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RAPLIXA®
(Fibrin Sealant (Human)) Powder for Topical Use Only
RAPLIXA is a fibrin sealant comprised of human plasma-derived fibrinogen and thrombin that is designed to be used as an adjunct to surgical hemostasis. Each component is separately spray dried with trehalose followed by blending the two components to provide a ready-to-use, pre-mixed, sterile, dry powder that is filled in sterile medical grade glass vials. RAPLIXA is manufactured aseptically, resulting in a sterile product in a sterile vial. RAPLIXA does not contain any preservatives.
Except for fibrinogen and thrombin, the product contains the following components added during the manufacturing: trehalose – 824 mg/g, calcium chloride – 11 mg/g, and traces of the components from the formulations of fibrinogen and thrombin raw materials: human albumin, sodium chloride, sodium citrate, and L-Arginine hydrochloride.
All human plasma used in the manufacture of RAPLIXA is tested for the presence of current specific virus infections using FDA-licensed serological assays and nucleic acid testing (NAT) assays for HBV, HIV-1/2, and HCV and found to be non-reactive (negative). The manufacturing procedures for fibrinogen and thrombin include processing steps designed to reduce the risk of viral transmission, including pasteurization, precipitation and adsorption steps.
Validation studies for fibrinogen and thrombin manufacturing steps were conducted for their capacity to inactivate and/or remove viruses. These in vitro validation studies were conducted, using samples from manufacturing intermediates spiked with virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The cumulative virus reduction factors (expressed as log10 ) are shown in Table 3 for each virus tested.
Table 3: Cumulative Virus Reduction Factors for Thrombin and Fibrinogen
| Cumulative Reduction Factors for Virus Removal/Inactivation of Human Thrombin |
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| Reduction Factors [log10 ] of Virusa tested | |||||
| Manufacturing step | HIV-1 | HSV | BVDV | CPV | HAV |
| Pasteurization, precipitation and adsorption steps | ≥19.6 | ≥21.4 | ≥13.4 | 6.6 | 8.7 |
| Cumulative Reduction Factors for Virus Removal/Inactivation of Human Fibrinogen | |||||
| Reduction Factors [log10 ] of Virusa tested | |||||
| Manufacturing step | HIV-1 | HSVb | BVDV | CPV | HAV |
| Pasteurization, precipitation and adsorption steps | ≥9.6 | ≥9.1 | ≥11.2 | ≥4.4 | ≥6.7 |
|
aHIV-1: Human Immunodeficiency Virus 1, HSV: Herpes Simplex Virus, BVDV:
Bovine Viral Diarrhea Virus, CPV: Canine Parvo Virus: a model for B19V, HAV:
Hepatitis A Virus, PRV: Pseudorabies Virus bAdditional reduction factor [log10] of 1.6 for PRV not included in cumulative reduction factor for HSV |
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RAPLIXA is a fibrin sealant indicated as an adjunct to hemostasis for mild to moderate bleeding in adults undergoing surgery when control of bleeding by standard surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical.
RAPLIXA is used in conjunction with an absorbable gelatin sponge (USP) and may be applied directly or using the RaplixaSpray device.
For topical use only.
Do not reconstitute. Use within one hour of opening.
The required amount of RAPLIXA needed to stop bleeding varies and is based on the size of the bleeding area to be treated. The maximum total dose of RAPLIXA per surgery is 3 grams. In clinical trials, it was demonstrated that smaller bleeding sites covering an area of less than 10 cm2 used 0.5 gram to 1.0 gram of RAPLIXA. Larger bleeding sites covering an area of 10-100 cm2 used 1.0 to 2.0 grams of RAPLIXA to stop bleeding. Using the RaplixaSpray device, 1.0 gram can cover a 100 cm2 bleeding surface area.
The required dose of RAPLIXA depends on the size of the bleeding area to be treated according to Table 1 below.
Table 1: Guideline for RAPLIXA Application
| Maximum Surface Area Direct Application from Vial | Maximum Surface Area Application Using RaplixaSpray Device | RAPLIXA Package Size |
| 25 cm2 | 50 cm2 | 0.5 g |
| 50 cm2 | 100 cm2 | 1 g |
| 100 cm2 | 200 cm2 | 2 g |
Applying to the surface of bleeding tissue only, administer RAPLIXA directly from the vial or using the RaplixaSpray device. RAPLIXA may be used at multiple bleeding sites in the same patient. Use no more than two vials of RAPLIXA with the RaplixaSpray device. To administer a third vial, open a new device.
Note: Refer to Absorbable Gelatin Sponge (USP) labeling for complete instructions for use.
OR
Note: Refer to the RaplixaSpray Device labeling for complete instructions for use. Refer to Absorbable Gelatin Sponge (USP) labeling for complete instructions for use.
RAPLIXA is available as dry, ready-to-use powder containing 79 mg human fibrinogen and 699 international units human thrombin per gram of powder. RAPLIXA is supplied in single-use glass vials in three sizes: 0.5 gram, 1 gram, and 2 grams per vial.
