What is the recommended dosing regimen for Fibryga (fibrinogen) in postpartum hemorrhage?

What is the recommended dosing regimen for Fibryga (fibrinogen) in postpartum hemorrhage?

Comment by InpharmD Researcher

Available guidance and literature do not provide a Fibryga (fibrinogen [human])-specific dosing regimen for postpartum hemorrhage (PPH). Fibrinogen concentrates have been studied more broadly in obstetric hemorrhage using fixed doses generally ranging from 2 to 4 g or individualized dosing based on fibrinogen levels or viscoelastic testing. Routine early administration has not consistently reduced blood loss or transfusion requirements, particularly in patients without substantial hypofibrinogenemia; however, some data suggest fibrinogen replacement may be most useful in severe PPH with low fibrinogen levels, particularly <200 mg/dL. Therefore, evidence supports a targeted approach rather than a standardized Fibryga dose for PPH.

Background

According to a 2017 American College of Obstetricians and Gynecologists (ACOG) guidance document on postpartum hemorrhage, fibrinogen concentrates are specifically approved for treating acute bleeding in patients with congenital fibrinogen deficiency. Nevertheless, limited data are available regarding the use of prothrombin complex concentrates (PCCs) and fibrinogen concentrates in postpartum hemorrhage (PPH) and disseminated intravascular coagulation. Consequently, their use is advised only after several rounds of standard massive transfusion agents have been administered and in consultation with an expert in massive hemorrhage. The guidance does not provide recommendations for specific fibrinogen concentrate products, including Fibryga, or product-specific dosing for PPH following vaginal or cesarean delivery. [1]

Several review articles have evaluated fibrinogen concentrate for PPH, with evidence suggesting that fibrinogen <200 mg/dL is associated with progression to severe PPH and that fibrinogen replacement may be most beneficial in patients with severe hypofibrinogenemia. Studies have evaluated various dosing approaches, including fixed doses of 2 g in women with PPH following vaginal or cesarean delivery and 3 g following vaginal delivery, as well as individualized dosing guided by viscoelastic testing. However, randomized studies generally did not demonstrate reductions in blood loss or transfusion requirements, particularly when fibrinogen concentrations were not substantially reduced. A systematic review of early fibrinogen replacement similarly found insufficient evidence for improved clinical outcomes and concluded that the optimal dose remains uncertain. Overall, the available literature supports targeting fibrinogen replacement to patients with hypofibrinogenemia rather than routine empiric administration; however, these studies did not specifically evaluate Fibryga. [2], [3], [4], [5], [6]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the recommended dosing regimen for Fibryga (fibrinogen) in postpartum hemorrhage?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage – an observational study
Design	Observational study N= 34
Objective	To examine the impact of the change from cryoprecipitate to fibrinogen concentrate on blood product use and clinical outcomes in major obstetric haemorrhage
Study Groups	Cryoprecipitate group (n= 14) Fibrinogen group (n= 20)
Inclusion Criteria	Women with major obstetric haemorrhage requiring fibrinogen between 1 January 2009 and 30 June 2011
Exclusion Criteria	Patients who received both cryoprecipitate and fibrinogen concentrate
Methods	Patients with major obstetric haemorrhage were identified from a database. Fibrinogen levels were measured using the Clauss method. The study compared blood product use and clinical outcomes between cryoprecipitate and fibrinogen concentrate groups. Statistical analysis was performed using SPSS
Duration	January 2009 to June 2011
Outcome Measures	Correction of hypofibrinogenaemia
Baseline Characteristics		Cryoprecipitate group (n = 14)	Fibrinogen group (n = 20)	P-value
	Age, years	32.8	31.0	0.39
	Parity (0: ≥1)	6:8	6:14	0.37
	Ethnicity (Caucasian:other)	9:5	14:6	0.72
	body mass index, kg/m2	25.8	24.5	0.51
	Previous cesarean section	6	2	0.04
	Booking Hb, g/dL	12.4	11.9	0.33
	Gestation at delivery, days	247	252	0.69
	Birth weight, kg	3.01	2.84	0.64
	The mean (±SEM) dose utilised was 2.21 ± 0.35 pools of cryoprecipitate and 4 ± 0.8 g of fibrinogen.
Results		Cryoprecipitate group (n = 14)	Fibrinogen group (n = 20)	P-value
	EBL, L	5.19	3.34	0.10
	RCC, U	7.21	5.90	0.40
	Octaplas, U	4.07	3.15	0.36
	Fibrinogen post-treatment, g/L	3.05	3.34	0.35
	EBL= Estimated Blood Loss; RCC= red cell concentrate
Adverse Events	No adverse reactions or thrombotic complications were reported
Study Author Conclusions	Purified virally inactivated fibrinogen concentrate is as efficacious as cryoprecipitate in correcting hypofibrinogenaemia in major obstetric haemorrhage.
Critique	The study provides valuable insights into the efficacy of fibrinogen concentrate compared to cryoprecipitate in major obstetric haemorrhage. However, the small sample size and observational design limit the generalizability of the findings. Additionally, the study did not reach statistical significance in some outcomes, which may be due to the limited number of participants.

