NDC 14537-828 Additive Formula 3

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

NDC Product Code 14537-828

NDC CODE: 14537-828

Proprietary Name: Additive Formula 3 What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Dextrose Monohydrate, Trisodium Citrate Dihydrate, Sodium Chloride, Sodium Phosphate, Monobasic, Monohydrate, Citric Acid Monohydrate, And Adenine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This product is used to treat dryness inside the nose (nasal passages). It helps add moisture inside the nose to dissolve and soften thick or crusty mucus. In babies and young children with stuffy noses who cannot blow their noses, using this product helps to make the mucus easier to remove with a nasal bulb syringe. This helps relieve stuffiness and makes breathing easier. This product contains a purified gentle salt solution (also called saline or sodium chloride solution). It does not contain any medication.

NDC Code Structure

  • 14537 - Terumo Bct, Ltd

NDC 14537-828-35

Package Description: 24 BAG in 1 CARTON > 350 mL in 1 BAG

NDC Product Information

Additive Formula 3 with NDC 14537-828 is a a human prescription drug product labeled by Terumo Bct, Ltd. The generic name of Additive Formula 3 is dextrose monohydrate, trisodium citrate dihydrate, sodium chloride, sodium phosphate, monobasic, monohydrate, citric acid monohydrate, and adenine. The product's dosage form is solution and is administered via intravenous form.

Labeler Name: Terumo Bct, Ltd

Dosage Form: Solution - A clear, homogeneous liquid1 dosage form that contains one or more chemical substances dissolved in a solvent or mixture of mutually miscible solvents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Additive Formula 3 Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • DEXTROSE MONOHYDRATE 1.1 g/100mL
  • TRISODIUM CITRATE DIHYDRATE .59 g/100mL
  • SODIUM CHLORIDE .41 g/100mL
  • SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE .28 g/100mL
  • CITRIC ACID MONOHYDRATE .042 g/100mL
  • ADENINE .03 g/100mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)
  • WATER (UNII: 059QF0KO0R)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Acidifying Activity - [MoA] (Mechanism of Action)
  • Calculi Dissolution Agent - [EPC] (Established Pharmacologic Class)
  • Anti-coagulant - [EPC] (Established Pharmacologic Class)
  • Decreased Coagulation Factor Activity - [PE] (Physiologic Effect)
  • Calcium Chelating Activity - [MoA] (Mechanism of Action)
  • Acidifying Activity - [MoA] (Mechanism of Action)
  • Calculi Dissolution Agent - [EPC] (Established Pharmacologic Class)
  • Anti-coagulant - [EPC] (Established Pharmacologic Class)
  • Decreased Coagulation Factor Activity - [PE] (Physiologic Effect)
  • Calcium Chelating Activity - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Terumo Bct, Ltd
Labeler Code: 14537
FDA Application Number: BN001214 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-29-2002 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Additive Formula 3 Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Use only with Trima Accel red blood cell (RBC) apheresis collections. [See Dosage and Administration (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.

Other

  • 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.

