Additive Formula 3

6 ADVERSE REACTIONS Citrate reactions or toxicity may occur with the infusion of blood products to patients. The recipient of the blood containing citrate should be monitored for the signs and symptoms of citrate toxicity. The signs and symptoms of citrate toxicity begin with paresthesia, a "tingling" sensation around the mouth or in the extremities, followed by severe reactions that are characterized by hypotension and possible cardiac arrhythmia. Citrate toxicity may occur more frequently in patients who are hypothermic, have impaired liver or renal function, or have low calcium levels because of an underlying disease. Citrate reactions or toxicity may occur with the infusion of blood containing citrate. The recipient of the blood containing citrate should be monitored for the signs and symptoms of citrate toxicity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Terumo BCT, Inc. at 1-877-339-4228 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS DO NOT INFUSE ADDITIVE SOLUTION FORMULA 3 (AS-3) DIRECTLY TO THE DONOR. DO NOT INFUSE AS-3 DIRECTLY TO THE DONOR. ( 4 )

11 DESCRIPTION ADDITIVE SOLUTION FORMULA 3 (AS-3) is designed to be added to packed RBC collected in apheresis procedures, and acts to preserve and extend the shelf life of packed RBC products for later transfusion to patients. The solution is intended to be metered by an apheresis device during apheresis procedures or added manually after a collection. The solution is sterile and non-pyrogenic, and it contains no bacteriostatic or antimicrobial agents. The formulas of the active ingredients are provided in Table 1. Table 1: Active Ingredients Ingredients Molecular Formula Molecular Weight Dextrose Monohydrate USP C 6 H 12 O 6 ∙ H 2 O 198.17 Trisodium Citrate Dihydrate USP C 6 H 9 Na 3 O 9 294.10 Sodium Chloride USP NaCl 58.44 Monobasic Sodium Phosphate Monohydrate USP NaH 2 PO 4 ∙ H 2 O 137.99 Citric Acid Monohydrate USP C 6 H 8 0 7 ∙ H 2 O 210.14 Adenine USP C 5 H 5 N 5 135.13 Water for Injection USP H 2 O 18.00 Each 100 mL of ADDITIVE SOLUTION FORMULA 3 (AS-3) contains: Dextrose Monohydrate USP 1.10 g; Trisodium Citrate Dihydrate USP 0.59 g; Sodium Chloride USP 0.41 g; Monobasic Sodium Phosphate Monohydrate USP 0.28 g; Citric Acid Monohydrate USP 0.042 g; Adenine USP 0.03 g; and Water for Injection USP. ADDITIVE SOLUTION FORMULA 3 is available in three volumes: 100 mL, 200 mL and 350 mL. The 100 mL bags are individually wrapped with a clear plastic film. Six individually wrapped bags are then vacuum-sealed in a foil pouch, which serves as a vapor barrier to prevent water loss during storage. After you remove the individual solution bags from the foil pouch, you can either leave them in the clear plastic film or remove and discard it. Once the foil pouch has been opened, use all six of the solution bags within 2 weeks. The 200 mL and 350 mL bags are individually wrapped with a clear plastic film. These larger volumes do not require the additional vapor barrier. Once the clear plastic film has been removed, use the solution within 2 weeks. The Polyolefin bag is not made with natural rubber latex. The bag is made from a multilayered film. It contains materials that have been tested to demonstrate the suitability of the container for storing pharmaceutical solutions. The bag is nontoxic and biologically inert. The bag-solution unit is a closed system and is not dependent upon entry of external air during administration.