Table 1 References:
[9] Ahmed S, Harrity C, Johnson S, et al. The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage--an observational study. Transfus Med. 2012;22(5):344-349. doi:10.1111/j.1365-3148.2012.01178.x

Fibrinogen concentrate and maternal outcomes in severe postpartum hemorrhage: A population-based cohort study with a propensity score-matched analysis
Design	Population-based cohort study with propensity score-matched analysis N= 730
Objective	To explore the association between fibrinogen concentrate administration and maternal outcomes in women with severe postpartum hemorrhage receiving red blood cell transfusion
Study Groups	Fibrinogen concentrate (n= 313) No fibrinogen concentrate (n= 417)
Inclusion Criteria	Women with severe postpartum hemorrhage and transfused with red blood cells during active bleeding
Exclusion Criteria	Conditions associated with anticipated or specific transfusion management, such as coagulopathy identified before delivery, prenatally diagnosed placenta accreta, secondary severe PPH, and amniotic fluid embolism
Methods	Fibrinogen concentrate administration was studied as a binary variable and by timing of administration. Multivariable analysis and propensity score matching were used to account for potential indication bias.
Duration	May 2012 to November 2013
Outcome Measures	Primary: Maternal near-miss or death Secondary: Total number of red blood cells units transfused
Baseline Characteristics		Fibrinogen concentrate (n= 313)*	No fibrinogen concentrate (n= 417)
	Age > 35	26.8%	25.2%
	Primiparous	47.1%	46.0%
	Multiple pregnancy	12.8%	8.2%
	Pregnancy-related hypertensive disorders	4.5%	1.0%
	Delivery before 37 weeks	23.1%	15.9%
	Vaginal delivery	47.0%	59.0%
	CD during labor	23.6%	18.9%
	CD before labor	29.4%	22.1%
	Baseline fibrinogen level <1 g.l−1	11.9%	1.6%
	Sulprostone	87.2%	67.2%
	Tranexamic acid	63.9%	30.7%
	FFP transfusion	87.2%	54.0%
	CD: cesarean delivery; FFP: fresh frozen plasma. Overall, 313 (42.9%) of the 730 women with severe PPH received fibrinogen concentrate, administered before or within 30 min after the start of RBC transfusion in 68.7% of cases, with a median total dose of 3.0 g (interquartile range 1.5–3.0)
Results		Fibrinogen concentrate (n= 313)	No fibrinogen concentrate (n= 417)	p-value
	Maternal near-miss or death	24.6%	15.6%	0.477
	Total number of RBCs units transfused, median (IQR)	4 (3–7)	3 (2–4)	0.120
	IQR= interquartile range
Adverse Events	Not specifically reported
Study Author Conclusions	The use of fibrinogen concentrate in severe postpartum hemorrhage needing red blood cell transfusion during active bleeding is not associated with improved maternal outcomes.
Critique	The study's strengths include its focus on a relevant population with severe PPH and the use of robust statistical methods to minimize bias. However, limitations include potential indication bias, lack of standardized fibrinogen level measurement, and inability to evaluate the risk of thrombosis or other adverse effects related to fibrinogen concentrate administration.

