ISOPLATE- sodium chloride, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, sodium phosphate, dibasic and potassium phosphate, monobasic solution
B. Braun Medical Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Isoplate™ Solution Platelet Additive Solution [PAS-F] safely and effectively. See full prescribing information for Isoplate™ Solution Platelet Additive Solution [PAS-F].

Isoplate™ Solution
Platelet Additive Solution [PAS-F]

Initial U.S. Approval: 2013

INDICATIONS AND USAGE

Isoplate™ Solution Platelet Additive Solution [PAS-F] is an isotonic solution to replace a portion of the plasma to store Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated collection on Terumo BCT’s Trima Accel® System. The solution should never be infused directly to the patient. Platelet Pheresis, Leukocytes Reduced Platelet Additive Solution [PAS] products are stored in a mix of 65% Isoplate™ and 35% plasma. Platelets in Isoplate™ Solution can be stored at a concentration range of 700-2100 x 106/mL for up to 5 days at 20-24°C with continuous agitation in the EXCEL® container.(1)

DOSAGE AND ADMINISTRATION

Isoplate™ Solution Platelet Additive Solution [PAS-F] may only be used with the Trima Accel® automated blood cell separator device. For full instructions on the use of Isoplate™ Solution Platelet Additive Solution [PAS-F] with the Trima Accel® see the Trima Accel® Operator's Manual. (2)

Directions for Connecting the Isoplate™ Solution Container to the Trima Accel® System

At the prompt to connect the platelet additive solution to the Trima Accel® tubing set:

1. Remove the overwrap by pulling down at notch and remove solution container.

2. Before use, perform the following checks:

Check for leaks by squeezing the bag firmly. If leaks are found, discard solution.
Ensure the solution is the Isoplate™ Solution Platelet Additive Solution [PAS-F] and is within the expiration date.
Inspect the solution for cloudiness, haze, or particulate matter. Suspect container should not be used.

3. Remove the protective cap from the port on the Isoplate™ Solution Platelet Additive Solution [PAS-F] container.

4. Connect the Isoplate™ container to the Trima Accel® set using aseptic technique and hang the solution.

5. Proceed per the Trima Accel® Operator’s Manual.

DOSAGE FORMS AND STRENGTHS

500 mL bag (3)

CONTRAINDICATIONS

There are no known contraindications. (4)

WARNINGS AND PRECAUTIONS

Isoplate™ Solution Platelet Additive Solution [PAS-F] is NOT FOR DIRECT INTRAVENOUS INFUSION. (5)
Verify that the Isoplate™ Solution Platelet Additive Solution [PAS-F] has been securely attached to the platelet additive solution line on the Trima Accel® disposable tubing set using aseptic technique. (5)
Multiple transfusions of Isoplate™-stored platelets may lead to overdosage of potassium, magnesium and gluconate (5, 10).

ADVERSE REACTIONS

Isoplate™ Solution Platelet Additive Solution [PAS-F] is added to leukoreduced hyperconcentrated platelets after the Trima Accel® apheresis procedure is complete. Isoplate™ Solution Platelet Additive Solution [PAS-F] is not expected to cause adverse events other than those normally associated with platelet transfusion. (6)

To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Isoplate™ Solution Platelet Additive Solution [PAS-F] is used as a storage solution for hyperconcentrated platelets and it is not intended for direct intravenous infusion. There are no known drug interactions in its use as a platelet storage solution. (7)

Revised: 03/2013

FULL PRESCRIBING INFORMATION: CONTENTS *

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

2.2 Directions for Connecting the Isoplate™ Solution Container to the Trima Accel® System

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

9 DRUG ABUSE AND DEPENDENCE

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

*: Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

2.2 Directions for Connecting the Isoplate™ Solution Container to the Trima Accel® System

At the prompt to connect the platelet additive solution to the Trima Accel® tubing set:

Remove the overwrap by pulling down at notch and remove solution container.
Before use, perform the following checks:
- Check for leaks by squeezing the bag firmly. If leaks are found, discard solution.
- Ensure the solution is the Isoplate™ Solution Platelet Additive Solution [PAS-F] and is within the expiration date.
- Inspect the solution for cloudiness, haze, or particulate matter. Suspect container should not be used.
Remove the protective cap from the port on the Isoplate™ Solution Platelet Additive Solution [PAS-F] container.
Connect the Isoplate™ container to the Trima Accel® set using aseptic technique and hang the solution.
Proceed per the Trima Accel® Operator’s Manual.

3 DOSAGE FORMS AND STRENGTHS

Isoplate™ Solution Platelet Additive Solution [PAS-F] in the EXCEL® Container

NDC	Cat. No.	Volume
0264-7771-10	L7771	500 mL

4 CONTRAINDICATIONS

There are no known contraindications.

