TriCitrasol

ADVERSE REACTIONS Citrate reactions or toxicity may occur with the infusion of blood products containing citrate anticoagulant 1. 9 11 . The recipient of the citrated blood product should be monitored for the signs and symptoms of citrate toxicity 1. 9 11 . 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 chills, stomach cramps, or pressure in the chest, followed by more severe reactions that are characterized by hypotension and possible cardiac arrhythmia 1. 9 11 . Citrate toxicity may occur more frequently in patients that are hypothermic 10 , have impaired liver or renal function 10 , or have low calcium levels because of an underlying disease 9 .

CONTRAINDICATIONS NOT FOR DIRECT INTRAVENOUS INFUSION.

DESCRIPTION triCitrasol ® Anticoagulant Sodium Citrate Concentrate, 46.7% Trisodium Citrate, is a sterile, non-pyrogenic solution of Trisodium Citrate (Dihydrate), USP. Each 30 mL of concentrate contains: Trisodium Citrate, dihydrate, USP 14.0 grams Water for Injection, USP q.s. pH adjusted with Citric Acid pH: 6.3 – 6.6 Single patient use only, on a single occasion. Chemical Structure

DOSAGE AND ADMINISTRATION The apheresis system will control the amount of the citrate/6% solution of HES that is added to the whole blood and the method of administration of the solution. Refer to the Operator's Manual of the apheresis medical device.

INDICATIONS AND USAGE triCitrasol ® Anticoagulant Sodium Citrate Concentrate, 46.7% Trisodium Citrate, is an anticoagulant used in granulocytapheresis procedures (granulocyte collection by apheresis). Just prior to performing granulocytapheresis, aseptically add 30 mL of triCitrasol ® to 500 mL of the 6% solution of Hydroxyethyl Starch (HES), e.g. Hespan ® 2-8 . Agitate the resultant solution for 1 minute to assure a uniform concentration of anticoagulant. The resultant solution of triCitrasol ® and 6% solution of HES contains the following concentration depending upon the volume used: Volume of triCitrasol ® Volume of HES Total Volume Final Concentration of triCitrasol ® 30 mL 500 mL (measured from HES bag) 530 mL 2.6% 30 mL 558 mL (injected directly into HES bag) 588 mL 2.4% The triCitrasol ® /HES solution is stable for up to 24 hours at room temperature after mixing. Refer to the manufacturer's Operator's Manual of the apheresis medical device for the directions to perform the granulocytapheresis procedure.

WARNINGS CONCENTRATED ANTICOAGULANT – DILUTE PRIOR TO USE.

OVERDOSAGE Since the bottle of triCitrasol ® contains only 30mL of the product, it is impossible to overdose the addition of the product to the 6% solution of HES. However, in the event of a reaction to the infusion of citrated blood products, evaluate the patient and institute appropriate corrective actions 1, 9 .

Drug Interactions There are no adverse reactions for the addition of the product to the rouleaux agent.

CLINICAL PHARMACOLOGY A sodium citrate solution acts as an anticoagulant by the action of the citrate ion chelating free ionized calcium; thus, the calcium ion is unavailable to the coagulation system 1 .

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triCitrasol Trisodium Citrate dihydrate TRISODIUM CITRATE DIHYDRATE ANHYDROUS CITRIC ACID

Carcinogenesis, mutagenesis, impairment of fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of triCitrasol ® .

BN010409

TriCitrasol

Trisodium Citrate dihydrate

23731-6030

HUMAN PRESCRIPTION DRUG

EXTRACORPOREAL

Laboratory Tests There are no laboratory tests for the drug product at this time.

PRINCIPAL DISPLAY PANEL - 10 Vial Case Label triCitrasol ® ANTICOAGULANT SODIUM CITRATE CONCENTRATE 46.7% Trisodium Citrate PN 6030 - 30 mL WARNING: CONCENTRATED ANTICOAGULANT Dilute prior to use NOT FOR DIRECT INTRAVENOUS INFUSION THIS CARTON CONTAINS 10 Sterile Units - 30 mL each Used with 6% Hydroxyethyl Starch 500 mL (diluent) for the Collection of Granulocytes by Apheresis. Do not use for other anticoagulant purposes. See package insert for directions for use. Manufactured & Distributed by: Citra Labs ™ A Biomet Inc. Company. 55 Messina Drive, Braintree, MA 02184 ● USA Phone Number: 1-800-299-3411 Fax Number: 781-848-6781 Sterile ■ Non-Pyrogenic Composition per 30 mL of Concentrate: Trisodium Citrate (Dihydrate), USP 14.0 g (pH adjusted with Citric Acid) CAUTION: Single Procedure Use - Discard Unused Portion Do Not Use Unless Solution is Clear and Seal is intact Store Between 15°C - 30° C (59° F - 86° F) Rx only Exp: Lot: LA6030-10B 5/15 PRINCIPAL DISPLAY PANEL - 10 Vial Case Label

ANTICOAGULANT SODIUM CITRATE CONCENTRATE – 46.7% Trisodium Citrate PN 6030, 30 mL NDC 23731-6030-3

Information for Patients None.

