG

30

Tablets

30

DAYS

Promacta

Eltrombopag Olamine Tab 25 MG (Base Equiv)

25 MG

30

Tablets

30

DAYS

Promacta

Eltrombopag Olamine Tab 50 MG (Base Equiv)

50 MG

60

Tablets

30

DAYS

Promacta

Eltrombopag Olamine Tab 75 MG (Base Equiv)

75 MG

60

Tablets

30

DAYS

Tavalisse

fostamatinib disodium tab

100 MG ; 150 MG

60

Tablets

30

DAYS

Alvaiz

eltrombopag choline tab

18 MG ; 36 MG ; 54 MG ; 9 MG

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Doptelet

avatrombopag maleate tab

20 MG

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Mulpleta

lusutrombopag tab

3 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

eltrombopag olamine powder pack for susp

12.5 MG ; 25 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

eltrombopag olamine tab

12.5 MG ; 25 MG ; 50 MG ; 75 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tavalisse

fostamatinib disodium tab

100 MG ; 150 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Alvaiz

eltrombopag choline tab

18 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Alvaiz

eltrombopag choline tab

9 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Alvaiz

eltrombopag choline tab

36 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Alvaiz

eltrombopag choline tab

54 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Doptelet

Avatrombopag Maleate Tab 20 MG (Base Equiv)

20 MG

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Mulpleta

Lusutrombopag Tab 3 MG

3 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

Eltrombopag Olamine Powder Pack for Susp 12.5 MG (Base Eq)

12.5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

Eltrombopag Olamine Powder Pack for Susp 25 MG (Base Equiv)

25 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

Eltrombopag Olamine Tab 12.5 MG (Base Equiv)

12.5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

Eltrombopag Olamine Tab 25 MG (Base Equiv)

25 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

Eltrombopag Olamine Tab 50 MG (Base Equiv)

50 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Promacta

Eltrombopag Olamine Tab 75 MG (Base Equiv)

