Written by: Julianna Darling, PharmD, Indiana University Health Simon Cancer Center
Positive Quality Intervention: Fostamatinib (Tavalisse) use in Chronic Immune Thrombocytopenia
Description: Fostamatinib is an oral spleen tyrosine kinase (Syk) inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. ITP is mediated by platelet antibodies that accelerate platelet destruction and inhibit their production. Common treatments for ITP include corticosteroids, rituximab, IVIG, splenectomy and/or thrombopoietin receptor agonists (TPO-RA). This PQI will review appropriate use of fostamatinib in this setting.
Background: SyK signaling is central to phagocytosis based, antibody mediated platelet destruction in adults with ITP. Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against SyK. The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B cell receptors, leading to decreased destruction of platelets.1 In two parallel, phase 3, multicenter, randomized, double blind, placebo-controlled trials (FIT1 and FIT2), adult patients with chronic ITP were randomized 2:1 to fostamatinib or placebo. Fostamatinib was dosed at 100mg BID for 24 weeks with a dose increase to 150mg BID in non-responders after 4 weeks. Primary endpoint was stable response, which was defined as platelet ≥50,000 x109/L at ≥4 of 6 biweekly visits, weeks 14 through 24, without rescue therapy. Stable responses occurred in 18% of patients in the fostamatinib group compared to 0% in the placebo group. Post hoc endpoints also showed an overall response rate of 43% and long term extension show 54% response by line of therapy. The most common adverse events were diarrhea, hypertension, nausea, dizziness, and ALT increase.
Upon receipt of fostamatinib:
- Confirm appropriate dosing: Typical starting dose is 100 mg twice daily2
- May increase to 150mg twice daily if 100 mg twice daily does not increase platelet count to >50,000 x109/L after 1 month
- Use the lowest possible dose to achieve and maintain a platelet count of at least 50,000 x109/L
- Fostamatinib may be taken with or without food. In the case of a missed dose, instruct patients to take their next dose at its regularly scheduled time
- Obtain baseline LFTs and repeat monthly throughout therapy
- Obtain baseline CBC and repeat monthly while on therapy. If ANC drops below 1.0 x 109/L for more than 72 hours temporarily interrupt until resolved
- Monitor blood pressure (BP) every 2 weeks after starting therapy until patient is established on a stable dose, then obtain BP monthly
- Screen for drug interactions with CYP3A4 inhibitors and inducers
- Fostamatinib is a prodrug that is metabolized into its active metabolite, R406. Co-administration of ketoconazole caused a 2-fold increase in R406 exposure, verapamil increased R406 exposure by 39% and rifampicin co-administration decreased exposure by 75%3
- Discontinue fostamatinib after 12 weeks of therapy if the platelet count does not increase to a level sufficient to avoid clinically important bleeding
Patient Centered Activities:
- Provide thorough verbal and written medication education; including, but not limited to, the Oral Chemotherapy Education (OCE) sheet
- Ensure the patient understands the lab schedule for follow up CBC, LFTs, and BP monitoring
- Avoid eating or drinking grapefruit and grapefruit juice while taking this medication
- If patient is of child-bearing age, review pregnancy and contraception information with them
Dose adjustments for toxicity2
|Usual maximum dose||150 mg twice daily|
|First dose reduction||100 mg twice daily|
|Second dose reduction||150 mg once in the morning|
|Third dose reduction||100 mg once in the morning|
- Clemons Bankston P, Al-Horani RA. New small molecule drugs for thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations. Int J Mol Sci. 2019;20(12):3013.
- Tavalisse® (fostamatinib) [prescribing information]. South San Francisco, CA: Rigel Pharmaceuticals, Inc; April 2018.
- Martin P, Gillen M, Millson D, et al. Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies. Drugs R D. 2016;16(1):81-92. doi:10.1007/s40268-015-0118-4.