Table 2 References:
[10] Deleu F, Deneux-Tharaux C, Chiesa-Dubruille C, Seco A, Bonnet MP; EPIMOMS study Group. Fibrinogen concentrate and maternal outcomes in severe postpartum hemorrhage: A population-based cohort study with a propensity score-matched analysis. J Clin Anesth. 2022;81:110874. doi:10.1016/j.jclinane.2022.110874

Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial
Design	Multicentre, double-blind, randomised placebo-controlled trial N= 437
Objective	To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management
Study Groups	Fibrinogen concentrate (n= 224) Placebo (n= 213)
Inclusion Criteria	Age ≥18 years, with PPH (vaginal bleeding ≥500 ml) following vaginal delivery requiring continuous intravenous prostaglandin administration, with at least one haemoglobin (Hb) value available for the third trimester of pregnancy
Exclusion Criteria	Administration of tranexamic acid (TXA) or fibrinogen within 48 hours prior to inclusion
Methods	Within 30 minutes after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo. The primary efficacy endpoint was a composite failure endpoint: at least 4 g/dl of hemoglobin decrease and/or transfusion of at least two units of packed red blood cells within 48 hours following investigational medicinal product administration
Duration	April 2014 to August 2018
Outcome Measures	Primary: Composite failure endpoint (≥4 g/dl Hb decrease and/or ≥2 RBC units transfusion within 48 hours) Secondary: PPH evolution, need for hemostatic procedures, maternal morbidity–mortality within 6 ± 2 weeks after delivery
Baseline Characteristics		Fibrinogen (n= 224)	Placebo (n= 213)
	Age, mean ± SD, y	30.5 ± 5.6	30.3 ± 5.4
	Weight before pregnancy, mean ± SD, kg	65.2 ± 13.9	65.5 ± 14.8
	Weight (last known), mean ± SD, kg	77.6 ± 13.6	77.8 ± 13.7
	Height, mean ± SD, cm	165.8 ± 5.8	165.8 ± 6.5
	Parity - Primiparous, n (%)	113 (50.4%)	96 (45.1%)
	Parity - Multiparous, n (%)	111 (49.6%)	117 (54.9%)
	Multiple pregnancy, n (%)	25 (11.2%)	24 (11.3%)
	Term, mean ± SD, weeks	39.2 ± 1.9	38.9 ± 2.3
	Prepartum Hb level, mean ± SD, g/dl	11.8 ± 1.0	11.9 ± 0.9
Results		Fibrinogen (n= 220)	Placebo (n= 210)	OR (95%CI)	P-value
	Failure, n (%)	88 (40.0%)	89 (42.4%)	0.99 (0.66–1.47)	0.96
	RBC transfusion ≥2 Units from H0 to D2, n (%)	51 (23.4%)	52 (25.0%)	1.00 (0.63–1.60)	0.98
	Hb loss ≥4 g/dl from reference level to D2, n (%)	42 (19.1%)	41 (19.5%)	1.02 (0.62;1.67)	0.95
	Total blood loss (from baseline to D2), mean ± SD, ml	1555 ± 849	1723 ± 1193		0.21
Adverse Events	No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group versus two in the placebo group
Study Author Conclusions	As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs or postpartum anemia, but did prevent plasma fibrinogen decrease without any subsequent thromboembolic events.
Critique	The study was well-designed as a multicentre, double-blind, randomized placebo-controlled trial, which is a strength. However, the inability to recruit enough patients with ongoing coagulopathy limits the generalizability of the findings. The study's failure to demonstrate a benefit from early fibrinogen administration may be due to improved PPH management practices, such as the use of TXA and intrauterine balloon tamponade, which were not accounted for in the study design.