5 WARNINGS AND PRECAUTIONS

Isoplate™ Solution Platelet Additive Solution [PAS-F] is NOT FOR DIRECT INTRAVENOUS INFUSION.
Multiple transfusions of Isoplate™-stored platelets may lead to overdosage of potassium, magnesium and gluconate [See Overdosage (10)].
Inspect each container. Read the label. Ensure solution is the one ordered and is within the expiration date.
Invert container and carefully inspect the solution in good light for cloudiness, haze, or particulate matter. Any container which is suspect should not be used.
Use only if solution is clear and container and seals are intact.
Do not reuse. Discard unused or partially used Isoplate™ Solution Platelet Additive Solution [PAS-F].
Protect from sharp objects.
Verify that the Isoplate™ Solution Platelet Additive Solution [PAS-F] has been securely attached to the platelet additive solution line on the Trima Accel® disposable tubing set using aseptic technique.

6 ADVERSE REACTIONS

Isoplate™ Solution Platelet Additive Solution [PAS-F] is added to Platelet Pheresis, Leukocytes Reduced PAS products after completion of a hyperconcentrated Trima Accel® apheresis collection procedure. It is not for direct intravenous infusion. Isoplate™ Solution Platelet Additive Solution [PAS-F] is not expected to cause adverse events other than those normally associated with platelet transfusion.

6.1 Clinical Trials Experience

No adverse reactions were reported in subjects infused with a small volume (< 10 mL) of radiolabeled platelets that had been stored for 5 days in 65% Isoplate™ Solution Platelet Additive Solution [PAS-F], but rinsed prior to infusion.

7 DRUG INTERACTIONS

Isoplate™ Solution Platelet Additive Solution [PAS-F] is used as a storage solution for hyperconcentrated platelets and it is not intended for direct intravenous infusion. There are no known drug interactions in its use as a platelet storage solution.

9 DRUG ABUSE AND DEPENDENCE

Isoplate™ Solution Platelet Additive Solution [PAS-F] is used as a storage solution for leukoreduced hyperconcentrated platelets and has no pharmacological effect.

10 OVERDOSAGE

Multiple transfusions of Isoplate™-stored platelets may lead to overdosage of potassium, magnesium and gluconate. Monitor changes in electrolyte concentration and acid-base balance when multiple transfusions of Isoplate™-stored platelets are administered. In the event of overdose, discontinue transfusion immediately and institute appropriate corrective treatment.

The signs and symptoms of potassium overdose include paresthesias of the extremities, areflexia, muscular or respiratory paralysis, mental confusion, weakness, hypotension, cardiac arrhythmias, heart block, electrocardiographic abnormalities and cardiac arrest. Treatment of hyperkalemia includes the following;

Dextrose Injection, USP 10% or 25%, containing 10 units of crystalline insulin per 20 grams of dextrose administered intravenously, 300 to 500 mL/hour.
Absorption and exchange of potassium using sodium or ammonium cycle cation exchange resin, orally and as retention enema.
Hemodialysis and peritoneal dialysis. The use of potassium-containing foods or medications must be eliminated. However, in cases of digitalization, too rapid a lowering of plasma potassium concentration can cause digitalis toxicity.

Gluconate overdose may cause metabolic alkalosis. Treatment of metabolic alkalosis may include administration of an acidifying agent such as ammonium chloride.

Signs of magnesium overdose include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and CNS depression proceeding to respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of magnesium overdose. In the event of overdosage artificial ventilation may be required until a calcium salt can be injected intravenously to antagonize the effects of magnesium.

11 DESCRIPTION

Isoplate™ Solution Platelet Additive Solution [PAS-F] is sterile, nonpyrogenic, and contains no bacteriostatic or antimicrobial agents. Isoplate™ Solution Platelet Additive Solution [PAS-F] is indicated as a platelet additive solution for the 5 day storage of Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated collection on Terumo BCT's Trima Accel® System. Platelets in Isoplate™ Solution Platelet Additive Solution [PAS-F] can be stored at a concentration range of 700-2100 x 106/mL for up to 5 days at 20-24 °C with agitation.

The formulas of the active ingredients are provided in Table 1.

Table 1: Active Ingredients
Ingredients	Molecular Formula	Molecular Weight
Sodium Chloride USP	NaCI	58.44
Sodium Acetate Trihydrate USP	CH3COONa•3H2O	136.08
Potassium Chloride USP	KCI	74.55
Magnesium Chloride Hexahydrate USP	MgCl2•6H2O	203.30
Dibasic Sodium Phosphate Heptahydrate USP	Na2HPO4•7H2O	268.07
Monobasic Potassium Phosphate NF	KH2PO4	136.09
Sodium Gluconate USP		218.14

Each 100 mL of Isoplate™ Solution Platelet Additive Solution [PAS-F] 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 Heptahydrate USP 0.012 g; Monobasic Potassium Phosphate NF 0.00082 g; Water for Injection USP qs

pH may be adjusted with Glacial Acetic Acid USP or Sodium Hydroxide NF

pH: 7.4 (7.0–7.8)

Calculated Osmolarity: 295 mOsmol/liter

Concentration of Electrolytes (mEq/liter): Sodium 141; Potassium 5; Magnesium 3; Chloride 98; Phosphate (HPO Character ) 1 (0.5 mmole P/liter); Acetate (CH3COO–) 27; Gluconate (HOCH2(CHOH)4COO–) 23

The EXCEL® Container is Latex-free, PVC-free, and Di(2-ethylhexyl)phthalate (DEHP)-free.