75 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tavalisse

fostamatinib disodium tab

100 MG ; 150 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PA

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 BOTH of the following:
         1. ONE of the following:
            1. The patient has a platelet count less than or equal to 30 X 10^9/L OR
            2. The patient has a platelet count greater than 30 X 10^9/L but less than 50 X 10^9/L AND has symptomatic bleeding and/or an increased risk for bleeding AND
         2. ONE of the following:
            1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP OR
            2. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP OR
            3. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP OR
            4. The patient has tried and had an inadequate response to another thrombopoietin receptor agonist (e.g., Nplate, Promacta) or Tavalisse OR
            5. The patient has tried and had an inadequate response to immunoglobulins (IVIg or Anti-D) OR
            6. The patient has had an inadequate response to a splenectomy OR
            7. The patient has tried and had an inadequate response to rituximab OR
      2. The patient has a diagnosis of thrombocytopenia and has chronic liver disease AND ALL of the following:
         1. The patient has a platelet count less than 50 X 10^9/L AND
         2. The patient is scheduled to undergo a procedure with an associated risk of bleeding (e.g., gastrointestinal endoscopy, liver biopsy, bronchoscopy, dental procedure) AND
         3. The patient would require a platelet transfusion unless platelet counts are clinically increased from baseline (prior to therapy with the requested agent) OR
      3. The patient has another FDA labeled indication for the requested agent OR
      4. The patient has another indication that is supported in compendia for the requested agent and route of administration OR
   2. 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 ALL of the following:
         1. The patient has a platelet count less than 50 X 10^9/L AND
         2. The patient is scheduled to undergo a procedure with an associated risk of bleeding (e.g., gastrointestinal endoscopy, liver biopsy, bronchoscopy, dental procedure) AND
         3. The patient would require a platelet transfusion unless platelet counts are clinically increased from baseline (prior to therapy with the requested agent) OR
      2.  The patient has another FDA labeled indication for the requested agent OR 
      3.  The patient has another indication that is supported in compendia for the requested agent and route of administration OR
   3. 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
      2. The patient has a diagnosis of immune (idiopathic) thrombocytopenia (ITP) AND ALL of the following:
         1. If the patient is a pediatric patient, then the patient has had ITP for at least 6 months AND
         2. ONE of the following:
            1. The patient has a platelet count less than or equal to 30 X 10^9/L OR 
            2. The patient has a platelet count greater than 30 X 10^9/L but less than 50 x 10^9/L AND has symptomatic bleeding and/or an increased risk for bleeding AND
         3. ONE of the following:
            1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP OR
            2. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP OR
            3. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP OR
            4. The patient has tried and had an inadequate response to immunoglobulins (IVIg or anti-D) OR
            5. The patient has had an inadequate response to a splenectomy OR
            6. The patient has tried and had an inadequate response to rituximab OR
      3. The patient has another FDA labeled indication for the requested agent OR
      4. The patient has another indication that is supported in compendia for the requested agent and route of administration OR
   4. 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 interferon therapy AND the patient’s platelet count is less than 75 x 10^9/L OR
         2. The patient is on concomitant therapy with interferon AND is at risk for discontinuing hepatitis C therapy due to thrombocytopenia OR
      2. 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 10^9/L
            2. Platelets less than 30 X 10^9/L
            3. Reticulocyte count less than 60 X 10^9/L AND
         2. The patient has 1 of the following marrow criteria:
            1. Severe hypocellularity: less than 25% OR
            2. Moderate hypocellularity, 25-50% with hematopoietic cells representing less than 30% of residual cells AND
         3. ONE of the following:
            1.  BOTH of the following:
               1. The patient will use the requested agent as first-line treatment AND
               2. The patient will use the requested agent in combination with standard immunosuppressive therapy (i.e., antithymocyte globulin [ATG] AND cyclosporine) OR
            2. ONE of the following:
               1. The patient has tried and had an inadequate response to BOTH antithymocyte globulin (ATG) AND cyclosporine therapy OR
               2. The patient has an intolerance or hypersensitivity to BOTH ATG AND cyclosporine OR
               3. The patient has an FDA labeled contraindication to BOTH ATG AND cyclosporine OR
      3. The patient has a diagnosis of persistent or chronic (defined as lasting for at least 3 months) immune (idiopathic) thrombocytopenia (ITP) AND BOTH of the following:
         1. ONE of the following:
            1. The patient has a platelet count less than or equal to 30 x 10^9/L OR
            2. The patient has a platelet count greater than 30 x 10^9/L but less than 50 x 10^9/L AND has symptomatic bleeding and/or an increased risk for bleeding AND
         2. ONE of the following:
            1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP OR
            2. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP OR
            3. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP OR
            4. The patient has tried and had an inadequate response to immunoglobulins (IVIg or anti-D) OR
            5. The patient has had an inadequate response to a splenectomy OR
            6. The patient has tried and had an inadequate response to rituximab OR
      4. The patient has another FDA labeled indication for the requested agent OR
      5. The patient has another indication that is supported in compendia for the requested agent and route of administration OR​​​
   5. The requested agent is Alvaiz (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 interferon therapy AND the patient’s platelet count is less than 75 x 10^9/L OR
         2. The patient is on concomitant therapy with interferon AND is at risk for discontinuing hepatitis C therapy due to thrombocytopenia OR
      2. 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 10^9/L
            2. Platelets less than 30 X 10^9/L
            3. Reticulocyte count less than 60 X 10^9/L AND
         2. The patient has 1 of the following marrow criteria:
            1. Severe hypocellularity: less than 25% OR
            2. Moderate hypocellularity, 25-50% with hematopoietic cells representing less than 30% of residual cells AND
         3. ONE of the following:
            1. The patient has tried and had an inadequate response to BOTH antithymocyte globulin (ATG) AND cyclosporine therapy OR
            2. The patient has an intolerance or hypersensitivity to BOTH ATG AND cyclosporine OR
            3. The patient has an FDA labeled contraindication to BOTH ATG AND cyclosporine OR
      3. The patient has a diagnosis of persistent or chronic (defined as lasting for at least 3 months) immune (idiopathic) thrombocytopenia (ITP) AND BOTH of the following:
         1. ONE of the following:
            1. The patient has a platelet count less than or equal to 30 x 10^9/L OR
            2. The patient has a platelet count greater than 30 x 10^9/L but less than 50 x 10^9/L AND has symptomatic bleeding and/or an increased risk for bleeding AND
         2. ONE of the following:
            1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP OR
            2. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP OR
            3. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP OR
            4. The patient has tried and had an inadequate response to immunoglobulins (IVIg or anti-D) OR
            5. The patient has had an inadequate response to a splenectomy OR
            6. The patient has tried and had an inadequate response to rituximab OR
      4. The patient has another FDA labeled indication for the requested agent OR
      5. The patient has another indication that is supported in compendia for the requested agent and route of administration OR
   6. 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 BOTH of the following:
         1. ONE of the following:
            1. The patient has a platelet count less than or equal to 30 X 10^9/L OR
            2. The patient has a platelet count greater than 30 X 10^9/L but less than 50 x 10^9/L AND has symptomatic bleeding and/or an increased risk for bleeding AND
         2. ONE of the following:
            1. The patient has tried and had an inadequate response to ONE corticosteroid used for the treatment of ITP OR
            2. The patient has an intolerance or hypersensitivity to ONE corticosteroid used for the treatment of ITP OR
            3. The patient has an FDA labeled contraindication to ALL corticosteroids used for the treatment of ITP OR
            4. The patient has tried and had an inadequate response to another thrombopoietin receptor agonist (e.g., Doptelet, Nplate, Promacta) OR
            5. The patient has tried and had an inadequate response to immunoglobulins (IVIg or Anti-D) OR
            6. The patient has had an inadequate response to a splenectomy OR
            7. The patient has tried and had an inadequate response to rituximab OR
      2. The patient has another FDA labeled indication for the requested agent OR
      3. The patient has another indication that is supported in compendia for the requested agent and route of administration AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. ONE of the following:
   1. The patient will NOT be using the requested agent in combination with another agent included in this program OR
   2. The patient will use the requested agent in combination with another agent included in this program AND BOTH of the following:
      1. The requested agent is Nplate AND
      2. The patient has a diagnosis of hematopoietic syndrome of acute radiation syndrome (HS-ARS) AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Compendia Allowed: AHFS, DrugDex 1 or 2a level of evidence, or NCCN 1 or 2a recommended use

