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April 17, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf

On April 17, 2018, the Food and Drug Administration approved fostamatinib disodium hexahydrate tablets (TAVALISSE™, Rigel Pharmaceuticals, Inc.) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment​.

Approval was based on two identical, double-blind, placebo-controlled trials, FIT-1 (NCT02076399) and FIT-2 (NCT02076412) that enrolled a total of 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment, which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonist. Patients were randomized 2:1 to fostamatinib (100 mg orally twice daily) or placebo for 24 weeks. Dose could be escalated to 150 mg orally twice daily after one month.

Efficacy was based on stable platelet response (at least 50 x109/L on at least 4 of the 6 visits between Weeks 14 to 24). In FIT-1, stable platelet response was demonstrated in 18% (n=9) of patients receiving fostamatinib compared with 0% (n=0) of patients receiving placebo (p=0.03). In FIT-2, stable platelet response was seen in 16% (n=8) and 4% (n=1) of patients, respectively (p=0.26). In the FIT-3 (NCT 02077192) extension study, a stable response was observed in 23% (n=10) of patients newly exposed to fostamatinib. Durable platelet responses were seen in the FIT-1, FIT-2 trials and the FIT-3 extension study.

The most common adverse reactions in at least 5% of patients treated with fostamatinib were diarrhea, hypertension, nausea, dizziness, alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia. In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving fostamatinib.

The recommended dose initially is 100 mg administered orally twice daily. After a month, if platelet count has not increased to at least 50x109/L, increase dose to 150 mg twice a day.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf

FDA granted this application standard review and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Fostamatinib Disodium Hexahydrate for the Treatment of Thrombocytopenia in Adult Patients with Chronic Immune Thrombocytopenia Who Have Had an Insufficient Response to a Previous Treatment

Author: Kirollos S. Hanna, PharmD BCOP BCPS
Hematology/Oncology Clinical Pharmacist
Mayo Clinic and University of Minnesota Medical Center
Minneapolis, MN

What is the potential role for fostamatinib in the treatment of chronic immune thrombocytopenia (ITP)?

  • Fostamatinib, approved by the U.S. Food and Drug Administration (FDA) on April 17, 2018, is the first and only spleen tyrosine kinase (Syk) inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to a previous treatment.1 The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptors, resulting in a reduction in antibody-mediated destruction of platelets.
  • The American Society of Hematology (ASH) recommends several treatment options that may be considered for ITP, including courses of corticosteroids, intravenous immunoglobulin (IVIG), rituximab, splenectomy, and thrombopoietin receptor agonists (TPO-RA).2 Selection of therapy is often tailored to the individual patient, taking into account the presence and severity of bleeding, the rapidity of desired platelet count rise, and possible side effects. Long courses of corticosteroids and IVIG are recommended as first-line therapy for patients who require treatments. Rituximab and TPO-RA are generally reserved for patients who are unresponsive to or relapse after initial therapy.
  • Approval was based on FIT-1 (NCT02076399) and FIT-2 (NCT02076412), two identical double-blind placebo-controlled phase 3 trials, which enrolled a total of 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment.1,3,4
    • Patient characteristics in the trials illustrate a difficult-to-treat population with long-standing ITP (median of 8.5 years, with approximately 75% having had ITP for 3 years), many attempts at prior therapy for ITP (median of 3 unique prior therapies, range 1–13), and an average platelet count at baseline that is typically associated with bleeding episodes (more than half were less than 15 x 109/L).5
    • Patients enrolled in the FIT-1 and FIT-2 fostamatinib trials had received various prior treatments, with the most common including corticosteroids (94%), immunoglobulins (53%), and TPO-RA (48%).3 Patients were allowed to continue one concomitant ITP medication throughout the study without any changes if they were on a stable dose for 14 days prior to baseline, and 70 (46%) patients did so.
    • Patients were randomized 2:1 to fostamatinib (100 mg taken orally twice daily) or placebo for 24 weeks. On the basis of platelet count and tolerability, if a patient’s platelet count did not increase to at least 50 x 109/L, the dose could be increased to 150 mg twice daily after 1 month. In the placebo-controlled studies, the median duration of therapy exposure was 86 days (range 8–183).
    • Efficacy was based on stable platelet response (greater than or equal to 50 x 109/L on at least 4 of the 6 visits between weeks 14 and 24).
    • In the FIT-1 trial, stable platelet response was demonstrated in 18% (n = 9) of patients receiving fostamatinib, compared with 0% (n = 0) of patients receiving placebo (p = .03). In the FIT-2 trial, stable platelet response was seen in 16% (n = 8) and 4% (n = 1) of patients, respectively (p = .26).
    • Overall responses (defined as 1 or more platelet counts greater than or equal to 50 x 109/L within the first 12 weeks of treatment) occurred in 43% of patients on fostamatinib versus 14% on placebo (p = .0006).5
    • The median time to reaching a platelet count greater than or equal to 50 x 109/L was 15 days for overall responders and 15.5 days for stable responders, at which time all patients were still receiving 100 mg twice daily except one patient who had decreased the dose to 150 mg daily. A response was achieved by week 4 in 22 (51%) overall responders and 11 (61%) stable responders.5
  • Durable platelet responses were seen in both phase 3 trials and in the FIT-3 (NCT02077192) extension study.1,3,4 In the latter study, a stable response was observed in 23% (n = 10) of patients newly exposed to fostamatinib. This ongoing study will broaden the understanding of the long-term clinical efficacy and safety of fostamatinib in adults with ITP.
  • ASH has yet to incorporate fostamatinib into its clinical practice guideline on the evaluation and management of ITP. The most recent updates were published in 2011, prior to FDA approval.

