6% HETASTARCH IN 0.9% SODIUM CHLORIDE

6% Hetastarch in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic solution for intravenous administration. Each 100 mL contains: Hetastarch............................................................................ 6 g Sodium Chloride, USP........................................................ 0.9 g Water for Injection, USP..................................................... qs pH adjusted with Sodium Hydroxide, NF if necessary Concentration of Electrolytes (mEq/L): Sodium (Na+) 154, Chloride (Cl-) 154 (not including ions for pH adjustment). pH: 5.5 (3.5 to 7.0) Total osmolar concentration is 308 mOsmol/liter (calc). Hetastarch is a synthetic colloid derived from a waxy starch composed almost entirely of amylopectin. Hydroxyethyl ether groups are introduced into the glucose units of the starch, and the resultant material is hydrolyzed to yield a product with a molecular weight suitable for use as a plasma volume expander and erythrocyte sedimenting agent. The molar substitution is approximately 0.75 which means hetastarch has an average of approximately 75 hydroxyethyl groups for every 100 glucose units. The weight average molecular weight is approximately 670,000 with a range of 550,000 to 800,000 and with at least 80% of the polymers falling within the range of 20,000 to 2,500,000. Hydroxyethyl groups are attached by ether linkage primarily at C-2 of the glucose unit and to a lesser extent at C-3 and C-6. The polymer resembles glycogen, and the polymerized D-glucose units are joined primarily by α-1,4 linkages with occasional α-1,6 branching linkages. The degree of branching is approximately 1:20 which means that there is one 1-6 branch for every 20 glucose monomer units. The chemical name for hetastarch is hydroxyethyl starch. The structural formula is as follows: Amylopectin derivative in which R2, R3, and R6 are H or CH2CH2OH, or R6 is a branching point in the starch polymer connected through a 1-6 linkage to additional alpha-D-glucopyranosyl units. Hetastarch is an artificial colloid pharmacologically classified as a plasma volume expander; 0.9% Sodium Chloride Injection is a fluid and electrolyte replenisher. 6% Hetastarch in 0.9% Sodium Chloride Injection is a clear, pale yellow to amber solution. Exposure to prolonged adverse storage conditions may result in a change to a turbid deep brown or the formation of a crystalline precipitate. Do not use the solution if these conditions are evident. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period. STRUCTURE

6% Hetastarch in 0.9% Sodium Chloride Injection is indicated in the treatment of hypovolemia when plasma volume expansion is desired. It is not a substitute for blood or plasma. The adjunctive use of 6% Hetastarch in 0.9% Sodium Chloride Injection in leukapheresis has also been shown to be safe and efficacious in improving the harvesting and increasing the yield of granulocytes by centrifugal means.

DOSAGE & ADMINISTRATION Dosage for Acute Use in Plasma Volume Expansion 6% Hetastarch in 0.9% Sodium Chloride Injection is administered by intravenous infusion only. Total dosage and rate of infusion depend upon the amount of blood or plasma lost and the resultant hemoconcentration. 2.1 Adults The amount usually administered is 500 to 1000 mL. Doses of more than 1500 mL per day for the typical 70 kg patient (approximately 20 mL per kg of body weight) are usually not required. Higher doses have been reported in postoperative and trauma patients where severe blood loss has occurred [see WARNINGS AND PRECAUTIONS (5 )]. 2.2 Leukapheresis 250 to 700 mL of 6% Hetastarch in 0.9% Sodium Chloride Injection with citrate anticoagulant is administered by aseptic addition to the input line of the centrifugation apparatus at a ratio of 1:8 to 1:13 to venous whole blood. The 6% Hetastarch in 0.9% Sodium Chloride Injection and citrate should be thoroughly mixed to assure effective anticoagulation of blood as it flows through the leukapheresis machine. 2.3 Direction for use for 6% Hetastarch in 0.9% Sodium Chloride Injection • Do not use plastic container in series connection. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. If administration is not controlled by a pumping device, refrain from applying excessive pressure (>300mmHg) causing distortion to the container such as wringing or twisting. Such handling could result in breakage of the container. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use only if solution is clear and container and seals are intact. • Intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours. • Withdraw or expel all air from the bag through the medication port prior to infusion if administration is by pressure infusion. • For single use only. The solution contains no bacteriostat, antimicrobial agent or added buffers (except for pH adjustment) and is intended only for single-dose injection. When smaller doses are required the unused portion should be discarded. CAUTION: Before administering to the patient, review these directions: Visual Inspection • Do not remove the plastic infusion container from its overwrap until immediately before use. • 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. To Open 1. Tear overwrap down at notch and remove solution container. 2. Check for minute leaks by squeezing solution container firmly. 3. If any leaks are found, discard solution as sterility may be impaired. Preparation for Administration 1. Remove plastic protector from sterile set port at bottom of container. 2. Attach administration set. Refer to complete directions accompanying set. When stored at room temperature, 6% Hetastarch in 0.9% Sodium Chloride Injection admixtures of 500-560 mL with citrate concentrations up to 2.5% were compatible for 24 hours. The safety and compatibility of additives other than citrate have not been established.

