Isoplate

6 ADVERSE REACTIONS ISOPLATE SOLUTION is added to platelets after the apheresis procedure is complete. It is not for direct intravenous infusion. It is expected to cause adverse events that are normally associated with platelet transfusion. ISOPLATE SOLUTION is expected to cause adverse events that are seen with platelet transfusion. ( 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 . 6.1 Clinical Trials Experience No adverse reactions were reported in the subjects infused with < 10 mL of radiolabeled platelets stored for 5 days in 65% ISOPLATE SOLUTION, and rinsed prior to infusion [See Clinical Studies (14) .]

4 CONTRAINDICATIONS DO NOT INFUSE ISOPLATE SOLUTION DIRECTLY TO THE PATIENTS. DO NOT INFUSE ISOPLATE SOLUTION DIRECTLY TO THE PATIENTS. ( 4 )

11 DESCRIPTION ISOPLATE SOLUTION - Platelet Additive Solution [PAS-F] is an isotonic solution designed to replace a proportion of the plasma used in the storage of Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated collection on Terumo BCT's Trima Accel system. The solution is sterile, nonpyrogenic and 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 Sodium Chloride USP NaCl 58.44 Sodium Acetate Trihydrate USP CH3COONa∙3H2O 136.08 Potassium Chloride USP KCl 74.55 Magnesium Chloride Hexahydrate USP MgCl2∙6H2O 203.30 Dibasic Sodium Phosphate Dihydrate USP Na2HPO4∙2H2O 177.98 Monobasic Potassium Phosphate NF KH2PO4 136.09 Sodium Gluconate USP C6H11NaO7 218.14 Each 100 mL of ISOPLATE SOLUTION contains: Sodium Chloride USP 0.53 g; Sodium Gluconate USP 0.5 g; Sodium Acetate Trihydrate USP 0.37 g; Potassium Chloride USP 0.037 g; Magnesium Chloride Hexahydrate USP 0.03 g; Dibasic Sodium Phosphate Dihydrate USP 0.008 g; Monobasic Potassium Phosphate NF 0.00082 g; in Water for Injection USP. pH may be adjusted with glacial Acetic Acid USP or Sodium Hydroxide NF pH: 7.4 (7.0-7.8). Concentration of Electrolytes (mEq/liter): Sodium 141; Potassium 5; Magnesium 3; Chloride 98; Phosphate (HPO=4 ) 1 (0.5 mmole P/liter); Acetate (CH3COO–) 27; Gluconate (HOCH2(CHOH)4COO–) 23. The polyolefin bag is not made with natural rubber latex or PVC. Di(2-ethylhexyl)phthalate (DEHP) is present only in sterile dock tube. 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 solution contact layer is an elasticized polyolefin. 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. The bag is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.

2 DOSAGE AND ADMINISTRATION ISOPLATE SOLUTION is added to hyperconcentrated platelets after the apheresis procedure is complete. ( 2 ) ISOPLATE SOLUTION may only be used with the Trima Accel system. For instructions on the use of the solution with the Trima Accel system, see the Trima Accel system operator's manual. ( 2.1 ) Follow the directions for connecting the ISOPLATE SOLUTION bag to the Trima Accel System. ( 2.2 ) 2.1 General Dosing Information ISOPLATE SOLUTION is added to hyperconcentrated platelets after the apheresis procedure is complete. It is not intended for direct intravenous infusion. ISOPLATE SOLUTION may only be used with the Trima Accel system for automated blood collection. For instructions on the use of the solution with the Trima Accel system, see the Trima Accel system operator's manual. 2.2 Administration Ensure solution is the ISOPLATE SOLUTION and is within the expiration date. Inspect the bag. Do not use if the container is damaged, leaking or if there is any visible sign of deterioration. Use only if solution is clear and free of particulate matter. Protect from sharp objects. Directions for Connecting the ISOPLATE SOLUTION Bag to the Trima Accel System At the prompt to connect the platelet additive solution to the Trima Accel system tubing set: Remove the overwrap by pulling down at notch, and remove the ISOPLATE SOLUTION bag. Before use, perform the following checks [See Warnings and Precautions (5) .] : Check for leaks by squeezing the bag. If leaks are found, discard bag. Ensure the solution is the ISOPLATE SOLUTION and is within the expiration date. Inspect the solution in good light. Bags showing cloudiness, haze, or particulate matter should not be used. Remove the protective cap from the port on the bag. Connect the bag to the Trima Accel system 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 per the Trima Accel system operator's manual. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