2 DOSAGE AND ADMINISTRATION AS-3 is added to tubing sets after apheresis collections, after the donor has been disconnected. ( 2 ) AS-3 may only be used with the Trima Accel apheresis device. For instructions on the use of the solution see the device operator's manual. ( 2.1 ) Follow the directions for connecting the AS-3 bag to the tubing set of a blood collection system. ( 2.2 ) 2.1 General Dosing Information ADDITIVE SOLUTION FORMULA 3 (AS-3) is connected to the tubing set used for an apheresis RBC collection procedure after the collection has been completed. For automated RBC procedures, the recommended dose is determined by the apheresis device and metered into the tubing set by the apheresis device. To add the product manually, refer to the apheresis system operator's manual to determine the recommended dose. For instructions on the use of the solution with the apheresis device and tubing set, see the device operator's manual. 2.2 Administration Directions for connecting the ADDITIVE SOLUTION FORMULA 3 (AS-3) bag to the apheresis device. Automated RBC additive solution procedures: Connect ADDITIVE SOLUTION FORMULA 3 (AS-3) after the collection is over and the donor is disconnected. For automated addition of the product, the system will prompt you to connect the bag. Remove the overwrap by pulling down at notch, and remove the AS-3 bag. Before use, perform the following checks: Ensure that the solution is the ADDITIVE SOLUTION FORMULA 3 (AS-3) and is within the expiration date. Inspect the bag in good light. Do not use if the container is damaged, leaking or if there is any visible sign of deterioration. Check for leaks by gently squeezing the bag. If leaks are found, discard the bag. Inspect the solution in good light. Use only if solution is clear and free of particulate matter. Bags showing cloudiness, haze, or particulate matter should not be used. Protect from sharp objects. Remove the protective cap from the port on the bag. Connect the bag to the apheresis device tubing set using aseptic technique and hang the solution. Break the frangible connector. When you break frangible connectors, bend them in both directions to ensure that you break them completely. Failure to do so may result in restricted flow. Proceed according to the apheresis device operator's manual. Manual RBC additive solution procedures: Connect ADDITIVE SOLUTION FORMULA 3 (AS-3) after the collection is over and the donor is disconnected. Seal the RBC product lines as close to the cassette as possible. Remove the overwrap by pulling down at notch, and remove the ADDITIVE SOLUTION FORMULA 3 bag. Before use, perform the following checks: Ensure that the solution is the ADDITIVE SOLUTION FORMULA 3 (AS-3) and is within the expiration date. Inspect the bag in good light. Do not use if the container is damaged, leaking or if there is any visible sign of deterioration. Check for leaks by gently squeezing the bag. If leaks are found, discard the bag. Inspect the solution in good light. Use only if solution is clear and free of particulate matter. Bags showing cloudiness, haze, or particulate matter should not be used. Protect from sharp objects. Remove the protective cap from the port on the bag. Connect the bag to the apheresis device tubing set using aseptic technique and hang the solution. Break the frangible connector. When you break frangible connectors, bend them in both directions to ensure that you break them completely. Failure to do so may result in restricted flow. Proceed according to the apheresis device operator's manual.

1 INDICATIONS AND USAGE Use only with Trima Accel red blood cell (RBC) apheresis collections. [See Dosage and Administration (2) .] Use only with Trima Accel red blood cell (RBC) apheresis collections. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ADDITIVE SOLUTION FORMULA 3 acts to preserve and extend the shelf life of packed RBC products for later transfusion to patients. The following ingredients are key components of the solution: Adenine to support adenosine triphosphate (ATP) levels Citrate for membrane protection, anticoagulation and pH regulation Sodium (Sodium Chloride and Sodium Citrate) and dextrose for isotonicity Dextrose for RBC nutrition This solution has no pharmacological effect.

12.1 Mechanism of Action ADDITIVE SOLUTION FORMULA 3 acts to preserve and extend the shelf life of packed RBC products for later transfusion to patients. The following ingredients are key components of the solution: Adenine to support adenosine triphosphate (ATP) levels Citrate for membrane protection, anticoagulation and pH regulation Sodium (Sodium Chloride and Sodium Citrate) and dextrose for isotonicity Dextrose for RBC nutrition This solution has no pharmacological effect.