Table 3 References:
[11] Ducloy-Bouthors AS, Mercier FJ, Grouin JM, et al. Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial. BJOG. 2021;128(11):1814-1823. doi:10.1111/1471-0528.16699

Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial
Design	Multicentre, double-blinded, parallel randomized controlled trial N= 249
Objective	To assess the efficacy of pre-emptive treatment with fibrinogen concentrate in reducing the need for red blood cell transfusion in patients with postpartum haemorrhage
Study Groups	Fibrinogen group (n= 123) Placebo group (n= 121)
Inclusion Criteria	Age ≥18 years; postpartum hemorrhage defined as bleeding from uterus and/or birth canal within 24 hours postpartum; Cesarean section with estimated perioperative blood loss >1 litre or vaginal delivery with estimated blood loss >0.5 litre and intended manual removal of placenta or estimated blood loss >1 litre and intended manual exploration of the uterus
Exclusion Criteria	Known inherited coagulation deficiencies; antenatal anti-thrombotic treatment; pre-pregnancy weight <45 kg; refusal to receive blood transfusion
Methods	Subjects with severe postpartum hemorrhage were randomized to receive a single dose of 2 g fibrinogen concentrate or placebo (saline). The dose was administered intravenously, independent of body weight and fibrinogen concentration at inclusion. The primary outcome was RBC transfusion up to 6 weeks postpartum. Secondary outcomes included total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g/litre, RBC transfusion within 4 hours, 24 hours, and 7 days, and a composite outcome of 'severe PPH'.
Duration	May 30, 2011 to July 11, 2013
Outcome Measures	Primary: RBC transfusion during a 6 week follow-up period postpartum Secondary: Total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g/litre, RBC transfusion within 4 hours, 24 hours, and 7 days, composite outcome of 'severe PPH'
Baseline Characteristics		Fibrinogen (n=123)	Placebo (n=121)
	Manual exploration of the uterus	67 (55%)	56 (46%)
	Manual removal of placenta	37 (30%)	44 (36%)
	Caesarean section	19 (15%)	21 (17%)
	Tone	68 (55%)	54 (45%)
	Trauma	54 (44%)	55 (46%)
	Tissue	76 (62%)	80 (66%)
	Thrombin	10 (8%)	13 (11%)
	Parity - Multipara	58 (47%)	58 (48%)
	Parity - Primipara	65 (53%)	63 (52%)
	Maternal weight at term (kg)	79 (13)	82 (14)
	BMI before pregnancy (kg/m²)	22.8 (3.3)	24.4 (4.5)
Results		Fibrinogen (n=123)	Placebo (n=121)	Relative Risk (95% CI)	P-value
	Need for RBC transfusion (6 weeks)	25 (20.3%)	26 (21.5%)	0.95 (0.58–1.54)	0.88
	Estimated blood loss after study drug (ml)	1700 [1500–2000]	1700 [1400–2000]	66 [278; 210]	0.37
	Need for RBC transfusion (up to 4 h)	4 (3.3%)	10 (8.3%)	0.39 (0.13–1.22)	0.11
	Need for RBC transfusion (up to 24 h)	14 (11.4%)	19 (15.7%)	0.72 (0.38–1.38)	0.35
	Severe PPH	20 (40.0%)	24 (52.2%)	0.77 (0.49–1.19)	0.31
Adverse Events	No thromboembolic events were detected. Adverse events included dizziness, shivering, fever, abdominal pain, headache, nausea or vomiting, fainting, palpitations, allergic reaction, urticaria, itching, shortness of breath, and facial edema. No significant differences in adverse events between groups
Study Author Conclusions	We found no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe postpartum haemorrhage in patients with normofibrinogenemia
Critique	The study was well-designed with a multicentre, double-blinded, randomized controlled trial format, enhancing its validity. However, the inability to include patients with massive and rapid bleeding due to the need for informed consent may have limited the study's ability to detect differences in transfusion needs. The lower-than-expected incidence of RBC transfusion also affected the power of the study. The study did not adjust fibrinogen dosing based on body weight or initial fibrinogen levels, which may have impacted the results. Despite these limitations, the study provides valuable insights into the use of fibrinogen concentrate in postpartum hemorrhage.

Table 4 References:
[12] Wikkels AJ, Edwards HM, Afshari A, et al. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth. 2015;114(4):623-633. doi:10.1093/bja/aeu444