The plastic container is made from a multilayered film. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Isoplate™ Solution Platelet Additive Solution [PAS-F] 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 activation1,2

Isoplate™ Solution Platelet Additive Solution [PAS-F] is used as a storage solution for leukoreduced hyperconcentrated platelets and it is not for direct intravenous infusion. 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.

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 on the Trima Accel® System, diluted in Isoplate™ Solution Platelet Additive Solution [PAS-F], 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 by apheresis and stored in Isoplate™ Solution Platelet Additive Solution [PAS-F].

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 on the Trima Accel® System, diluted in Isoplate™ Solution Platelet Additive Solution [PAS-F], 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 hyperconcentrated platelets collected by apheresis and stored in Isoplate™ Solution Platelet Additive Solution [PAS-F].

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Isoplate™ Solution Platelet Additive Solution [PAS-F] is supplied sterile and nonpyrogenic In EXCEL® Containers. The 500 mL containers are packaged 24 per case.

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F). [See USP Controlled Room Temperature.]

Rx only

Issued: March 2013

EXCEL is a registered trademark and Isoplate is a trademark of B. Braun Medical Inc. Trima Accel is a registered trademark of Terumo BCT Inc.

B. Braun Medical Inc.
Irvine, CA 92614-5895 USA
Made in USA

Y36-002-738

PRINCIPAL DISPLAY PANEL - 500 mL Bag Label

Isoplate™ Solution
Platelet Additive Solution [PAS-F]

REF L7771
NDC 0264-7771-10
500 mL
EXCEL® CONTAINER

Electrolytes (mEq/liter):
Na+ 141
K+ 5
Mg++ 3
CI– 98
Acetate 27
Gluconate 23
Phosphate (HPO Character ) 1 (0.5 mmole P/L)

Each 100 mL contains: Sodium Chloride USP 0.53 g;
Sodium Gluconate USP 0.5 g; Sodium Acetate•3H20 USP 0.37 g;
Potassium Chloride USP 0.037 g; Magnesium Chloride•6H20 USP 0.03 g;
Dibasic Sodium Phosphate•7H20 USP 0.012 g; Monobasic Potassium
Phosphate NF 0.00082 g; Water for Injection USP qs

pH may be adjusted with Glacial Acetic Acid USP or Sodium
Hydroxide NF

pH: 7.4 (7.0-7.8) Calc. Osmolarity: 295 mOsmol/liter

Sterile, nonpyrogenic. Single use container.

Use only if solution is clear and container and seals are intact.

Warnings: Not for direct intravenous infusion.

Recommended Storage: Store at 20°C to 25°C (68°F to 77°F),
excursions permitted between 15°C and 30°C (between 59°F and 86°F).
[See USP Controlled RoomTemperature.] See Package Insert.

Rx only

The EXCEL Container is Latex-free, PVC-free, and DEHP-free.

EXCEL is a registered trademark and Isoplate is a trademark of B.Braun
Medical Inc.

B. Braun Medical Inc.
Irvine, CA 92614-5895 USA
Made in USA

Y94-002-912

Do not remove overwrap until ready for use. After removing the
overwrap, check for minute leaks by squeezing container firmly.
If leaks are found, discard solution as sterility may be impaired.

EXP
LOT

ISOPLATE
sodium chloride, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, sodium phosphate, dibasic, and potassium phosphate, monobasic solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG LABEL	Item Code (Source)	NDC:0264-7771
Route of Administration	INTRAVENOUS	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
SODIUM CHLORIDE (SODIUM CATION and CHLORIDE ION)	SODIUM CHLORIDE	0.53 g in 100 mL
SODIUM GLUCONATE (GLUCONIC ACID)	SODIUM GLUCONATE	0.5 g in 100 mL
SODIUM ACETATE (ACETIC ACID)	SODIUM ACETATE	0.37 g in 100 mL
POTASSIUM CHLORIDE (POTASSIUM CATION and CHLORIDE ION)	POTASSIUM CHLORIDE	0.037 g in 100 mL
MAGNESIUM CHLORIDE (MAGNESIUM CATION and CHLORIDE ION)	MAGNESIUM CHLORIDE	0.03 g in 100 mL
SODIUM PHOSPHATE, DIBASIC (PHOSPHATE ION and SODIUM CATION)	SODIUM PHOSPHATE, DIBASIC	0.012 g in 100 mL
POTASSIUM PHOSPHATE, MONOBASIC (PHOSPHATE ION)	POTASSIUM PHOSPHATE, MONOBASIC	0.00082 g in 100 mL

Inactive Ingredients
Ingredient Name	Strength
WATER

Packaging
#	Item Code	Package Description
1	NDC:0264-7771-10	24 in 1 CASE
1		500 mL in 1 CONTAINER

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA090067	03/05/2013

Labeler - B. Braun Medical Inc. (002397347)

Revised: 03/2013

Document Id: e4c7f8e2-0fd3-4b2f-9436-8d017cd217aa

Set id: 2213f370-d547-4a64-a48d-dcb9dc9d5da0

Version: 13

Effective Time: 20130312

B. Braun Medical Inc.