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3 DOSAGE FORMS AND STRENGTHS 100 mL, 200 mL and 350 mL ADDITIVE SOLUTION FORMULA 3 (AS-3) products are sterile solutions in a Polyolefin bag. Each 100 mL contains: Dextrose Monohydrate USP 1.10 g; Trisodium Citrate Dihydrate USP 0.59 g; Sodium Chloride USP 0.41 g; Monobasic Sodium Phosphate Monohydrate USP 0.28 g; Citric Acid Monohydrate USP 0.042 g; Adenine USP 0.03 g; and Water for Injection USP. 100 mL, 200 mL, or 350 mL sterile fluid in a Polyolefin bag. ( 3 )

Additive Formula 3 Dextrose Monohydrate, Trisodium Citrate Dihydrate, Sodium Chloride, Sodium Phosphate, Monobasic, Monohydrate, Citric Acid Monohydrate, and Adenine Dextrose Monohydrate ANHYDROUS DEXTROSE Trisodium Citrate Dihydrate ANHYDROUS CITRIC ACID Sodium Chloride CHLORIDE ION SODIUM CATION SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE PHOSPHATE ION SODIUM CATION Citric Acid Monohydrate ANHYDROUS CITRIC ACID Adenine Adenine Water Additive Formula 3 Dextrose Monohydrate, Trisodium Citrate Dihydrate, Sodium Chloride, Sodium Phosphate, Monobasic, Monohydrate, Citric Acid Monohydrate, and Adenine Dextrose Monohydrate ANHYDROUS DEXTROSE Trisodium Citrate Dihydrate ANHYDROUS CITRIC ACID Sodium Chloride CHLORIDE ION SODIUM CATION SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE PHOSPHATE ION SODIUM CATION Citric Acid Monohydrate ANHYDROUS CITRIC ACID Adenine Adenine Water Additive Formula 3 Dextrose Monohydrate, Trisodium Citrate Dihydrate, Sodium Chloride, Sodium Phosphate, Monobasic, Monohydrate, Citric Acid Monohydrate, and Adenine Dextrose Monohydrate ANHYDROUS DEXTROSE Trisodium Citrate Dihydrate ANHYDROUS CITRIC ACID Sodium Chloride CHLORIDE ION SODIUM CATION SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE PHOSPHATE ION SODIUM CATION Citric Acid Monohydrate ANHYDROUS CITRIC ACID Adenine Adenine Water

BN001214

Additive Formula 3

Dextrose Monohydrate, Trisodium Citrate Dihydrate, Sodium Chloride, Sodium Phosphate, Monobasic, Monohydrate, Citric Acid Monohydrate, and Adenine

14537-826

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 100 mL Bag Pouch Carton Label Additive Solution Formula 3 (AS-3) Catalog # 40824 Polyolefin Bag 6 X 6 X 100 mL units NDC 14537-824-10 Use only with Trima Accel red blood cell apheresis collections. See apheresis device operator's manual for complete instructions. Read the package insert before use. Sterile. Non-pyrogenic. Sterilized with steam. Caution: Do not use if the bag is damaged. Use only if solution is clear and free of particulate matter. Single use bag. Discard any unused product. Not for direct intravenous infusion. Rx Only. Recommended storage: Up to 25 °C. Protect from freezing. Protect from light. Each 100 mL contains: Dextrose Monohydrate USP 1.10 g Trisodium Citrate Dihydrate USP 0.588 g Sodium Chloride USP 0.410 g Monobasic Sodium Phosphate Monohydrate USP 0.276 g Citric Acid Monohydrate USP 0.042 g Adenine USP 0.030 g In Water for Injection USP Manufactured by Terumo BCT, Inc. TERUMOBCT 10811 W. Collins Ave., Lakewood CO 80215, USA 777965-076 Lot Expiry Date PRINCIPAL DISPLAY PANEL - 100 mL Bag Pouch Carton Label

