MASAC Document 295 - Recommendation on the Use and Management of Antithrombin in Inhibitors

CHAPTER 1 Recommendation on the Use and Management of Antithrombin in Inhibitors

EXPERTS:  Magdalena D Lewandowska MD ¹, Janice Staber MD², Amy Dunn MD on behalf of MASAC 

¹(Innovative Hematology, Indiana, USA)

² (Iowa Hemophilia and Thrombosis Center, University of Iowa, Iowa, USA)

TOPIC: Fitusiran (Qfitlia®) for treatment of hemophilia A or B > 12 years of age WITH or WITHOUT inhibitors

BACKGROUND

• Fitusiran is a subcutaneously administered small RNA interference (RNAi) therapeutic that promotes hemostasis by lowering antithrombin (AT) levels.  Fitusiran was shown to be safe and effective in adults and children 12 years or older with hemophilia A or B with or without inhibitors.^1-5

RECOMMENDATION 1.1

• Fitusiran may be considered for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients 12 years of age and older with hemophilia A or B with inhibitors.
• REMARK: Fitusiran is initially administered subcutaneously at a fixed dose of 50 mg every two months to target antithrombin activity of 15-35%.  Antithrombin activity needs to be checked using an FDA-cleared test, prior to initiation of therapy (therapy should not be used if baseline antithrombin <60%) ,  at Weeks 4 (Month 1), 12 (Month 3), 20 (Month 5), and 24 (Month 6) following treatment initiation or any dose adjustment. Thereafter, antithrombin activity may be measured annually.  Please see prescribing information.
• REMARK: If antithrombin activity is <15%, fitusiran dose should be reduced, with lower dose given three months after the prior dose.  If any antithrombin activity is 35% after 6 months or if the patient has not achieved satisfactory bleed control, dose escalation may be considered. Antithrombin measurements should be restarted after dose reduction or escalation.  As real-world experience grows, laboratory monitoring guidance may need to be adjusted.  Please refer to prescribing information for additional information. ⁷

• REMARK: Fitusiran does not interfere with standard coagulation assays

• REMARK: Fitusiran is available as a 50 mg single-use prefilled pen and a 20 mg vial
• REMARK: After discontinuing fitusiran, the duration of persistent antithrombin activity <60% (non-negligible impact on anticoagulation) is approximately six months.
• REMARK: When changing from other products to fitusiran, the half-life of the previous product should be considered to ensure complete wash-out. For example:12 hours for recombinant FVIIa (rFVIIa), 48 hours for activated prothrombin complex concentrate (aPCC), 24 hours for standard half-life (SHL) factor VIII (FVIII) or factor IX (FIX) product.  There is no data on changing from FVIII mimetic therapy or anti tissue factor inhibitor therapy to fitusiran. The complete washout period for emicizumab is six months. 

RECOMMENDATION 1.2

• Fitusiran is used for prophylaxis, not for treatment of bleeding episodes.   
• REMARK: PwH receiving fitusiran prophylaxis should have a treatment plan in place for management of breakthrough bleeding episodes in consultation with their hemophilia treatment center (HTC).  The PwH’s HTC should be consulted before treatment administration, as long as this does not result in significant treatment delay.
• REMARK: For treatment of breakthrough bleeding episodes in patients on fitusiran, recommended dosing of additional hemostatic agent administration is significant lower with more infrequent dosing intervals.   Clinical patient characteristics need to be considered, including prothrombotic risk factors. Exceeding of maximum doses should be avoided without clinical justification.  As real-world experience grows, breakthrough bleeding treatment guidance and laboratory monitoring guidance may need to be adjusted.  Please refer to prescribing information for additional information. ⁷

Treatment of breakthrough bleeding episodes in patients on fitusiran

REMARK:  Real world data on surgical management in patients on fitusiran is limited. There have been 60 major and 71 minor surgical procedures reported in clinical trials in PwH on fitusiran with or without inhibitors, without discontinuation of fitusiran.  Bleed management guideline found in the prescribing information should be used during the perioperative period with consideration of individual clinical patient factors.  Please note that above dosing is specific to eptacog alpha and may not be extrapolated to eptacog beta.

RECOMMENDATION 1.3a

• Patients should be educated on the risk, signs, and symptoms of thromboembolic events with fitusiran prophylaxis.
• REMARK: A black boxed warning has been issued for thromboembolic events. 

Clinical trials have raised safety considerations around thrombotic risk, particularly when antithrombin activity levels fell below 10%. These findings prompted a protocol revision that introduced an AT-guided dosing strategy to maintain levels between 15% and 35.  Risk mitigation strategies include close AT monitoring, dose adjustments based on AT levels, and conservative use of additional hemostatic agents during breakthrough bleeding.