Lengths of Approval:
Doptelet: thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure - 1 month; all other indications - 6 months
Mulpleta: thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure - 1 month; all other indications - 6 months
Nplate: HS-ARS - 1 time; ITP - 4 months; all other indications - 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; all other indications - 6 months
Alvaiz:  ITP - 2 months; thrombocytopenia in hep C - 3 months; all other severe aplastic anemia - 4 months; all other indications - 6 months
Tavalisse: all indications - 6 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

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

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review]. (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
2. 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 greater than or equal to 50 x 10^9/L OR
      2. The patient’s platelet count has increased sufficiently to avoid clinically significant bleeding OR
   2. The patient has the diagnosis of hepatitis C associated thrombocytopenia AND BOTH of the following:
      1. The patient will be initiating or maintaining hepatitis C therapy with interferon AND
      2. ONE of the following:
         1. The patient’s platelet count is greater than or equal to 90 x 10^9/L OR
         2. The patient’s platelet count has increased sufficiently to initiate or maintain interferon therapy for the treatment of hepatitis C OR
   3. The patient has a diagnosis other than ITP or hepatitis C associated thrombocytopenia AND has had clinical benefit with the requested agent AND
3. The patient will NOT be using the requested agent in combination with another agent included in this program AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Lengths of Approval: thrombocytopenia in hepatitis C - 6 months; all other indications - 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria  

QL

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication

Initial Lengths of Approval:
Doptelet: thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure - 1 month; all other indications - up to 6 months
Mulpleta: thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure - 1 month; all other indications - up to 6 months
Nplate: HS-ARS - 1 time; ITP - up to 4 months; all other indications - up to 6 months
Promacta: ITP - up to 2 months; thrombocytopenia in hep C - up to 3 months; first-line therapy in severe aplastic anemia - up to 6 months; all other severe aplastic anemia - up to 4 months; all other indications - up to 6 months
Alvaiz:  ITP - 2 months; thrombocytopenia in hep C - 3 months; all other severe aplastic anemia - 4 months; all other indications - 6 months
Tavalisse: all indications - up to 6 months

Renewal Lengths of approval: thrombocytopenia in hepatitis C - up to 6 months; all other indications - up to 12 months