VA Class:BL116
Thrombin alfa (thrombin [recombinant]), a biosynthetic (recombinant DNA origin) preparation of naturally occurring human thrombin, is a topical hemostatic agent.1, 2, 3, 4, 5, 6, 7, 11
Thrombin alfa (thrombin [recombinant]) is used topically as an aid in achieving hemostasis at accessible sites of oozing blood and minor bleeding from capillaries and small venules when control of bleeding using standard surgical measures (e.g., suture, ligature, electrocautery) is ineffective or impractical.1, 2, 4, 6, 11 The drug should not be used for massive or brisk arterial bleeding.1, 6 (See Cautions: Contraindications.) Thrombin alfa may be used alone or in conjunction with an absorbable gelatin sponge to establish hemostasis during various types of surgery (e.g., spinal surgery, liver resection, peripheral arterial bypass surgery).1, 2, 4, 6, 12
Safety and efficacy of thrombin alfa as an aid to hemostasis in surgery is based principally on results of a phase 3 randomized, double-blind, active-controlled study in 411 adults undergoing various surgical procedures (i.e., spinal surgery, hepatic surgery, peripheral arterial bypass surgery, arteriovenous graft formation).1, 2, 4, 6 Patients received thrombin alfa or bovine thrombin 1000 units/mL, applied directly to selected bleeding sites with an absorbable gelatin sponge.1, 2, 4, 6, 12 Thrombin alfa and bovine thrombin were found to be equally effective in establishing hemostasis (defined as the incidence of hemostasis [visible bleeding cessation] within 10 minutes of drug application); hemostasis was achieved in 95.4 or 95.1% of patients receiving thrombin alfa or bovine thrombin, respectively.1, 2, 4, 6, 11, 12
Reconstitution and Administration
Thrombin alfa (thrombin [recombinant]) is applied topically to surfaces of bleeding tissue.1, 2, 6 The drug must not be injected into the circulatory system because of the risk of thrombosis and even death .1, 7, 11 (See Cautions: Contraindications.) Topical thrombin solutions should be separated from parenteral preparations to avoid inadvertent injection. 102 Reconstituted solutions should never be left in a syringe as an intermediate step. 102
Commercially available thrombin alfa lyophilized powder is reconstituted by adding 5 or 20 mL of the manufacturer-supplied diluent (0.9% sodium chloride injection) to a vial labeled as containing 5000 or 20,000 units, respectively, of thrombin alfa to provide a solution containing 1000 units/mL of the drug.1, 6 The vial should be gently swirled until the powder is completely dissolved; reconstitution usually takes less than 1 minute at room temperature.1 The reconstituted product should be drawn into a sterile syringe and an auxiliary label indicating that the product is for topical use only should be applied.1, 102 The resultant solution must be used within 24 hours of reconstitution.1
Reconstituted thrombin alfa solutions may be applied or sprayed directly onto bleeding tissue (using a sterile syringe sprayer or spray pump) or applied topically using an absorbable gelatin sponge.1, 6, 12 The syringe sprayer or spray pump (available as part of the spray applicator kit) should be used according to the accompanying instructions provided by the manufacturer.1, 12 When used in conjunction with an absorbable gelatin sponge, the reconstituted solution should be transferred to a sterile bowl or basin.1, 6 Sponge strips of the desired size are then immersed in the reconstituted solution to allow complete saturation with thrombin.1, 6 The saturated strips should be squeezed gently to remove excess thrombin and then applied in a single layer to the bleeding site.1, 6 The manufacturer's labeling should be consulted for detailed instructions on use of absorbable gelatin sponge preparations.1
The volume of thrombin alfa required to achieve hemostasis varies depending on the total number of bleeding sites, the surface area being treated, and the method of application.1, 6 In clinical studies, most patients achieved hemostasis within 10 minutes following a single application of thrombin alfa.1, 2, 3, 4
Do not inject directly into the circulatory system.1, 6, 11 (See Thrombosis under Warnings/Precautions: Warnings, in Cautions.)
