6% HETASTARCH IN 0.9% SODIUM CHLORIDE

BOXED WARNING BOXED WARNING

5 WARNINGS AND PRECAUTIONS 5.1 Renal Dysfunction • Avoid use in patients with pre-existing renal dysfunction • Discontinue use of 6% Hetastarch in 0.9% Sodium Chloride Injection at the first sign of renal injury • Continue to monitor renal function in hospitalized patients for at least 90 days as use of RRT has been reported up to 90 days after administration of HES products, including 6% Hetastarch in 0.9% Sodium Chloride Injection 5.2 Coagulopathy • 6% Hetastarch in 0.9% Sodium Chloride Injection is not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired. Discontinue use of 6% Hetastarch in 0.9% Sodium Chloride Injection at first sign of coagulopathy 1-2 6% Hetastarch in 0.9% Sodium Chloride Injection has not been adequately evaluated to establish its safety in uses over extended periods other than leukapheresis. 6% Hetastarch in 0.9% Sodium Chloride Injection has been associated with coagulation abnormalities in conjunction with an acquired, reversible von Willebrand's-like syndrome and/or Factor VIII deficiency when used over a period of days. Replacement therapy should be considered if a severe Factor VIII deficiency is identified. If a coagulopathy develops, it may take several days to resolve. Certain conditions may affect the safe use of 6% Hetastarch in 0.9% Sodium Chloride Injection on a chronic basis. For example, in patients with subarachnoid hemorrhage where 6% Hetastarch in 0.9% Sodium Chloride Injection is used repeatedly over a period of days for the prevention of cerebral vasospasm, significant clinical bleeding may occur. Intracranial bleeding resulting in death has been reported.3 Slight declines in platelet counts and hemoglobin levels have been observed in donors undergoing repeated leukapheresis procedures using 6% Hetastarch in 0.9% Sodium Chloride Injection due to the volume expanding effects of hetastarch and to the collection of platelets and erythrocytes. Hemoglobin levels usually return to normal within 24 hours. Hemodilution by 6% Hetastarch in 0.9% Sodium Chloride Injection may also result in 24 hour declines of total protein, albumin, calcium, and fibrinogen levels. Regular and frequent clinical evaluation and complete blood counts (CBC) are necessary for proper monitoring of 6% Hetastarch in 0.9% Sodium Chloride Injection use during leukapheresis. If the frequency of leukapheresis is to exceed the guidelines for whole blood donation, you may wish to consider the following additional tests: total leukocyte and platelet counts, leukocyte differential count, hemoglobin and hematocrit, prothrombin time (PT), and partial thromboplastin time (PTT). 5.3 Hypersensitivity Reactions Life threatening anaphylactic/anaphylactoid reactions including death have been rarely reported with 6% Hetastarch in 0.9% Sodium Chloride Injection. Patients may develop hypersensitivity reaction to corn starch from which this product is made. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. 5.4 Circulatory Overload 6% Hetastarch in 0.9% Sodium Chloride Injection has not been adequately evaluated to establish its safety in situations other than treatment of hypovolemia in elective surgery. Large volumes of 6% Hetastarch in 0.9% Sodium Chloride Injection may transiently alter the coagulation mechanism due to hemodilution and a direct inhibitory action on Factor VIII. Administration of volumes of 6% Hetastarch in 0.9% Sodium Chloride Injection that are greater than 25% of the blood volume in less than 24 hours may cause significant hemodilution reflected by lower hematocrit and plasma protein values. Administration of packed red cells, platelets, or fresh frozen plasma should be considered if clinically indicated. When using 6% Hetastarch in 0.9% Sodium Chloride Injection for plasma volume expansion, caution should be taken to avoid excessive hemodilution and circulatory overload especially in those patients at risk for developing congestive heart failure and pulmonary edema. 6% Hetastarch in 0.9% Sodium Chloride Injection is primarily excreted via the kidneys so caution should be exercised in patients who have impaired renal function. Although the risk of circulatory overload is largely dependent on the clinical circumstances, use of doses higher than 20 mL/kg/24h will increase the risk significantly. Increased risk of coagulation abnormalities and bleeding is also associated with higher doses. Monitor patients' vital signs and hemoglobin, hematocrit, platelet count, prothrombin time and partial thromboplastin time. 5.5 Liver Function Test • Monitor liver function in patients receiving HES products, including 6% Hetastarch in 0.9% Sodium Chloride Injection 5.6 Drug/Laboratory Test Interactions Bilirubin Levels Indirect bilirubin levels of 8.3 mg/L (normal 0.0-7.0 mg/L) have been reported in 2 out of 20 normal subjects who received multiple infusions of 6% Hetastarch in 0.9% Sodium Chloride Injection. Total bilirubin was within normal limits at all times; indirect bilirubin returned to normal by 96 hours following the final infusion. The significance, if any, of these elevations is not known; however, caution should be observed before administering 6% Hetastarch in 0.9% Sodium Chloride Injection to patients with a history of liver disease. Serum Amylase Levels Elevated serum amylase levels may be observed temporarily following administration of 6% Hetastarch in 0.9% Sodium Chloride Injection although no association with pancreatitis has been demonstrated. Serum amylase levels cannot be used to assess or to evaluate for pancreatitis for 3-5 days after administration of 6% Hetastarch in 0.9% Sodium Chloride Injection. Elevated serum amylase levels persist for longer periods of time in patients with renal impairment. Hetastarch has not been shown to increase serum lipase. Hemodialysis 6% Hetastarch in 0.9% Sodium Chloride Injection is not eliminated by hemodialysis. The utility of other extracorporeal elimination techniques has not been evaluated.

6 ADVERSE REACTIONS 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.