Issued: July 18, 2018 Manufactured by Terumo BCT, Inc. Lakewood, CO 80215

14 CLINICAL STUDIES The in vivo and in vitro quality of RBCs stored for 42 days in ADDITIVE SOLUTION FORMULA 3 (AS-3) storage solution has been assessed in three clinical studies. In Vivo Recovery of Autologous Radiolabeled RBC A single-arm, multicenter, in vivo study was conducted to assess the recovery of radiolabeled RBCs 24 hours post infusion. Acceptability of in vivo recovery was determined using established FDA-CBER acceptance criteria. Double collection RBCs (dRBC) were collected using the Trima Accel system and stored in ADDITIVE SOLUTION FORMULA 3 (AS-3) solution for 42 days, then radiolabeled with 51 Chromium, and transfused back to the original subject. Table 2 summarizes the in vivo recovery data. Of the 27 units transfused, 26 had > 75% RBC recovery. Table 2: In vivo Radiolabeled RBC Recovery Outcome Measure Study Site (N) Average (SD) Min, Max Abbreviations: Max= Maximum, Min= Minimum, N= Number of Units Transfused, RBC= Red Blood Cell, SD= Standard Deviation Overall Day 42 infused, 24-hour RBC Radiolabel Recovery (%) Site 1 (12) 79.3 (5.6) 67.5, 86.5 Site 2 (15) 87.1 (5.5) 79.0, 98.1 FDA-CBER Criteria for Acceptable Recovery: Radiolabeled RBC recoveries should average at least 75%, with a standard deviation of at most 9%. In addition, the 95% one-sided lower confidence limit for the population proportion of successes should be > 70%, with success being defined as an individual red blood cell in vivo recovery of at least 75%. No more than 3 out of 24 data points may have less than 75% radiolabeled red cell recovery at 24 hours post infusion. The primary outcome was met for RBCs collected on the Trima Accel system and stored in ADDITIVE SOLUTION FORMULA 3 (AS-3) storage solution. In Vitro RBC Quality Studies The in vitro quality of RBCs collected in single RBC collection (sRBC) and dRBC procedures using the Trima Accel system was assessed after 42 days of storage in ADDITIVE SOLUTION FORMULA 3 (AS-3) solution in a multicenter, paired study. In vitro quality was determined using established FDA-CBER acceptance criteria. The quality of RBCs stored in ADDITIVE SOLUTION FORMULA 3 (AS-3) solution (test) was compared to RBCs stored in plasma (control). Table summarizes the in vitro RBC quality data for collection on the Trima Accel system and storage in ADDITIVE SOLUTION FORMULA 3 (AS-3) solution. Table 3: In Vitro Quality Measures for RBCs Collected using the Trima Accel System and Stored in ADDITIVE SOLUTION FORMULA 3 (AS-3) Outcome Measure Site (N) Average (SD) Min, Max Abbreviations: HCT = hematocrit, HgB = hemoglobin, Max = Maximum, Min = Minimum, N = Number of Units, RBC = Red Blood Cell, SD = Standard Deviation Day 42 Hemolysis for Single RBC Collection Percent hemolysis was calculated from plasma free hemoglobin using the equation: %Hemolysis = (100 – RBC Product HCT)* Plasma Hgb / (RBC Product Hgb). (%) Site 1 (32) 0.16 (0.06) 0.06, 0.33 Site 2 (18) 0.34 (0.18) 0.12, 0.70 Site 3 (18) 0.26 (0.11) 0.09, 0.47 Day 42 Hemolysis for Double RBC Collection (%) Site 1 (25) 0.15 (0.05) 0.06, 0.29 Site 2 (24) 0.39 (0.19) 0.16, 0.95 Site 3 (21) 0.26 (0.12) 0.13, 0.61 Change in