CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. ISOPLATE SOLUTION contains the following key components to maintain platelet function:Sodium chloride for osmolarityAcetate to fuel platelet metabolismGluconate or phosphate for bufferingMagnesium and potassium to reduce platelet activation1,2 This solution has no pharmacological effect; the solution provides the appropriate components for platelet function while allowing for lower volume of plasma in the platelet product during storage.. Sodium chloride for osmolarity. Acetate to fuel platelet metabolism. Gluconate or phosphate for buffering. Magnesium and potassium to reduce platelet activation1,2.

ADVERSE REACTIONS SECTION.

6ADVERSE 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.. 6.1Clinical Trials Experience. No adverse reactions were reported in the subjects infused with 10 mL of radiolabeled platelets stored for days in 65% ISOPLATE SOLUTION, and rinsed prior to infusion [See Clinical Studies (14).].

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. In Vivo radiolabeled recovery and survivalA 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 summarizes the in vivo radiolabeled platelet recovery and survival data.Table - In Vivo Radiolabeled Platelet Recovery and Survival Data (N 23)RecoverySurvivalTestControlTest/ControlTestControlTest/Control%%%DaysDays%Average51.160.2856.68.776St. Dev.10.910.2101.20.912Min32.640.4664.56.452Max84.182.81028.810.0104The primary outcomes for this study were:Recovery: Test minus 66% Control is equal to or greater than zero with one-sided 97.5% confidence limitSurvival: Test minus 58% Control is equal to or greater than zero with one-sided 97.5% confidence limitBoth primary outcomes were met for hyperconcentrated leukocyte reduced platelets collected on the Trima Accel system and stored in ISOPLATE SOLUTION.. In Vitro Platelet Quality StudyA 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 summarizes the in vitro platelet quality data.Table - In Vitro Platelet Quality Data (N 66)Functional AssayIsoplate Stored Apheresis Platelets (Test) Average (Standard Deviation)Plasma Stored Apheresis Platelets (Control) Average (Standard Deviation)pH7.4 (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 pH (22 C) greater than 6.2 with 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.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11DESCRIPTION. ISOPLATE SOLUTION Platelet Additive Solution [PAS-F] is an isotonic solution designed to replace proportion of the plasma used in the storage of Platelet Pheresis, Leukocytes Reduced PAS products collected using hyperconcentrated collection on Terumo BCTs 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 IngredientsIngredientsMolecular FormulaMolecular WeightSodium Chloride USPNaCl58.44Sodium Acetate Trihydrate USPCH3COONa3H2O136.08Potassium Chloride USPKCl74.55Magnesium Chloride Hexahydrate USPMgCl26H2O203.30Dibasic Sodium Phosphate Dihydrate USPNa2HPO42H2O177.98Monobasic Potassium Phosphate NFKH2PO4136.09Sodium Gluconate USPC6H11NaO7218.14Each 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 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 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.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE 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 operators manual. (2.1)Follow the directions for connecting the ISOPLATE SOLUTION bag to the Trima Accel System. (2.2). 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 operators manual. (2.1). Follow the directions for connecting the ISOPLATE SOLUTION bag to the Trima Accel System. (2.2). 2.1General 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 operators 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.. 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 SystemAt 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 operators manual.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. 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. 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 operators manual.

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. 500 mL ISOPLATE SOLUTION Platelet Additive Solution [PAS-F] is sterile isotonic solution in 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). 500 mL sterile fluid in polyolefin bag (3).

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. ISOPLATE SOLUTION Platelet Additive Solution [PAS-F] is clear solution supplied in sterile and nonpyrogenic polyolefin bags. The ISOPLATE SOLUTION bags are packaged 18 bags per case.SIZECATALOG NUMBERNDC NUMBER500 mL4085014537-408-50. STORAGEStore up to 25 [See USP Controlled Room Temperature].Platelets Pheresis PAS Added Leukocytes Reduced products are stored in mix of 65% ISOPLATE SOLUTION and 35% plasma. Platelets in the solution can be stored at concentration range of 0.7 to 2.1 106/uL for up to days at 20-24 with continuous agitation in the Terumo BCT ELP bag [citrated polyvinyl chloride (PVC)].

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. ISOPLATE SOLUTION Platelet Additive Solution [PAS-F] is an isotonic solution to replace portion of the plasma to store Platelets Pheresis Platelet Additive Solution (PAS) Added Leukocytes Reduced products collected using hyperconcentrated collection on Terumo BCTs Trima Accel system [See Dosage and Administration (2).] Platelets Pheresis PAS Added Leukocytes Reduced products are stored in mix of 65% ISOPLATE SOLUTION and 35% plasma. Platelets in the solution can be stored at concentration range of 0.7 to 2.1 106/uL for up to days at 20-24 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 portion of the plasma to store Platelets Pheresis Platelet Additive Solution (PAS) Added Leukocytes Reduced products collected using hyperconcentrated collection on Terumo BCTs Trima Accel system. Platelets Pheresis PAS Added Leukocytes Reduced products are stored in mix of 65% Isoplate and 35% plasma.Platelets in ISOPLATE SOLUTION can be stored at concentration range of 0.7 to 2.1 106/uL for up to days at 20-24 with continuous agitation in the Terumo BCT ELP bag [citrated polyvinyl chloride (PVC)]. (1).

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. ISOPLATE SOLUTION contains the following key components to maintain platelet function:Sodium chloride for osmolarityAcetate to fuel platelet metabolismGluconate or phosphate for bufferingMagnesium and potassium to reduce platelet activation1,2 This solution has no pharmacological effect; the solution provides the appropriate components for platelet function while allowing for lower volume of plasma in the platelet product during storage.. Sodium chloride for osmolarity. Acetate to fuel platelet metabolism. Gluconate or phosphate for buffering. Magnesium and potassium to reduce platelet activation1,2.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 500 mL Bag Label. Isoplate SolutionPlatelet Additive Solution [PAS-F]Catalog 40850Polyolefin Bag500 mLNDC 14537-408-50Sterile. Non-pyrogenic. Do not use unless the solution is clear andthe container is intact. Rx only. Single use container.Caution: Not for direct intravenous infusion.Recommended storage: Store up to 25 (See USP Controlled RoomTemperature).Each 100 mL contains:Sodium Chloride USP 0.53 gSodium Gluconate USP 0.5 gSodium Acetate Trihydrate USP 0.37 gPotassium Chloride USP 0.037 gMagnesium Chloride Hexahydrate USP 0.03 gDibasic Sodium Phosphate Dihydrate USP 0.008 gMonobasic Potassium Phosphate NF 0.00082 gIn Water for Injection USPManufactured by Terumo BCT, Inc.10811 W. Collins Ave., Lakewood CO 80215, USA777969-551 TERUMOBCTLotExpiry Date. PRINCIPAL DISPLAY PANEL 500 mL Bag Label.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)5/2015.

REFERENCES SECTION.

15REFERENCES. 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.. 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.

SPL UNCLASSIFIED SECTION.

2.1General 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 operators manual.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

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.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Verify that the solution bag has been securely attached to the platelet additive solution line on the Trima Accel system tubing set using aseptic technique.Do not reuse. Discard unused or partially used solution bags.. Verify that the solution bag has been securely attached to the platelet additive solution line on the Trima Accel system tubing set using aseptic technique.. Do not reuse. Discard unused or partially used solution bags.. Verify that the ISOPLATE SOLUTION has been securely attached to the platelet additive solution line on the Trima Accel system tubing set using aseptic technique. (5). Verify that the ISOPLATE SOLUTION has been securely attached to the platelet additive solution line on the Trima Accel system tubing set using aseptic technique. (5).