What role can the pharmacist play in the management of patients on fostamatinib?

  • The recommended initial dose of fostamatinib is 100 mg administered orally twice daily with or without food. After a month, if the platelet count has not increased to at least 50 x 109/L, the dose should be increased to 150 mg twice daily.3
  • No dosage adjustments are provided in the manufacturer's labeling for baseline hepatic or renal impairment. Impairment does not alter fostamatinib pharmacokinetics; therefore, dosage adjustment is not likely to be necessary.3
  • The most common adverse reactions in at least 5% of patients treated with fostamatinib were diarrhea, hypertension, nausea, dizziness, increased alanine aminotransferase/aspartate aminotransferase (ALT/AST), respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia.
    • In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, each of which occurred in 1% of patients receiving fostamatinib.1,3
  • Recommended dose modifications and management for specific adverse reactions (hypertension, hepatoxicity, diarrhea, and neutropenia) are provided in the manufacturer’s labeling and below.
    • Dose reduction schedule (reduce one level based on current dose if a reduction is needed):
      • Daily dose 300 mg/day—administer as 150 mg twice daily
      • Daily dose 200 mg/day—administer as 100 mg twice daily
      • Daily dose 150 mg/day—administer as 150 mg once daily in the morning
      • Daily dose 100 mg/day—administer as 100 mg once daily in the morning
      • If further dose reduction below 100 mg/day is required, discontinue fostamatinib.
    • Table 1 outlines dose modifications and management.3
  • It is important to counsel patients on signs and symptoms of bleeding. During the placebo-controlled studies, the incidence of bleeding occurred in 29% of patients in the fostamatinib arm. Moderate, severe, and serious bleeding events also occurred, and all severe events led to hospitalizations.3
  • Patients should be informed that periodic monitoring of blood pressure, liver enzymes, and complete blood counts is required because abnormalities may necessitate interruption, reduction, or discontinuation of the therapy.
  • Patients should be advised to use supportive care measures for diarrhea; severe cases of diarrhea may require treatment modification.3
  • Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite of fostamatinib), which may increase the risk of adverse reactions. Toxicity monitoring is necessary and may warrant dose reduction (see Table 1). The use of strong CYP3A4 inducers is not recommended with fostamatinib.3
  • Updates on patient assistance programs from Rigel Pharmaceuticals, Inc., are available at https://tavalisse.com/patient-resources.

Table 1: Recommended Dose Modifications and Management for Specific Adverse Reactions3

