RECOTHROM

1 INDICATIONS AND USAGE RECOTHROM Thrombin topical (Recombinant), is a topical thrombin indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age. RECOTHROM may be used in conjunction with an absorbable gelatin sponge, USP. RECOTHROM Thrombin topical (Recombinant), is a topical thrombin indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age. (1) RECOTHROM may be used in conjunction with an absorbable gelatin sponge, USP. (1)

2 DOSAGE AND ADMINISTRATION For topical use only. DO NOT INJECT. For topical use only. DO NOT INJECT. (2) • Reconstitute RECOTHROM Thrombin topical (Recombinant) powder with sterile 0.9% sodium chloride, USP, yielding a solution containing 1,000 units (international units of potency) per mL. (2.1) • Apply RECOTHROM solution with absorbable gelatin sponge or RECOTHROM Spray Applicator Kit directly to the bleeding site surface. The amount required depends upon the area of tissue to be treated. (2.2) • 5,000-unit RECOTHROM may be used in conjunction with FLOSEAL NT Hemostatic Matrix, 5mL ( 2.2 ) 2.1 Reconstitution of RECOTHROM Thrombin The volume of reconstituted RECOTHROM Thrombin topical (Recombinant) required will vary depending on the size and number of bleeding sites to be treated and the method of application. Inspect the integrity of the RECOTHROM package and contents. Do not use if the packaging or contents have been damaged or opened. Reconstitute the lyophilized powder using the supplied diluent. Use aseptic technique when handling vials and syringes. 5,000-unit RECOTHROM Thrombin topical (Recombinant) Reconstitution Units used herein represent international units of potency determined using a reference standard that has been calibrated against the World Health Organization Second International Standard for Thrombin. 1. Remove flip-off cap from the top of the RECOTHROM vial. 2. Attach the needle-free vial access device (VAD) and snap it into place on the vial by placing the vial on a flat surface and pushing the VAD straight down into the center of the vial stopper. 3. Attach the prefilled diluent syringe to the VAD. 4. Transfer the 5 mL of diluent from the syringe into the RECOTHROM vial. 5. DO NOT reuse the diluent syringe for transfer of the reconstituted product. Remove and discard the diluent syringe. 6. Gently swirl and invert the RECOTHROM vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature. RECOTHROM solution should remain in the vial until ready for transfer to a labeled sterile bowl or basin. 7. Withdraw reconstituted RECOTHROM solution into transfer syringe labeled For topical use only, DO NOT INJECT. Transfer RECOTHROM solution into a labeled sterile bowl or basin. 8. RECOTHROM is ready for application. RECOTHROM is for topical use only – DO NOT INJECT. See Application techniques below (2.2). RECOTHROM is for single use only. Discard unused contents. 20,000-unit RECOTHROM Thrombin topical (Recombinant) Reconstitution 1. Remove the flip-off cap from the top of the RECOTHROM vial and the diluent vial. 2. There are two needle-free vial access devices (VADs) provided. Attach one VAD to the RECOTHROM vial and one VAD to the diluent vial. To attach a VAD to a vial, place the vial on a flat surface and push straight down on the VAD into the center of the vial stopper. 3. Attach the empty 20-mL transfer syringe to the VAD on the diluent vial (injection of air into the diluent vial may facilitate withdrawal of the diluent). This syringe will be used twice: 1. To draw up the diluent from the diluent vial to be transferred into the RECOTHROM vial for reconstitution and 2. To draw up the reconstituted RECOTHROM solution. 4. Draw up 20 mL of diluent from the vial into the syringe. 5. Remove the diluent-filled syringe from the diluent vial and attach the syringe to the VAD on the RECOTHROM vial. 6. Transfer the 20 mL of diluent from the syringe into the RECOTHROM vial. 7. Leave the syringe attached and gently swirl and invert the RECOTHROM vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature. RECOTHROM solution should remain in the vial until ready for transfer to a labeled sterile bowl or basin. 8. Withdraw reconstituted RECOTHROM solution into the attached transfer syringe labeled For topical use only, DO NOT INJECT. Use the transfer syri…

5 WARNINGS AND PRECAUTIONS • RECOTHROM Thrombin topical (Recombinant) causes thrombosis if it enters the circulatory system. (5.1) • Hypersensitivity reactions, including anaphylaxis, may occur. (5.2) 5.1 Thrombosis RECOTHROM Thrombin topical (Recombinant) causes thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT. 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, may occur. RECOTHROM Thrombin topical (Recombinant) is produced in a genetically modified Chinese Hamster Ovary (CHO) cell line and may contain hamster or snake proteins [see Contraindications (4) and Description (11) ] .

