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 HESPAN® (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 HESPAN® 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 HESPAN®

• 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. Discard unused portion.

CAUTION: Before administering to the patient, review these directions:

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 coagulopathy1-2

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

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:

8.1 Pregnancy

Hetastarch has been shown to have an embryocidal effect on New Zealand rabbits when given intravenously over the entire organogenesis period in a daily dose 1/2 times the maximum recommended therapeutic human dose (1500 mL) and on BD rats when given intraperitoneally, from the 16th to the 21st day of pregnancy, in a daily dose 2.3 times the maximum recommended therapeutic human dose. When hetastarch was administered to New Zealand rabbits, BD rats, and swiss mice with intravenous daily doses of 2 times, 1/3 times, and 1 times the maximum recommended therapeutic human dose respectively over several days during the period of gestation, no evidence of teratogenicity was evident.

There are no adequate and well-controlled studies in pregnant women. HESPAN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether hetastarch is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HESPAN® is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of hetastarch in pediatric patients have not been established. Adequate, well-controlled clinical trials to establish the safety and effectiveness of HESPAN® in pediatric patients have not been conducted.

12.1 Mechanism of Action

The plasma volume expansion produced by HESPAN® approximates that of 5% Albumin (Human). Intravenous infusion of HESPAN® results in expansion of plasma volume.

12.2 Pharmacodynamics

HESPAN® results in expansion of plasma volume that decreases over the succeeding 24 to 36 hours. The degree of plasma volume expansion and improvement in hemodynamic state depend upon the patient’s intravascular status.

12.3 Pharmacokinetics

Hetastarch molecules below 50,000 molecular weight are rapidly eliminated by renal excretion. A single dose of approximately 500 mL of HESPAN® (approximately 30 g) results in elimination in the urine of approximately 33% of the dose within 24 hours. This is a variable process but generally results in an intravascular hetastarch concentration of less than 10% of the total dose injected by two weeks. A study of the biliary excretion of HESPAN® in 10 healthy males accounted for less than 1% of the dose over a 14 day period. The hydroxyethyl group is not cleaved by the body but remains intact and attached to glucose units when excreted. Significant quantities of glucose are not produced as hydroxyethylation prevents complete metabolism of the smaller polymers.

The addition of hetastarch to whole blood increases the erythrocyte sedimentation rate. Therefore, HESPAN® is used to improve the efficiency of granulocyte collection by centrifugal means.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies of animals have not been performed to evaluate the carcinogenic potential of hetastarch.