Treatment of massive or brisk arterial bleeding.1, 6
Known hypersensitivity to thrombin alfa (thrombin [recombinant]), hamster proteins, or any ingredient in the formulation.1, 6
Potential risk of thrombosis if thrombin is absorbed systemically.1, 6, 11 Thrombin alfa should not be injected directly into the circulatory system; serious complications including hypotension, systemic thrombosis, and death may result .1, 7, 11, 12 (See Cautions: Contraindications.) Precautionary measures should be taken to avoid inadvertent injection.102
Potential for allergic reactions in patients with known hypersensitivity to snake proteins (due to use of snake-venom-derived prothrombin activator in production process).1, 11
Patients receiving thrombin alfa may develop antibodies to the drug.1 In clinical trials, approximately 1-2% of patients developed non-neutralizing anti-thrombin alfa antibodies following exposure to thrombin alfa; however, a relationship between antibody formation and clinically important adverse effects (e.g., excessive bleeding) has not been observed.1, 2, 3, 6 In contrast, antibody development in patients receiving bovine-derived thrombin preparations have occasionally been associated with hemostatic abnormalities ranging from asymptomatic alterations in hemostatic indices (e.g., prothrombin time, partial thromboplastin time) to thrombosis, bleeding, and/or death.2, 3, 5, 6, 7, 8, 10, 11
Current evidence suggests that the risk of antibody development with thrombin alfa is lower than that associated with bovine-derived thrombin.1, 2, 4, 6, 7 In a comparative study in patients who received thrombin alfa or bovine thrombin for surgical hemostasis, the incidence of specific anti-product antibody formation (defined as seroconversion or antibody titer increase of more than 1 unit) at postoperative day 29 was substantially lower in patients who received the thrombin alfa versus the bovine-derived thrombin preparation (1.5% versus 22%, respectively).1, 2, 6, 11 None of the antibodies detected in patients receiving thrombin alfa were neutralizing to human thrombin.1, 2 Although formation of antibodies in either treatment group did not result in any clinically important adverse effects (e.g., excessive bleeding), the study was not of sufficient size or duration to detect such a correlation.1, 2, 4, 12 In addition, variations in antibody assays, patient populations, and other underlying factors make it difficult to compare these rates of immunogenicity with those reported in other clinical studies.1
Presence of preexisting antibodies to bovine thrombin does not appear to affect the immunogenicity of thrombin alfa.14 There are limited data on repeated exposure to thrombin alfa.1, 6, 7 An additional study is being performed to evaluate immunogenicity and safety of reexposure to thrombin alfa.6, 12
Category C.1 (See Users Guide.)
Thrombin alfa has been evaluated in a limited number of pediatric patients (12-17 years of age) undergoing burn wound excision prior to grafting.13 Manufacturer states that safety and efficacy in pediatric patients younger than 12 years of age have not been established.12, 13
Among the total number of patients enrolled in the phase 2 and phase 3 pivotal trials of thrombin alfa applied with an absorbable gelatin sponge, 38% were 65 years of age or older, and 16% were 75 years of age or older.1, 12 Although no overall differences in efficacy or safety were observed between geriatric and younger patients and other clinical experience has not revealed any evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1
The most common adverse effects reported in patients receiving thrombin alfa in clinical studies were incision site complications, procedural pain, nausea, constipation, insomnia, and vomiting; such adverse effects are expected to be common in a postoperative population and a causal relationship to the drug has not been established.1, 2, 3, 4, 6, 12
Formal drug interaction studies with thrombin alfa (thrombin [recombinant]) have not been performed to date.1
Thrombin alfa (thrombin [recombinant]) is a sterile, lyophilized powder containing thrombin prepared using recombinant DNA technology.1, 5, 10, 11 Thrombin alfa is structurally and pharmacologically similar to endogenous human thrombin; the amino acid sequences of both proteins are identical.1, 4, 5, 6, 7, 11