4 CONTRAINDICATIONS • Do not inject directly into the circulatory system. • Do not use for the treatment of massive or brisk arterial bleeding. • Do not administer to patients with a history of hypersensitivity to RECOTHROM Thrombin topical (Recombinant) or any components of RECOTHROM. • Do not use in patients with known hypersensitivity to hamster proteins. • Do not inject directly into the circulatory system. (4) • Do not use for the treatment of massive or brisk arterial bleeding. (4) • Do not administer to patients with a history of hypersensitivity to RECOTHROM Thrombin topical (Recombinant), any components of RECOTHROM or hamster proteins. (4)

8.1 Pregnancy Risk Summary There are no available data regarding RECOTHROM Thrombin topical (Recombinant) in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with RECOTHROM. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

6 ADVERSE REACTIONS Thromboembolic adverse reactions were reported in 6% of surgical patients treated with RECOTHROM Thrombin topical (Recombinant) in all completed clinical trials (N=644) [see Warnings and Precautions (5.1) ] . Antibody formation to RECOTHROM occurred in <1% of patients. None of the antibodies detected neutralized native human thrombin [see Adverse Reactions (6.2) ] . • The most common adverse reaction (incidence 6%) was thromboembolic events. (5.1 , 6) • Antibody formation to RECOTHROM Thrombin topical (Recombinant) occurred in <1% of patients. None of the antibodies detected neutralized native human thrombin. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials have been performed with RECOTHROM Thrombin topical (Recombinant) applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to RECOTHROM in these studies. RECOTHROM Thrombin topical (Recombinant) Used in Conjunction with Absorbable Gelatin Sponge Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared RECOTHROM to bovine thrombin. Both thrombins were applied with a gelatin sponge in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access. 1 The incidence of thromboembolic adverse reactions was similar between the RECOTHROM and bovine thrombin treatment groups (see Table 1 ). Table 1: Incidence of Adverse Reactions with RECOTHROM Thrombin topical (Recombinant) and Bovine Thrombin Adverse Reaction Category RECOTHROM (N=205) n (%) Bovine Thrombin THROMBIN-JMI Thrombin, Topical (Bovine) (N=206) n (%) Thromboembolic events 11 (5%) 12 (6%) In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine thrombin within the previous three years were treated with RECOTHROM when undergoing surgeries (spinal, peripheral arterial bypass, or arteriovenous graft formation for hemodialysis access). 2 The incidence of thromboembolic adverse reactions in this study was 9%. In an open-label, single-group trial of re-exposure to RECOTHROM (N=31), patients with documented prior exposure to RECOTHROM were treated with RECOTHROM during surgery (spinal, peripheral arterial bypass, arteriovenous graft formation, or other procedures). 3 The incidence of thromboembolic adverse reactions in this study was 3%. In other randomized, double-blind trials across a range of surgical settings (N=130; spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the safety of RECOTHROM (n=88 patients) was compared to placebo (RECOTHROM excipients reconstituted with sterile 0.9% sodium chloride, USP) (n=42 patients). The incidence of thromboembolic adverse reactions in this study was 5% for RECOTHROM and 12% for placebo. RECOTHROM Thrombin topical (Recombinant) Applied with Spray Applicator RECOTHROM was applied with a spray applicator in two open-label clinical trials: a single-group trial in adult and pediatric burn patients (N=72; ≤16 years of age, (n=4) and ≥17 years of age, (n=68)) treated with RECOTHROM applied to the wound excision site prior to autologous skin grafting 4 ; and in a single-group trial in pediatric patients (one month to 17 years of age) undergoing synchronous burn wound excision and autologous skin grafting (N=30; ≤16 years of age, (n=26); ≥17 years of age, (n=4)). 5 In the first study, the incidence of thromboembolic adverse reactions was 1%. I…