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These highlights do not include all the information needed to use ADDITIVE SOLUTION FORMULA 3 (AS-3) safely and effectively. See full prescribing information for ADDITIVE SOLUTION FORMULA 3 (AS-3). ADDITIVE SOLUTION FORMULA 3 (AS-3) Sterile FluidPolyolefi | Additive Formula 3 [Terumo BCT, Ltd] | BioPortfolio

12:28 EST 27th January 2019 | BioPortfolio
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Use only with Trima Accel red blood cell (RBC) apheresis collections. [See Dosage and Administration (2).]

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 instructions on the use of the solution with the apheresis device and tubing set, see the device operator's manual.

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.

Manual RBC additive solution procedures:

Connect ADDITIVE SOLUTION FORMULA 3 (AS-3) after the collection is over and the donor is disconnected.

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 0.42 g; Adenine USP 0.03 g; and Water for Injection USP.

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

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.

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

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.

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 0.42 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.

Table 1: Active Ingredients
Ingredients Molecular Formula Molecular Weight
Dextrose Monohydrate USP C6H12O6 ∙ H2O 198.17
Trisodium Citrate Dihydrate USP C6H9Na3O9 294.10
Sodium Chloride USP NaCl 58.44
Monobasic Sodium Phosphate Monohydrate USP NaH2PO4 ∙ H2O 137.99
Citric Acid Monohydrate USP C6H807 ∙ H2O 210.14
Adenine USP C5H5N5 135.13
Water for Injection USP H2O 18.00

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:

This solution has no pharmacological effect.

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 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 CollectionPercent 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 CollectionThe 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).

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.

Table 4: In Vitro Quality Measures for RBCs Collected using the Trima Accel System and Stored in ADDITIVE SOLUTION FORMULA 3 (AS-3)
Outcome MeasureAll outcome measures are shown after 42 days of storage in AS-3 solution. Site RBC Unit P ValueAll 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
pCO2, 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
pO2, 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 FragilityOsmotic 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

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.

Issued: July 18, 2018

Manufactured by Terumo BCT, Inc. Lakewood, CO 80215

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

Additive Solution Formula 3 (AS-3)

Catalog # 40826 Polyolefin Bag 30 X 200 mL units NDC 14537-826-20

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 777965-078

Lot Expiry Date

Additive Solution Formula 3 (AS-3)

Catalog # 40828 Polyolefin Bag 24 X 350 mL units NDC 14537-828-35

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 777965-080

Lot Expiry Date

Manufacturer

Terumo BCT, Ltd

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