FDA label 867d0f70-645f-44c7-96c6-ba29f052076b

WARNING: MORTALITY; KIDNEY INJURY; COAGULOPATHY Use of hydroxyethyl starch (HES) products, including HESPAN®, increases risk of Mortality Kidney injury (5.1) Coagulopathy (5.2) DO NOT use HES products, including HESPAN®, unless adequate alternative treatment is unavailable. (1) WARNING: MORTALITY ; KIDNEY INJURY; COAGULOPATHY See full prescribing information for complete boxed warning. Use of hydroxyethyl starch (HES) products, including HESPAN®, increases risk of Mortality Kidney injury Coagulopathy DO NOT use HES products, including HESPAN®, unless adequate alternative treatment is unavailable.

5 WARNINGS AND PRECAUTIONS Avoid use in patients with pre-existing renal dysfunction ( 5.1 ) Increased risk of mortality and acute kidney injury (AKI) in critically ill patients, including patients with sepsis; surgical patients; and blunt trauma patients (5.1) Discontinue use of HESPAN® at the first sign of renal injury ( 5.1 ) Continue to monitor renal function for at least 90 days as use of RRT has been reported up to 90 days after administration of HES products, including HESPAN® ( 5.1 ) HESPAN® 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 HESPAN® at first sign of coagulopathy ( 5.2 ) Monitor liver function in patients receiving HES products, including HESPAN® ( 5.2 ) 5.1 Mortality and Renal Dysfunction Critically ill patients, including patients with sepsis, are at increased risk of mortality and acute kidney injury (AKI), including need for renal replacement therapy (RRT). Surgery patients are at increased risk of mortality and AKI Blunt trauma patients are at increased risk of mortality and AKI. Avoid use in patients with pre-existing renal dysfunction Discontinue use of HESPAN® at the first sign of renal injury Continue to monitor renal function for at least 90 days as use of RRT has been reported up to 90 days after administration of HES products, including HESPAN® 5.2 Coagulopathy HESPAN® 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. Monitor the coagulation status of surgery patients, as excess bleeding has been reported with HES solutions in this population. Discontinue use of HESPAN® at first sign of coagulopathy 1-2 HESPAN® has not been adequately evaluated to establish its safety in uses over extended periods other than leukapheresis. HESPAN® has been associated with coagulation abnormalities in conjunction with an acquired, reversible von Willebrand’s-like syndrome and/or Factor Vlll deficiency when used over a period of days. Replacement therapy should be considered if a severe Factor Vlll deficiency is identified. If a coagulopathy develops, it may take several days to resolve. Certain conditions may affect the safe use of HESPAN® on a chronic basis. For example, in patients with subarachnoid hemorrhage where HESPAN® 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 HESPAN® 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 HESPAN® 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 HESPAN® 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 HESPAN®. 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 HESPAN® has not been adequately evaluated to establish its safety in situations other than treatment of hypovolemia in elective surgery. Large volumes of HESPAN® may transiently alter the coagulation mechanism due to hemodilution and a direct inhibitory action on Factor Vlll. Administration of volumes of HESPAN® 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 HESPAN® 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. HESPAN® 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 HESPAN® 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 HESPAN® (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 HESPAN® to patients with a history of liver disease. Serum Amylase Levels Elevated serum amylase levels may be observed temporarily following administration of HESPAN® 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 HESPAN®. 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 HESPAN® is not eliminated by hemodialysis. The utility of other extracorporeal elimination techniques has not been evaluated.