Do not use hydroxyethyl starch (HES) products, including 6% Hetastarch in 0.9% Sodium Chloride Injection, in critically ill adult patients, including patients with sepsis, due to increased risk of mortality and renal replacement therapy (RRT). • Do not use HES products, including 6% Hetastarch in 0.9% Sodium Chloride Injection, in patients with severe liver disease • Do not use HES products, including 6% Hetastarch in 0.9% Sodium Chloride Injection, in patients with known hypersensitivity to hydroxyethyl starch • Do not use HES products, including 6% Hetastarch in 0.9% Sodium Chloride Injection, in clinical conditions where volume overload is a potential problem (such as, congestive heart failure or renal disease with anuria or oliguria not related to hypovolemia). • Do not use HES products, including 6% Hetastarch in 0.9% Sodium Chloride Injection, in patients with pre-existing coagulation or bleeding disorders

The serious adverse events reported in clinical trials are increased mortality and renal replacement therapy renal in critically ill patients. Most common adverse reactions are hypersensitivity, coagulopathy, hemodilution, circulatory overload and metabolic acidosis. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Three randomized controlled trials (RCTs) followed critically ill adult patients treated with different HES products for 90 days. One trial (N=804) in severe sepsis patients using HES product (not approved in the U.S.) reported increased mortality (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03) and RRT (relative risk, 1.35; 95% CI, 1.01 to 1.80; p=0.04) in the HES treatment arm.4 Another trial (N=196) using different HES in severe sepsis patients reported no difference in mortality (relative risk, 1.20; 95% CI, 0.83 to 1.74; p=0.33) and a trend for RRT (relative risk, 1.83; 95% CI, 0.93 to 3.59; p=0.06) in HES patients.5 A third trial (N=7000) using different HES in a heterogeneous patient population consisting of critically ill adult patients admitted to the ICU reported no difference in mortality (relative risk, 1.06; 95% CI, 0.96 to 1.18; p=0.26) but increased use of RRT (relative risk, 1.21; 95% CI, 1.00 to 1.45; p=0.04) in HES patients.6 6.2 Postmarketing Experience Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. The following adverse reactions have been identified and reported during the post-approval use of HES products: Mortality Renal need for renal replacement therapy Hypersensitivity reactions including death, life-threatening anaphylactic/anaphylactoid reactions, cardiac arrest, ventricular fibrillation, severe hypotension, non-cardiac pulmonary edema, laryngeal edema, bronchospasm, angioedema, wheezing, restlessness, tachypnea, stridor, fever, chest pain, bradycardia, tachycardia, shortness of breath, chills, urticaria, pruritus, facial and periorbital edema, coughing, sneezing, flushing, erythema multiforme, and rash [see WARNINGS AND PRECAUTIONS (5.3)]. Cardiovascular reactions including circulatory overload, congestive heart failure, and pulmonary edema [see WARNINGS AND PRECAUTIONS (5.4)]. Hematologic reactions including intracranial bleeding, bleeding and/or anemia due to hemodilution [see Warnings and Precautions (5.4)] and/or Factor VIII deficiency, acquired von Willebrand's-like syndrome, and coagulopathy including rare cases of disseminated intravascular coagulopathy and hemolysis. Metabolic reactions including metabolic acidosis. Other reactions including vomiting, peripheral edema of the lower extremities, submaxillary and parotid glandular enlargement, mild influenza-like symptoms, headaches, and muscle pains. Hydroxyethyl starch-associated pruritus has been reported in some patients with deposits of hydroxyethyl starch in peripheral nerves.

6% Hetastarch in 0.9% Sodium Chloride Injection should be used with caution in patients who have been anticoagulated with other drugs that negatively influence the coagulation system. • The safety and compatibility of other additives have not been established.