1 INDICATIONS AND USAGE ISOPLATE SOLUTION - Platelet Additive Solution [PAS-F] is an isotonic solution to replace a portion of the plasma to store Platelets Pheresis Platelet Additive Solution (PAS) Added Leukocytes Reduced products collected using a hyperconcentrated collection on Terumo BCT's Trima Accel system [See Dosage and Administration (2) .] Platelets Pheresis PAS Added Leukocytes Reduced products are stored in a mix of 65% ISOPLATE SOLUTION and 35% plasma. Platelets in the solution can be stored at a concentration range of 0.7 to 2.1 × 10 6 /µL for up to 5 days at 20-24 °C with continuous agitation in the Terumo BCT ELP bag [citrated polyvinyl chloride (PVC)] [See Clinical Studies (14) .] ISOPLATE SOLUTION - Platelet Additive Solution [PAS-F] is an isotonic solution to replace a portion of the plasma to store Platelets Pheresis Platelet Additive Solution (PAS) Added Leukocytes Reduced products collected using a hyperconcentrated collection on Terumo BCT's Trima Accel system. Platelets Pheresis PAS Added Leukocytes Reduced products are stored in a mix of 65% Isoplate and 35% plasma. Platelets in ISOPLATE SOLUTION can be stored at a concentration range of 0.7 to 2.1 × 10 6 /µL for up to 5 days at 20-24 °C with continuous agitation in the Terumo BCT ELP bag [citrated polyvinyl chloride (PVC)]. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ISOPLATE SOLUTION contains the following key components to maintain platelet function: Sodium chloride for osmolarity Acetate to fuel platelet metabolism Gluconate or phosphate for buffering Magnesium and potassium to reduce platelet activation 1,2 This solution has no pharmacological effect; the solution provides the appropriate components for platelet function while allowing for a lower volume of plasma in the platelet product during storage.

12.1 Mechanism of Action ISOPLATE SOLUTION contains the following key components to maintain platelet function: Sodium chloride for osmolarity Acetate to fuel platelet metabolism Gluconate or phosphate for buffering Magnesium and potassium to reduce platelet activation 1,2 This solution has no pharmacological effect; the solution provides the appropriate components for platelet function while allowing for a lower volume of plasma in the platelet product during storage.

20181204

6

3 DOSAGE FORMS AND STRENGTHS 500 mL ISOPLATE SOLUTION - Platelet Additive Solution [PAS-F] is a sterile isotonic solution in a polyolefin bag. Each 100 mL contains: Sodium Chloride 0.53 g; Sodium Gluconate 0.5 g; Sodium Acetate Trihydrate 0.37 g; Potassium Chloride 0.037 g; Magnesium Chloride Hexahydrate 0.03 g; Dibasic Sodium Phosphate Dihydrate 0.008 g; Monobasic Potassium Phosphate 0.00082 g; in Water for Injection. 500 mL sterile fluid in polyolefin bag ( 3 )

Isoplate SODIUM CHLORIDE, SODIUM GLUCONATE, SODIUM ACETATE, POTASSIUM CHLORIDE, MAGNESIUM CHLORIDE, SODIUM PHOSPHATE, DIBASIC, and POTASSIUM PHOSPHATE, MONOBASIC SODIUM CHLORIDE SODIUM CATION CHLORIDE ION SODIUM GLUCONATE GLUCONIC ACID SODIUM CATION SODIUM ACETATE ACETATE ION SODIUM CATION POTASSIUM CHLORIDE POTASSIUM CATION CHLORIDE ION MAGNESIUM CHLORIDE MAGNESIUM CATION CHLORIDE ION SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM PHOSPHATE ION SODIUM CATION POTASSIUM PHOSPHATE, MONOBASIC PHOSPHATE ION POTASSIUM CATION WATER

BN090067

Isoplate

SODIUM CHLORIDE, SODIUM GLUCONATE, SODIUM ACETATE, POTASSIUM CHLORIDE, MAGNESIUM CHLORIDE, SODIUM PHOSPHATE, DIBASIC, and POTASSIUM PHOSPHATE, MONOBASIC

14537-408

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 500 mL Bag Label Isoplate Solution Platelet Additive Solution [PAS-F] Catalog # 40850 Polyolefin Bag 500 mL NDC 14537-408-50 Sterile. Non-pyrogenic. Do not use unless the solution is clear and the container is intact. Rx only. Single use container. Caution: Not for direct intravenous infusion. Recommended storage: Store up to 25 °C (See USP Controlled Room Temperature). Each 100 mL contains: Sodium Chloride USP 0.53 g Sodium Gluconate USP 0.5 g Sodium Acetate Trihydrate USP 0.37 g Potassium Chloride USP 0.037 g Magnesium Chloride Hexahydrate USP 0.03 g Dibasic Sodium Phosphate Dihydrate USP 0.008 g Monobasic Potassium Phosphate NF 0.00082 g In Water for Injection USP Manufactured by Terumo BCT, Inc. 10811 W. Collins Ave., Lakewood CO 80215, USA 777969-551 TERUMO BCT Lot Expiry Date PRINCIPAL DISPLAY PANEL - 500 mL Bag Label