Adverse Reaction Recommended Action
Hypertension  
Stage 1: systolic pressure of 130–139 mmHg or diastolic pressure of 80–89 mmHg
  • Initiate or increase dosage of antihypertensive medication for patients with increased cardiovascular risk, and adjust as needed until BP is controlled.
  • If the BP target is not met after 8 weeks, reduce fostamatinib to the next lower daily dose.
Stage 2: systolic pressure at least 140 mmHg or diastolic pressure at least 90 mmHg
  • Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled.
  • If BP remains 140/90 mmHg or higher for more than 8 weeks, reduce fostamatinib to the next lower daily dose.
  • If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue fostamatinib.
Hypertensive crisis: systolic pressure over 180 mmHg or diastolic pressure over 120 mmHg or both
  • Interrupt or discontinue fostamatinib.
  • Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled. If BP returns to less than the target BP, resume fostamatinib at the same daily dose.
  • If repeat BP is 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive treatment, discontinue fostamatinib.
Hepatotoxicity
AST/ALT is 3 x ULN or higher and less than 5 x ULN If patient is symptomatic (e.g., nausea, vomiting, abdominal pain):
  • Interrupt fostamatinib.
  • Recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 x ULN) and total BL remains less than 2 x ULN.
  • Resume fostamatinib at the next lower daily dose.
If patient is asymptomatic:
  • Recheck LFTs every 72 hours until ALT/AST values are below 1.5 x ULN and total BL remains less than 2 x ULN.
  • Consider interruption or dose reduction of fostamatinib if ALT/AST and total BL remain in this category (AST/ALT is 3–5 x ULN; and total BL remains less than 2 x ULN).
  • If dosing is interrupted, resume fostamatinib at the next lower daily dose when ALT/AST values are no longer elevated (below 1.5 x ULN) and total BL remains less than 2 x ULN.
AST/ALT is 5 x ULN or higher, and total BL is less than 2 x ULN
  • Interrupt fostamatinib.
  • Recheck LFTs every 72 hours.
  • If AST and ALT decrease, recheck until ALT and AST are no longer elevated (below 1.5 x ULN) and total BL remains less than 2 x ULN; resume fostamatinib at the next lower daily dose.
  • If AST/ALT persist at 5 x ULN or higher for 2 weeks or more, discontinue fostamatinib.
AST/ALT is 3 x ULN or higher, and total BL is greater than 2 x ULN
  • Discontinue fostamatinib.
Elevated unconjugated (indirect) BL in absence of other LFT abnormalities
  • Continue fostamatinib with frequent monitoring because an isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition.
Diarrhea
 
  • Manage diarrhea using supportive measures (e.g., dietary changes, hydration, or antidiarrheal medication) early after the onset until symptoms have resolved.
  • If symptoms become severe (Grade 3 or above), temporarily interrupt fostamatinib.
  • If diarrhea improves to mild (Grade 1), resume fostamatinib at the next lower daily dose.
Neutropenia
 
  • If absolute neutrophil count decreases (ANC less than 1.0 x 109/L) and remains low after 72 hours, temporarily interrupt fostamatinib until resolved (ANC greater than 1.5 x 109/L).
  • Resume fostamatinib at the next lower daily dose.

ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BL = bilirubin; BP = blood pressure; LFTs = liver function tests (AST, ALT, total BL with fractionation if elevated, alkaline phosphatase); AST/ALT = AST or ALT; ULN = upper limit of normal.

Clinical Pearls

  • Fostamatinib is available in 100-mg and 150-mg tablet sizes and supplied in 60-count bottles with two desiccant canisters that should not be removed. Fostamatinib should be stored at room temperature.3
  • The phase 3 trials excluded patients who had secondary ITP, a major cardiovascular event, coagulopathy (including prothrombotic conditions such as Factor V Leiden, activated protein C resistance, antithrombin III deficiency and lupus anticoagulant, and arterial or deep venous thrombosis) within 6 months, ITP Bleeding Scale Grade 2 at the screening visit, poorly controlled hypertension, or disorders that, in the investigator’s opinion, could affect the conduct of the study.5
  • In the case of a missed dose, patients should be instructed to take their next dose at the regularly scheduled time.3
  • Future studies will investigate whether higher response rates will be seen when fostamatinib is given earlier in the course of ITP, further examine the mechanism of Syk inhibition, and explore which patients are most likely to respond to treatment.

References

  1. U.S. Food and Drug Administration. April 17, 2018. FDA approves fostamatinib tablets for ITP [news release]. Silver Spring, MD: FDA. Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm604956.htm.
    Accessed May 14, 2018.
  2. Neunert C, Lim W, Crowther M, et al. American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207.
  3. Tavalisse (fostamatinib) [package insert]. South San Francisco, CA: Rigel Pharmaceuticals, Inc.; April 2018.
  4. National Institutes of Health U.S. National Library of Medicine. Fostamatinib. Available at http://www.clinicaltrials.gov. Accessed May 11, 2018.
  5. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018; doi:10.1002/ajh.25125. [Epub ahead of print]
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