Thromboembolic events were reported in 2.6% patients treated with the non-approved 80 mg once-monthly fixed dose.  In the approved antithrombin-based dosing regimen (AT-DR), the thrombotic risk was 1.4%.  Thrombotic risk factors included antithrombin activity < 15%, underlying comorbidities, post-operative settings with use of high doses of hemostatic agents. Regular monitoring of antithrombin activity is essential.  Fitusiran prophylaxis should be interrupted if a thrombotic event occurs.

• REMARK: Concomitant use of systemic antifibrinolytic agents has not been studied and should generally be avoided. Topical use of antifibrinolytics may be considered.

Recommendation 1.3b

• Patients should be counseled on increased risk of gallbladder disease and hepatotoxicity with fitusiran prophylaxis.  Caution should be exercised I patients with a history of symptomatic gallbladder disease.
• REMARK:  Fitusiran has been associated with cholelithiasis and cholecystitis in 17% of patients on the non-approved fixed-dose regimen, with 4% requiring cholecystectomy.  On the AT-DR, gallbladder events occurred in 3.8% of patients with one cholecystectomy reported.  
• REMARK:  Fitusiran is not recommended in patients with hepatic impairment (Child-Pugh A–C). Baseline and regular liver function monitoring is advised—monthly for at least six months following initiation or dose adjustment, and periodically thereafter. Treatment should be interrupted if ALT/AST levels exceed 5× ULN or if jaundice occurs; permanent discontinuation is advised if hepatotoxicity is confirmed. Elevations in ALT and AST >3× ULN were observed in up to 32% of patients receiving the non-approved 80 mg monthly dose. Under the AT-DR, 3.4% of patients experienced transient transaminase elevations.⁷

FUTURE RESEARCH NEEDS:

• The safety and efficacy of fitusiran use in patients receiving ongoing immune tolerance induction (ITI) have not been established, therefore shared decision making should be implemented to discuss risks and benefits of continued ITI treatment if fitusiran s initiated.
• There is no data on the optimal approach to safely switch from a FVIII mimetic or other rebalancing agent (i.e.,marstacimab) to fitusiran.
• Optimal surgical management of patients on fitusiran is not known.
• The safety of concomitant use of systemic antifibrinolytic therapy in patients on fitusiran has not been established.
• There is no safety data on the use of fitusiran in pregnancy or lactation.
• Safety and efficacy have not been established in patients <12 years old
• Establishing long-term safety and efficacy surveillance, reporting of adverse effects, and research collaborations for monitoring are encouraged.  This includes registry enrollment and open-label extensions of ongoing phase III and future phase IV clinical trials. 

KEYWORDS: antithrombin-directed small interfering ribonucleic acid, RNAi, fitusiran

REFERENCES

1. Young G, Liesner R, Makris M, et al. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, a multicentre, open-label, randomised phase 3 trial. Lancet. Lancet. 2023 Apr 29;401(10386):1427-1437. doi: 10.1016/S0140-6736(23)00284-2. Epub 2023 Mar 29.

2. Srivastava A, Santagostino E, Dougall A, et al. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2023 May;10(5):e322-e332. doi: 10.1016/S2352-3026(23)00037-6. Epub 2023 Mar 29.

3.Pipe SW, Lissitchkov T, Georgiev P et al.  Long-term Safety and Efficacy of Fitusiran in Hemophilia. Blood Advances.  2025 9 (5): 1147–1158.

https://doi.org/10.1182/bloodadvances.2024013900

4. Young G, Pasi KJ, Jiménez-Yuste V, et al. Long-term safety and efficacy of fitusiran in people with haemophilia A or B, with or without inhibitors: Final results from a phase 2 study. Blood Adv. 2023;9(5):1147–1158. doi:10.1182/bloodadvances.2022009137.doi: 10.1016/j.jtha.2022.10.004. Epub 2022 Dec 22.

5. Pasi KJ, Rangarajan S, Georgiev P et al.  Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.N Engl J Med. 2017 Aug 31;377(9):819-828. doi: 10.1056/NEJMoa1616569.

6. U.S. Food and Drug Administration. Published March 23, 2025. FDA approves novel treatment for hemophilia A or B with or without factor inhibitors  Accessed March 30, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-treatment-hemophilia-or-b-or-without-factor-inhibitors. Accessed August 22, 2025.

7.  Qfitlia (fitusiran) [prescribing information]. Genzyme corporation; 2025.