6 ADVERSE REACTIONS Serious adverse reactions reported in postmarket clinical trials include increased mortality and AKI (including need for RRT) in critically ill subjects, including subjects with sepsis, and surgical subjects. Clinical trials have also shown increased mortality and AKI in blunt trauma subjects. Increased coagulopathy was reported in surgical subjects. Most common adverse reactions are hypersensitivity, coagulopathy, hemodilution, circulatory overload and metabolic acidosis. Most common adverse reactions are hypersensitivity, coagulopathy, hemodilution, circulatory overload and metabolic acidosis. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-854-6851 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. (Note: All of the studies listed below used licensed HES products except for reference 4.) A randomized controlled 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 randomized controlled 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 randomized controlled 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 In a retrospective study of adult patients (N=1442) undergoing pulmonary or esophageal surgery who were prophylactically fluid restricted during the procedure, 74 developed AKI (5.1%) within the first 72 hours postoperatively. Fluid restriction neither increased nor was a risk factor for AKI. AKI occurred more often when HES products were administered to patients with decreased renal function or having >2 risk factors with normal renal function, whereas restriction of crystalloid was unrelated to AKI, regardless of preoperative renal function. 12 In a retrospective case series of high-risk adult vascular surgery patients (N=796) receiving fluid therapy during a vascular surgery procedure, logistic regression analysis using prespecified confounding variables or suspected risk factors for AKI showed that intraoperative administration of an HES product was associated with increased likelihood of 30-day mortality and need for RRT, compared with use of crystalloids alone. 13 In a retrospective study of adult subjects undergoing elective noncardiac surgery, patients (N=14,680) receiving an HES product and crystalloid were propensity-matched with patients (N=14,680) receiving only crystalloid. After controlling for potential confounding variables, odds of experiencing AKI of severe intensity with HES was 21% greater than with crystalloid alone. In addition, AKI risk increased as a function of HES volume. 14 In a prospective observational study assessing the impact of HES products on recipient renal graft outcomes in brain-dead organ donors, data were obtained on 986 kidneys transplanted from 529 donors. Kidneys from donors who received HES had a higher rate of delayed graft function in recipient subjects (41% versus 31%). After accounting for the propensity of donors to receive HES products, HES product administration was independently associated with an increased risk of delayed graft function in recipients.A dose response relationship also was evident. 15 In a randomized, controlled trial of adult subjects (N=33) undergoing elective cystectomy comparing an HES product versus lactated Ringer’s, administration of HES reduced clot strength (Maximum Amplitude; p<0.001) and increased blinded evaluation of perioperative blood loss by more than 50% (2181 mL versus 1370 mL, respectively; p=0.04). There was no significant between-group difference with respect to frequency of reoperation or length of hospital stay. 16 In a prospective, sequential, observational study in adult subjects undergoing open heart surgery in association with cardiopulmonary bypass, fluid therapy using only an HES product (2004-2006, N=2137), 4% gelatin (2006-2008, N=2324) and crystalloids (N=2017, 2008-2010) led to increased need for renal replacement therapy after HES and gelatin, compared with crystalloid. Propensity score stratification confirmed greater use of RRT in the HES and gelatin periods compared to the crystalloid period. Fluid intake was higher in the crystalloid group only during the first 20 hours. 17 In a retrospective observational study, 606 adult patients underwent open heart surgery in association with cardiopulmonary bypass. Until July 2013 they received an HES product (N=247) both as pump prime (1500 mL) and intraoperative fluid replacement (1000 mL), but only crystalloid (N=359) from August 2013 onward. The frequency (percent) of postoperative AKI was higher in patients receiving HES (N=53; 21.5%) than those receiving crystalloid (N=34; 9.5%). Surgical revision for rebleeding also was higher for HES (N=11; 4.6%) than for crystalloid (N=5; 1.4%). 18 In a meta-analysis of RCTs (n=15) in adult subjects (N=4409) undergoing surgery who received an HES product, significantly more HES subjects (83/2157; 3.8%) than controls (56/2252; 2.5%) underwent RRT (relative risk, 1.44; 95% CI, 1.04, 2.01). 19 In a retrospective observational study of adult blunt and penetrating trauma patients, use of an HES product was a significant independent predictor of AKI after blunt trauma, but not penetrating trauma, in multiple logistic regression analysis. In separate logistic regression models, HES also was a significant predictor of mortality after blunt trauma but not penetrating trauma. 20 In a retrospective observational study of severely injured adult blunt (89%) and penetrating (11%) trauma patients (N=413) admitted to the ICU, 103 patients developed AKI within the first week of ICU admission. AKI was associated with increased 30-day (17.5% versus 5.8%, AKI versus non-AKI cohorts, respectively) and 1-year mortality (26.2% versus 7.1%). Univariate and multivariable regression analyses of prespecified risk factors for AKI found that volume loading using an HES product was independently associated with postinjury AKI within the first 24 hours. 21 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: 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 Vlll 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.