Activated by both the intrinsic and extrinsic blood coagulation pathways, thrombin promotes hemostasis principally by converting fibrinogen to fibrin, the final step in the coagulation cascade.1, 2, 4, 5, 6, 7, 10, 11 However, thrombin's effects in hemostasis are complex and include other mechanisms (e.g., platelet activation and aggregation, activation of factor XIII leading to fibrin crosslinking and clot stabilization).1, 4, 5, 7, 10, 11 Thrombin is capable of converting fibrinogen directly to fibrin at the site of vessel injury without the addition of other substances, thus providing a rationale for its use as a topical hemostatic agent.1, 3, 4, 5, 10 Clot integrity and time to hemostasis are dependent on concentrations of thrombin and fibrinogen present during clot formation.8, 9, 15
Studies with radiolabeled drug in animal models indicate that thrombin alfa is rapidly (less than 5 minutes) inactivated in the circulation after complexation with endogenous inhibitors; the resulting complexes are then removed by the liver.1, 11, 12
Thrombin alfa is prepared by recombinant DNA technology in a genetically modified mammalian cell (Chinese hamster ovary) expression system free of known infectious agents; the drug does not contain human or animal additives.1, 2, 3, 5, 11 The manufacturing process includes additional purification steps (nanofiltration, solvent/detergent) to further reduce the risk of viral transmission.1, 5
Risk of blood clotting disorders if absorbed systemically; importance of contacting a clinician if any new or unusual symptoms of thrombosis occur.1, 9
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Powder | 5000 units | Recothrom® (with 0.9% sodium chloride diluent; package also contains needle-free transfer device and 5-mL sterile syringe) | ZymoGenetics |
20,000 units | Recothrom® (with 0.9% sodium chloride diluent; package also contains 2 sterile needle-free transfer devices and 20-mL sterile syringe) | ZymoGenetics | ||
Recothrom® (with 0.9% sodium chloride diluent; spray applicator kit contains spray pump, spray bottle, syringe spray tip, syringe, and bowl) | ZymoGenetics |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions November 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. ZymoGenetics, Inc. Recothrom® (thrombin [recombinant]) powder for solution prescribing information. Seattle, WA; 2009 May.
2. Chapman WC, Singla N, Genyk Y et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg . 2007; 205:256-65. [PubMed 17660072]
3. Chapman WC, Lockstadt H, Singla N et al. Phase 2, randomized, double-blind, placebo-controlled, multicenter clinical evaluation of recombinant human thrombin in multiple surgical indications. J Thromb Haemost . 2006; 4:2083-5. [PubMed 16961621]
4. Weaver FA, Lew W, Granke K et al. A comparison of recombinant thrombin to bovine thrombin as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures. J Vasc Surg . 2008; 47:1266-73. [PubMed 18440754]
5. Bishop PD, Lewis KB, Schultz J et al. Comparison of recombinant human thrombin and plasma-derived human alpha-thrombin. Semin Thromb Hemost . 2006; 32 Suppl 1:86-97. [PubMed 16673270]
6. Cada DJ, Levien T, Baker DE. Thrombin, topical (recombinant). Hosp Pharm . 2008; 43:577-85.
7. Heffernan JK, Ponce RA, Zuckerman LA et al. Preclinical safety of recombinant human thrombin. Regul Toxicol Pharmacol . 2007; 47:48-58. [PubMed 16971028]
8. King Pharmaceuticals, Inc. Thrombin-JMI® thrombin (bovine origin) prescribing information. Middleton, WI; 2007 Nov.
9. Johnson and Johnson Wound Management. Evithrom® thrombin (human) for topical use prescribing information. Somerville, NJ; 2007 Sep.
10. Lundblad RL, Bradshaw RA, Gabriel D et al. A review of the therapeutic uses of thrombin. Thromb Haemost . 2004; 91:851-60. [PubMed 15116244]
11. Anderson CD, Bowman LJ, Chapman WC. Topical use of recombinant human thrombin for operative hemostasis. Expert Opin Biol Ther . 2009; 9:133-7. [PubMed 19063699]
12. Zymogenetics, Seattle, WA: Personal communication.
13. Greenhalgh DG, Gamelli RL, Collins J et al. Recombinant thrombin: Safety and immunogenicity in burn wound excision and grafting. J Burn Care Res . 2009; 30:1-9. [PubMed 19060769]
14. Singla NK, Ballard JL, Moneta G et al. A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis. J Am Coll Surg . 2009; 209:68-74. [PubMed 19651065]
15. Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev . 2007; 21:131-42. [PubMed 17,208341]
102. Cohen MR, Smetzer JL. ISMP medical error report analysis: danger of giving topical thrombin intravascularly. Hosp Pharm. 2007; 42:284-5.