pH from Day 0 to Day 42 for Single RBC Collection The difference in pH between Test and Control on Day 42 was calculated as: ΔpH = │pHTest – pHControl│ ≤ 0.5 where the difference was expected to be less than or equal to 0.5 pH units. Site 1 (31) 0.03 (0.02) 0.00, 0.08 Site 2 (18) 0.03 (0.03) 0.00, 0.11 Site 3 (16) 0.02 (0.02) 0.00, 0.07 Change in pH from Day 0 to Day 42 for Double RBC Collection Site 1 (23) 0.02 (0.02) 0.00, 0.05 Site 2 (23) 0.02 (0.03) 0.00, 0.15 Site 3 (19) 0.02 (0.02) 0.00, 0.08 Ratio of ATP Retention for Single Collection RBC Units (test/control) ATP retention was determined for test and control units across all sites and calculated as ATP Level on Day 42 / ATP Level on Day 0. All sites (65) 1.02 (0.18) 0.46, 1.47 Ratio of ATP Retention for Double Collection RBC Units (test/control) All sites (65) 1.07 (0.19) 0.55, 1.51 Ratio of the Normalized Leaked Potassium for Single Collection RBC Units (test/control) Normalized potassium was calculated by determining the total number of millimoles of potassium leaked from the RBCs into the supernatant volume and dividing this by the total hemoglobin in the stored product. Normalized Leaked Potassium = Volume*(1-Hct/100)*(d42[K+] – d0[K+]) / Total Hemoglobin All sites (65) 0.98 (0.07) 0.76, 1.13 Ratio of the Normalized Leaked Potassium for Double Collection RBC Units (test/control) All Sites (64) 1.00 (0.08) 0.85, 1.24 FDA-CBER Criteria for Acceptable Day 42 Hemolysis: Zero failures (hemolysis ≥ 1% after 42-day storage) out of 60 test units that were not excluded from analysis by the Extreme Studentized Deviate test with α=0.05, which satisfies the binomial distribution testing requirement that, with 95% probability and a one-sided 95% lower confidence limit, the post-storage hemolysis was less than 1% per unit. There were 0/68 sRBC test units and 0/70 dRBC test units with Day 42 hemolysis ≥ 1%. No donors were excluded as hemolysis was < 1% for all test units. Therefore, the primary objective was met for RBCs stored in ADDITIVE SOLUTION FORMULA 3 (AS-3). The in vitro quality of sRBC and dRBC units collected using the Trima Accel system was assessed after 42 days of storage in AS-3 solution in a multicenter study. The quality of RBCs was compared between sRBC and dRBC units, and between units A and B of the dRBC collection. Table summarizes the in vitro RBC quality data for collection using the Trima Accel system and storage in ADDITIVE SOLUTION FORMULA 3 (AS-3). Table 4: In Vitro Quality Measures for RBCs Collected using the Trima Accel System and Stored in ADDITIVE SOLUTION FORMULA 3 (AS-3) Outcome Measure All outcome measures are shown after 42 days of storage in AS-3 solution. Site RBC Unit P Value All comparisons were performed using a Student's T-test. A 2-tailed paired comparison was performed for dRBC A v dRBC B. A 2- tailed, two sample, equal variance comparison was performed for sRBC v dRBC units. dRBC A dRBC B sRBC dRBC A v dRBC B sRBC v dRBC Abbreviations: dRBC A = Unit A of the Double Red Blood Cell Collection, dRBC B = Unit B of the Double Red Blood Cell Collection, sRBC = Single Red Blood Cell Unit, SD = Standard Deviation Hematocrit (%), mean (SD) Site 1 54.4 (3.7) 53.9 (3.6) 55.8 (4.4) 0.132 0.253 Site 2 56.0 (3.9) 53.3 (11.6) 58.4 (3.6) 0.398 0.149 pH, mean (SD) Site 1 6.4 (0.04) 6.4 (0.05) 6.5 (0.08) 0.760 0.643 Site 2 6.4 (0.1) 6.4 (0.1) 6.4 (0.1) 0.175 0.217 pCO 2 , mean (SD) Site 1 140 (8) 137 (8) 139 (12) 0.172 0.525 Site 2 130.5 (11.7) 130.4 (12.4) 125.6 (11.1) 1.00 0.316 pO 2 , mean (SD) Site 1 46 (7) 47 (7) 46 (7) 0.104 0.825 Site 2 52.0 (10.6) 51.4 (12.5) 46.2 (3.4) 0.878 0.157 ATP (μmols/g HB), mean (SD) Site 1 2.6 (0.6) 2.6 (0.6) 2.9 (0.5) 0.759 0.306 Site 2 3.0 (0.5) 3.0 (0.6) 2.6 (0.5) 0.845 0.110 K (mEq/L), mean (SD) Site 1 46.5 (7.9) 47.5 (8.2) 49.3 (10.1) 0.396 0.620 Site 2 40.5 (5.8) 41.1 (5.9) 44.7 (5.7) 0.575 0.128 Na (mEq/L), mean (SD) Site 1 122 (7) 123 (6) 126 (17) 0.016 0.609 Site 2 105.6 (5.4) 104.2 (5.5) 100.0 (5.5) 0.004 0.069 Total Hemoglobin (g/dL) Site 1 60.5 (5.8) 60.0 (5.3) 61.0 (4.7) 0.546 0.627 Site 2 58.5 (5.5) 59.6 (5.8) 60.3 (5.0) 0.264 0.747 Plasma Hemoglobin (mg/dL), mean (SD) Site 1 149.9 (151.6) 141.2 (145.3) 152.7 (86.3) 0.034 0.815 Site 2 139.0 (61.0) 126.7 (80.4) 135.5 (82.1) 0.241 0.790 Hemolysis (%), mean (SD) Site 1 0.33 (0.34) 0.32 (0.34) 0.30 (0.15) 0.05 0.855 Site 2 0.34 (0.13) 0.31 (0.16) 0.31 (0.19) 0.363 0.995 Osmotic Fragility Osmotic fragility was measured as percent hemolysis in 0.55% saline at Site 1 and as the percent saline at ≥ 50% hemolysis at Site 2. Site 1 20.0 (14.4) 19.6 (15.2) 31.0 (22.3) 0.885 0.152 Site 2 0.51 (0.03) 0.51 (0.03) 0.49 (0.02) 0.935 0.009 The primary outcome of this study was to demonstrate RBC collection, storage, and viability in vitro . The sRBC and dRBC units collected were comparable. The hematocrits, blood gasses, ATP, potassium, total hemoglobin, and osmotic fragility were within acceptable ranges following storage. Two statistically significant differences were identified between the A and B units in the dRBC collection at Day 42 (sodium and plasma free hemoglobin), but these differences were not clinically significant. There was no difference between dRBC units in hemolysis following storage in ADDITIVE SOLUTION FORMULA 3 (AS-3). A statistically significant difference was identified in the osmotic fragility of RBCs stored in ADDITIVE SOLUTION FORMULA 3 (AS-3) following sRBC collection or dRBC collection at Day 42, but the difference was not clinically significant. All the RBC units collected averaged less than 1% hemolysis on Day 42. These results are consistent with US and European guidelines for hemolysis on transfusion. ATP recovery was greater than 70% of all units, which is predictive of good in vivo viability, and potassium levels on Day 42 average less than 50 mEq/L indicating good RBC membrane stability over the storage period.

8 USE IN SPECIFIC POPULATIONS ADDITIVE SOLUTION FORMULA 3 (AS-3) has not been studied in controlled clinical trials with specific populations.

16 HOW SUPPLIED/STORAGE AND HANDLING ADDITIVE SOLUTION FORMULA 3 (AS-3) is a clear solution supplied in sterile and non-pyrogenic Polyolefin bags. SIZE CATALOG NUMBER NDC NUMBER QUANTITY PER CASE 100 mL 40824 14537-824-10 36 200 mL 40826 14537-826-20 30 350 mL 40828 14537-828-35 24 STORAGE Up to 25 °C. Protect from freezing.

STORAGE Up to 25 °C. Protect from freezing.