The RAPLIXA powder is supplied in sterile medical grade single-use glass vials with rubber stopper and aluminum tear-off crimp seal with a white polypropylene flip-off, packaged in an aluminum pouch, and contains no preservative.
RAPLIXA is supplied in three different presentations: 0.5 gram (NDC 62238-008-01), 1 gram (NDC 62238-008-02), and 2 gram (NDC 62238-008-03) vials.
REFERENCES
Bochicchio GV, Gupta N, Porte RJ, et al. The FINISH-3 trial: a phase 3, international, randomized, single-blind, controlled trial of topical Fibrocaps in intraoperative surgical hemostasis. J Am Coll Surg. 2015: 220(1): 70-81.
Verhoef C, Singla N, Moneta G, et al. Fibrocaps for surgical hemostasis: two randomized, controlled phase II trials. J Surg Res. 2015:194(2):679-87.
Manufactured by Nova Laboratories, Ltd., Leicester, LE18 4YL, United Kingdom. Revised: Feb 2017
The most commonly reported adverse reactions (> 5% subjects) were procedural pain, nausea, constipation, pyrexia, and hypotension.
The RAPLIXA clinical trials safety data base consists of two randomized, single-blind, controlled Phase 2 trials and one randomized single-blind controlled Phase 3 trial. All of the trials evaluated the safety and immunogenicity of RAPLIXA topically applied with a gelatin sponge and included patients undergoing spinal surgery, vascular surgery, hepatic resection, soft tissue dissection/general surgery. These trials resulted in an overall safety database of 566 patients treated with RAPLIXA with gelatin sponge. Most patients (94%) were exposed to a 1 gram vial of RAPLIXA. Overall, the incidence of adverse reactions was similar between treatment groups (Table 2).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Table 2: Commonly Reported Adverse Reactions (> 5% subjects ) in
RAPLIXA Clinical Trials
| Phase 2a | Phase 3b | Total c | ||||
| N (%) of Patients Preferred Term | R+Gd (N=86) |
Gd (N=39) |
R+Gd (N=480) |
Gd (N=239) |
R+Gd (N=566) |
Gd (N=278) |
| Procedural pain | 40 (47) | 16 (41) | 257 (54) | 134 (56) | 297 (52) | 150 (54) |
| Nausea | 26 (30) | 13 (33) | 120 (25) | 48 (20) | 146 (26) | 61 (22) |
| Constipation | 21 (24) | 9 (23) | 72 (15) | 31 (13) | 93 (16) | 40 (14) |
| Incision site pain |
5 (6) | 3 (8) | 63 (13) | 32 (13) | 68 (12) | 35 (13) |
| Pyrexia | 7 (8) | 5 (13) | 37 (8) | 11 (5) | 44 (8) | 16 (6) |
| Anemia | 4 (5) | 2 (5) | 33 (7) | 17 (7) | 37 (7) | 19 (7) |
| Vomiting | 11 (13) | 2 (5) | 26 (5) | 12 (5) | 37 (7) | 14 (5) |
| Hypotension | 2 (2) | 2 (5) | 38 (8) | 16 (7) | 40 (7) | 18 (6) |
| Pruritus | 3 (3) | 1 (3) | 33 (7) | 8 (3) | 36 (6) | 9 (3) |
| Hypertension | 1 (1) | 0 | 25 (5) | 10 (4) | 26 (5) | 10 (4) |
|
aFC-002 US and FC-002 NL clinical trials combined bFC-004 Pivotal Phase 3 clinical trial cSorted on Total RAPLIXA + Gelatin Sponge subjects dR+G = RAPLIXA + Gelatin Sponge; G = Gelatin Sponge Alone |
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The incidence of antibody formation in the Phase 3 trial was evaluated. Antibodies were detectable at baseline in 9/440 of RAPLIXA-treated patients (2%) and 9/222 of gelatin sponge-treated patients (4%). Nine of 440 patients (2%) in the RAPLIXA group and 6 of 222 patients (3%) in the gelatin sponge alone group developed anti-thrombin antibodies (non-neutralizing) during the trial. The clinical significance of these antibodies is not known.
Anti-fibrinogen antibodies were not detected pre- or post-treatment in any subjects that were positive for anti-thrombin antibodies.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RAPLIXA with the incidence of antibodies to other products may be misleading.
No Information Provided
Included as part of the "PRECAUTIONS" Section
Life-threatening thromboembolic events may result from intravascular application of RAPLIXA.
Air or gas embolism has occurred with the use of spray devices employing pressure regulators to administer fibrin sealants. This appears to be related to the use of the spray device at higher than manufacturer recommended pressures and in close proximity to the tissue surface. Reports with the use of other devices describe air emboli that are life-threatening and include fatality. To minimize this risk, operate the RaplixaSpray device according to the manufacturer's instructions. In the absence of instructions, operate at a maximum air pressure of 1.5 bar (22 psi) and at a minimum distance of 5 cm (2 inches) from the bleeding surface. Monitor changes in blood pressure, pulse, oxygen saturation, and end tidal CO2 for signs and symptoms of embolism.