REFERENCES Grindon, A. J., "Adverse Reactions to Whole Blood Donation and Plasmapheresis", CRC Crit. Rev Clin. Lab. Sci ., 17 :51-75, 1982. Rock, G., and McCombie, N., "Alternate Dosage Regimens for High-Molecular-Weight Hydroxyethyl Starch", Transfusion , 25 :417-419, 1985. Strauss, R. G., Hester, J. P., Vogler, W.R., Higby, D. J., Snikeris, A. C., Imig, K. M., Greazel, C., Mallard, G., Burnett, D., Gupta, S., and Hulse, J.D., "A Multicenter Trial to Document the Efficacy and Safety of a Rapidly Excreted Analog of Hydroxyethyl Starch for Leukapheresis with a Note on Steroid Stimulation of Granulocyte Donors", Transfusion , 26 :258-264, 1986. Strauss, R.G., Rohret, P.A., Randels, M. J., and Wihegarden, D. C., "Granulocyte Collection", J. of Clin. Apheresis , 6 :241-243, 1991. Lee, J.H., and Klein, H. G., "The Effect of Donor Red Cell Sedimentation Rate on Efficiency of Granulocyte Collection by Centrifugal Leukapheresis", Transfusion, 35 :384-388, 1995. Adkins, D., Ali., S. Despotis, G., Dynis, M. and Goodnough, L. T., "Granulocyte Collection Efficiency and Yield are Enhanced by the Use of a Higher Interface Offset During Apheresis of Donors Given Granulocyte-Colony-Stimulating Factor", Transfusion , 38 :557-564, 1998. Jendiroba, D. B., Lichtiger, B., Anaissie, E., Reddy, V., O'Brien, S., Kantarjian, H., and Freireich, E. J., "Evaluation and Comparison of Three Mobilization Methods for the Collection of Granulocytes". Transfusion , 38 :722-728, 1998. Leavey P. J., Thurman, G., and Anbruso, D. R., "Functional Characteristics of Neutrophils Collected and Stored After Administration of G-CSF", Transfusion . 40 :414-419, 2000. AABB Technical Manual , 14 th Edition, page 590, 2001. Denlinger, J.V., Nahrwold, M. L., Gibbs, P.S., and Lecky, J.H., "Hypocalcemia During Rapid Blood Transfusion in Anaesthetized Man", Br. J. Anaesth ., 48 -995-1000, 1976. Stack, G., Judge, J.V., and Snyder, E.L., "Febrile and Nonimmune Transfusion Reactions", in Principles of Transfusion Medicine , pp. 780-781, editors Rossi, E.C., Simon, T.L., Moss, G.S., and Gould, S.A., Williams & Wilkins, Baltimore, MD, 2 nd ed., 1996.

Pediatric Use The safety and effectiveness of triCitrasol ® in children have not been established.

Pregnancy Long-term studies in animals have not been performed to evaluate the effects of triCitrasol ® on pregnant women.

HOW SUPPLIED triCitrasol ® Anticoagulant Sodium Citrate Concentrate 46.7% Trisodium Citrate REF SIZE CASE PN 6030-25 30 mL Vial 25 Vials/Case PN 6030-10 30 mL Vial 10 Vials/Case It is recommended that the product be stored at ambient room temperature, 24°C (75°F); however, the product can be stored between 15°C (59°F) and 30°C (86°F). Protect from freezing and exposure to excessive heat should be minimized.

It is recommended that the product be stored at ambient room temperature, 24°C (75°F); however, the product can be stored between 15°C (59°F) and 30°C (86°F). Protect from freezing and exposure to excessive heat should be minimized.

General Aseptic technique must be maintained at all times. triCitrasol ® Anticoagulant Sodium Citrate Concentrate is a clear/colorless solution. If the product shows any cloudiness or turbidity, the concentrate should be discarded. The cap/stopper system provides a biological barrier and should be intact – discard product if system is comprised.

PRECAUTIONS General Aseptic technique must be maintained at all times. triCitrasol ® Anticoagulant Sodium Citrate Concentrate is a clear/colorless solution. If the product shows any cloudiness or turbidity, the concentrate should be discarded. The cap/stopper system provides a biological barrier and should be intact – discard product if system is comprised. Information for Patients None. Laboratory Tests There are no laboratory tests for the drug product at this time. Drug Interactions There are no adverse reactions for the addition of the product to the rouleaux agent. Carcinogenesis, mutagenesis, impairment of fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of triCitrasol ® . Pregnancy Long-term studies in animals have not been performed to evaluate the effects of triCitrasol ® on pregnant women. Pediatric Use The safety and effectiveness of triCitrasol ® in children have not been established.