Dosage and Administration ( 2.2 ) 5/2015

Issued: May 2015 Manufactured by Terumo BCT, Inc. Lakewood, CO 80215 USA

14 CLINICAL STUDIES In Vivo radiolabeled recovery and survival A paired study was completed to verify that in vivo radiolabeled recovery and survival of hyperconcentrated leukocyte reduced platelets collected by apheresis on the Trima Accel system, diluted in ISOPLATE SOLUTION, and stored for five days (Test) meet FDA acceptance criteria in comparison with fresh autologous platelets (Control). Table 2 summarizes the in vivo radiolabeled platelet recovery and survival data. Table 2 – In Vivo Radiolabeled Platelet Recovery and Survival Data (N = 23) Recovery Survival Test Control Test/Control Test Control Test/Control % % % Days Days % Average 51.1 60.2 85 6.6 8.7 76 St. Dev. 10.9 10.2 10 1.2 0.9 12 Min 32.6 40.4 66 4.5 6.4 52 Max 84.1 82.8 102 8.8 10.0 104 The primary outcomes for this study were: Recovery: Test minus 66% Control is equal to or greater than zero with one-sided 97.5% confidence limit Survival: Test minus 58% Control is equal to or greater than zero with one-sided 97.5% confidence limit Both primary outcomes were met for hyperconcentrated leukocyte reduced platelets collected on the Trima Accel system and stored in ISOPLATE SOLUTION. In Vitro Platelet Quality Study A paired study was completed to verify that in vitro platelet quality (functional assays) of hyperconcentrated leukocyte reduced platelets collected by apheresis on the Trima Accel system, diluted in ISOPLATE SOLUTION, and stored for five days (Test) meet FDA acceptance criteria in comparison to plasma-stored platelets (Control). Table 3 summarizes the in vitro platelet quality data. Table 3 – In Vitro Platelet Quality Data (N = 66) Functional Assay Isoplate Stored Apheresis Platelets (Test) Average (Standard Deviation) Plasma Stored Apheresis Platelets (Control) Average (Standard Deviation) pH 7.4 (0.2) 7.5 (0.1) CD62 Expression; P-Selectin (%) 22.8 (15.6) 15.0 (9.8) Morphology Score (Max Score 400) 289 (49) 292 (47) Hypotonic Shock Response (%) 53.3 (12.4) 55.9 (10.9) Extent of Shape Change (%) 23.2 (5.0) 25.0 (6.0) The primary outcome for this study was: pH: 95% or more of test units will have a pH (22 °C) greater than 6.2 with a one-sided confidence interval of 95% All 66 platelet products collected in this study had pH > 6.2 therefore the primary outcome for pH was met for hyperconcetrated platelets collected on the Trima Accel system and stored in ISOPLATE SOLUTION.

15 REFERENCES Gulliksson H. Platelet storage media. Transfus Apher Sci 2001;24:241-4. Ringwald J, Zimmermann R, Eckstein R. The new generation of platelet additive solution for storage at 22 degrees C: development and current experience. Transfus Med Rev 2006;20:158-64.

8 SPECIAL POPULATIONS ISOPLATE SOLUTION has not been adequately studied in controlled clinical trials with specific populations. ISOPLATE SOLUTION has not been studied in controlled clinical trials with specific populations.

16 HOW SUPPLIED/STORAGE AND HANDLING ISOPLATE SOLUTION - Platelet Additive Solution [PAS-F] is a clear solution supplied in sterile and nonpyrogenic polyolefin bags. The ISOPLATE SOLUTION bags are packaged 18 bags per case. SIZE CATALOG NUMBER NDC NUMBER 500 mL 40850 14537-408-50 STORAGE Store up to 25 °C [See USP Controlled Room Temperature]. Platelets Pheresis PAS Added Leukocytes Reduced products are stored in a mix of 65% ISOPLATE SOLUTION and 35% plasma. Platelets in the solution can be stored at a concentration range of 0.7 to 2.1 × 106/µL for up to 5 days at 20-24 °C with continuous agitation in the Terumo BCT ELP bag [citrated polyvinyl chloride (PVC)].

STORAGE Store up to 25 °C [See USP Controlled Room Temperature]. Platelets Pheresis PAS Added Leukocytes Reduced products are stored in a mix of 65% ISOPLATE SOLUTION and 35% plasma. Platelets in the solution can be stored at a concentration range of 0.7 to 2.1 × 106/µL for up to 5 days at 20-24 °C with continuous agitation in the Terumo BCT ELP bag [citrated polyvinyl chloride (PVC)].