Because the biological components of this product are made of human plasma, RAPLIXA may carry a risk of transmitting infectious agents, such as viruses the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite manufacturing steps designed to reduce the risk of infectious agent transmission. The risk of transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain infectious agents, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products.
All infections considered by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Mallinckrodt Hospital Products Inc. at 1-800- 778-7898.
Allergic type hypersensitivity reactions may occur. Signs of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, discontinue administration immediately.
Long-term animal studies to evaluate the carcinogenic potential of RAPLIXA or studies to determine the effects of RAPLIXA on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of RAPLIXA was completed and suggests minimal carcinogenic risk from product use.
Animal reproduction studies have not been conducted with RAPLIXA. It is also not known whether RAPLIXA can cause fetal harm when administered to pregnant women or can affect reproductive capacity. RAPLIXA should be given to a pregnant woman only if clearly needed.
It is not known whether RAPLIXA is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administering to a nursing woman.
Safety and effectiveness of RAPLIXA in pediatric patients has not been established.
Clinical trials included 207/566 subjects of 65 years of age or older who were treated with RAPLIXA. No differences in safety and efficacy were observed between elderly and younger patients.
No Information Provided
RAPLIXA contains a spray-dried mixture of human plasma-derived fibrinogen and human plasmaderived thrombin powders that are designed to mimic the final steps in the coagulation cascade. RAPLIXA dissolves readily on contact with aqueous fluids (e.g., blood) activating thrombin which triggers an immediate conversion of fibrinogen into fibrin, and subsequent clot formation.
Formal pharmacokinetic studies have not been performed. Because RAPLIXA is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.
Single or multiple dose implantation studies applying RAPLIXA with the absorbable gelatin sponge (USP) into liver or spleen surgical wounds showed progressive biodegradation of RAPLIXA, consistent with metabolism via fibrinolysis and phagocytosis. Approximately 5 to 10% of RAPLIXA and the carrier gelatin sponge remained at the application site at study termination 12 weeks after surgery.
RAPLIXA (plus gelatin sponge) was evaluated in a randomized (2:1), single-blind, controlled clinical study against absorbable gelatin sponge (USP) in mild (oozing and/or capillary leakage) to moderate (gradual and steady flow) surgical bleeding. RAPLIXA was applied directly or using the RaplixaSpray device. The study enrolled approximately 180 subjects in each of four surgical indications: spinal surgery, hepatic resection, vascular surgery, and soft tissue dissection. Each surgical indication was evaluated separately for efficacy.
The objective of the study was to demonstrate the superiority of RAPLIXA (applied directly or using RaplixaSpray) plus gelatin sponge, as compared to gelatin sponge alone. Efficacy was evaluated by time to hemostasis within the 5 minute observation period.
The study included 721 subjects randomized in a single-blinded manner during surgery, in a 2:1 ratio to treatment with RAPLIXA plus gelatin sponge (active group) or gelatin sponge alone (control group) after an appropriate target bleeding site (TBS) was identified. There were 181 subjects treated for soft tissue surgery, 183 subjects treated for spinal surgery, 180 subjects treated for hepatic resection and 175 subjects treated for vascular surgery.
Results of this study demonstrated that treatment with RAPLIXA plus gelatin sponge was superior in achieving hemostasis compared to treatment with gelatin sponge alone. These results were statistically significant in the efficacy (n=719) and ITT (n=721) populations. Table 4 summarizes the primary efficacy endpoint of the time to hemostasis within 5 minutes in the efficacy population.
Table 4: Efficacy Endpoint: Time to Hemostasis within 5 Minutes (Efficacy Population)
| Surgery Type | ||||
| Spinal (n=183)a |
Vascular (n=175)b |
Hepatic
Resection (n=180)c |
Soft Tissue Dissection (n=181)d | |
| Median TTH: RAPLIXA plus gelatin sponge (95% CI) | 1.0 (-, -) | 2.0 (1.5, 2.5) | 1.0 (1.0, 1.5) | 1.5 (1.0, 1.5) |
| Median TTH: gelatin sponge (95% CI) | 2.5 (2, 3) | 4.0 (3, 5) | 2.0 (1.5, 2.5) | 2.5 (2.0, 3.5) |
| P valuee | <0.0001 | <0.0001 | <0.0001 | <0.0001 |
| Cox proportional hazard ratio (95% CI) | 3.3 [2.3 , 4.7] |
2.1 [1.5 , 3.1] |
2.3 [1.6 , 3.2] |
3.4 [2.3 , 4.8] |
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aRAPLIXA + Gelatin Sponge n=122; Gelatin Sponge Alone n=61 bRAPLIXA + Gelatin Sponge n=117; Gelatin Sponge Alone n=58 cRAPLIXA + Gelatin Sponge n=119; Gelatin Sponge Alone n=61 dRAPLIXA + Gelatin Sponge n=122; Gelatin Sponge Alone n=59 eLog Rank Test |
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