In Vivo Recovery of Autologous Radiolabeled RBCA 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 51Chromium, 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 RecoveryOutcome MeasureStudy Site (N)Average (SD)Min, MaxAbbreviations: Max= Maximum, Min= Minimum, N= Number of Units Transfused, RBC= Red Blood Cell, SD= Standard DeviationOverall Day 42 infused, 24-hour RBC Radiolabel Recovery (%)Site 1 (12)79.3 (5.6)67.5, 86.5Site 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 StudiesThe 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 MeasureSite (N)Average (SD)Min, MaxAbbreviations: HCT = hematocrit, HgB = hemoglobin, Max = Maximum, Min = Minimum, N = Number of Units, RBC = Red Blood Cell, SD = Standard DeviationDay 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, 0.33Site 2 (18)0.34 (0.18)0.12, 0.70Site 3 (18)0.26 (0.11)0.09, 0.47Day 42 Hemolysis for Double RBC Collection (%)Site 1 (25)0.15 (0.05)0.06, 0.29Site 2 (24)0.39 (0.19)0.16, 0.95Site 3 (21)0.26 (0.12)0.13, 0.61Change 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, 0.08Site 2 (18)0.03 (0.03)0.00, 0.11Site 3 (16)0.02 (0.02)0.00, 0.07Change in pH from Day 0 to Day 42 for Double RBC CollectionSite 1 (23)0.02 (0.02)0.00, 0.05Site 2 (23)0.02 (0.03)0.00, 0.15Site 3 (19)0.02 (0.02)0.00, 0.08Ratio 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, 1.47Ratio of ATP Retention for Double Collection RBC Units (test/control)All sites (65)1.07 (0.19)0.55, 1.51Ratio 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 HemoglobinAll sites (65)0.98 (0.07)0.76, 1.13Ratio 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 MeasureAll outcome measures are shown after 42 days of storage in AS-3 solution.SiteRBC UnitP 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 AdRBC BsRBCdRBC A v dRBC BsRBC v dRBCAbbreviations: 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 DeviationHematocrit (%), mean (SD)Site 154.4 (3.7)53.9 (3.6)55.8 (4.4)0.1320.253Site 256.0 (3.9)53.3 (11.6)58.4 (3.6)0.3980.149pH, mean (SD)Site 16.4 (0.04)6.4 (0.05)6.5 (0.08)0.7600.643Site 26.4 (0.1)6.4 (0.1)6.4 (0.1)0.1750.217pCO2, mean (SD)Site 1140 (8)137 (8)139 (12)0.1720.525Site 2130.5 (11.7)130.4 (12.4)125.6 (11.1)1.000.316pO2, mean (SD)Site 146 (7)47 (7)46 (7)0.1040.825Site 252.0 (10.6)51.4 (12.5)46.2 (3.4)0.8780.157ATP (μmols/g HB), mean (SD)Site 12.6 (0.6)2.6 (0.6)2.9 (0.5)0.7590.306Site 23.0 (0.5)3.0 (0.6)2.6 (0.5)0.8450.110K (mEq/L), mean (SD)Site 146.5 (7.9)47.5 (8.2)49.3 (10.1)0.3960.620Site 240.5 (5.8)41.1 (5.9)44.7 (5.7)0.5750.128Na (mEq/L), mean (SD)Site 1122 (7)123 (6)126 (17)0.0160.609Site 2105.6 (5.4)104.2 (5.5)100.0 (5.5)0.0040.069Total Hemoglobin (g/dL)Site 160.5 (5.8)60.0 (5.3)61.0 (4.7)0.5460.627Site 258.5 (5.5)59.6 (5.8)60.3 (5.0)0.2640.747Plasma Hemoglobin (mg/dL), mean (SD)Site 1149.9 (151.6)141.2 (145.3)152.7 (86.3)0.0340.815Site 2139.0 (61.0)126.7 (80.4)135.5 (82.1)0.2410.790Hemolysis (%), mean (SD)Site 10.33 (0.34)0.32 (0.34)0.30 (0.15)0.050.855Site 20.34 (0.13)0.31 (0.16)0.31 (0.19)0.3630.995Osmotic 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 120.0 (14.4)19.6 (15.2)31.0 (22.3)0.8850.152Site 20.51 (0.03)0.51 (0.03)0.49 (0.02)0.9350.009The 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.

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

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

4 Contraindications

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

5 Warnings And Precautions

  • Verify that the AS-3 bag has been securely attached to the system tubing set. Use aseptic technique throughout all procedures to ensure product quality.Do not reuse. Discard unused or partially used solution bags.

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.

8 Use In Specific Populations

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

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 IngredientsIngredientsMolecular FormulaMolecular WeightDextrose Monohydrate USPC6H12O6 ∙ H2O198.17Trisodium Citrate Dihydrate USPC6H9Na3O9294.10Sodium Chloride USPNaCl58.44Monobasic Sodium Phosphate Monohydrate USPNaH2PO4 ∙ H2O137.99Citric Acid Monohydrate USPC6H807 ∙ H2O210.14Adenine USPC5H5N5135.13Water for Injection USPH2O18.00Each 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.

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) levelsCitrate for membrane protection, anticoagulation and pH regulationSodium (Sodium Chloride and Sodium Citrate) and dextrose for isotonicityDextrose for RBC nutritionThis solution has no pharmacological effect.

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.

16 How Supplied/Storage And Handling

ADDITIVE SOLUTION FORMULA 3 (AS-3) is a clear solution supplied in sterile and non-pyrogenic Polyolefin bags.SIZECATALOG NUMBERNDC NUMBERQUANTITY PER CASE100 mL4082414537-824-1036200 mL4082614537-826-2030350 mL4082814537-828-3524

Storage And Handling

STORAGEUp to 25 °C.Protect from freezing.

* Please review the disclaimer below.