HETASTARCH: 100 Adverse Event Reports & Safety Profile

HEXTEND ® (6% Hetastarch in Lactated Electrolyte Injection) is a sterile, nonpyrogenic solution for intravenous administration. The composition, pH, and osmolarity are given in Table 1 and the electrolyte composition in Table 2 .

Table

1 Each 100 mL contains Hetastarch 6 g Sodium Chloride, USP 672 mg Sodium Lactate Anhydrous, USP 317 mg Dextrose Hydrous, USP 99 mg Calcium Chloride Dihydrate, USP 37 mg Potassium Chloride, USP 22 mg Magnesium Chloride Hexahydrate, USP 9 mg Water for Injection, USP qs pH: approximately 5.9 with negligible buffering capacity Calculated Osmolarity: approximately 307 mOsM Table 2 Concentration of Electrolytes (mEq/L)

Sodium

143 Chloride 124 Lactate 28 Calcium 5 Potassium 3 Magnesium

0.9 HEXTEND (6% Hetastarch in Lactated Electrolyte Injection) is an artificial colloidal solution, pharmacologically classified as a plasma volume expander, and is intended to support oncotic pressure as well as provide electrolytes. HEXTEND contains high molecular weight hetastarch at a concentration of 6% as an oncotic agent to permit retention of intravascular fluid until the hetastarch is replaced by blood proteins. Hetastarch is an artificial 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. Hetastarch is characterized by its molar substitution and also by its molecular weight. 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 450,000 to 800,000 and with at least 80% of the polymer units 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 an average of approximately one α-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 R 2 and R 3 are H or CH 2 CH 2 OH and R 6 is H, CH 2 CH 2 OH, or a branching point in the starch polymer connected through an α-1,6 link to additional D-glucopyranosyl units HEXTEND 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. HEXTEND is formulated with normal physiological levels of calcium. Calcium chloride in water dissociates to provide calcium (Ca ++ ) and chloride (Cl - ) ions. These are the normal constituents of the body fluids and are dependent on various physiologic mechanisms for maintenance of balance between intake and output.

Approximately

80% of body calcium is excreted in the feces as insoluble salts; urinary excretion accounts for the remaining 20%. HEXTEND also contains normal physiological levels of sodium. Additionally, chloride is present at levels closer to those normally found in blood than in plasma expanders in 0.9% Sodium Chloride Injection. Sodium chloride in water dissociates to provide sodium (Na + ) and chloride (Cl - ) ions. Sodium (Na + ) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl - ) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of sodium (Na + ) and chloride (Cl - ) are largely under the control of the kidneys, which maintain a balance between intake and output. HEXTEND also contains slightly lower than normal physiological levels of potassium and magnesium. Potassium chloride in water dissociates to provide potassium (K + ) and chloride (Cl - ) ions. Potassium is found in low concentrations in plasma and extracellular fluids (3.5 to 5.0 mEq/L in a healthy adult). It is the most abundant cation within the body's cells (160 mEq/L of intracellular water). Potassium plays an important role in electrolyte balance. Normally about 80 to 90% of the potassium intake is excreted in the urine with the remainder in the stools and, to a small extent, in the perspiration. The kidney does not conserve potassium well so that during fasting or in patients on a potassium-free diet, potassium loss from the body continues thereby resulting in potassium depletion. Magnesium chloride in water dissociates to provide magnesium (Mg ++ ) and chloride (Cl - ). Magnesium is largely an intracellular ion with low concentrations (1.5 to 2.5 mEq/L) found in plasma. Dextrose is included in the formulation. Solutions containing carbohydrate in the form of dextrose yield blood glucose, provide calories, and may also aid in minimizing liver glycogen depletion thereby exerting a protein sparing effect. Dextrose injected parenterally undergoes oxidation to carbon dioxide and water. Lactate is provided at 28 mEq/L. Sodium lactate in water dissociates to provide sodium (Na + ) and lactate (C 3 H 5 O 3 - ) ions. The lactate anion provides an alkaline effect resulting from simultaneous removal of lactate and hydrogen ions by the liver. In the liver, the lactate is metabolized to glycogen, which is ultimately converted to carbon dioxide and water by oxidative metabolism. The lactate anion acts as a source (alternate) of bicarbonate when normal production and utilization of lactic acid is not impaired as a result of disordered lactate metabolism. Since metabolic conversion is dependent on the integrity of cellular oxidative processes, lactate may be inadequate or ineffective as a source of bicarbonate in patients suffering from acidosis associated with shock or other disorders involving reduced perfusion of body tissues. When oxidative activity is intact, one to two hours is required for metabolism of lactate. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. The average normal adult daily requirement ranges from 2 to 3 L (1.0 to 1.5 L each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments, and sodium (Na + ) plays a major role in maintaining physiological equilibrium. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. 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. The container solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary. The closure system has two ports; the one for the administration set has a tamper evident plastic protector. hetastarch structural formula

AND USAGE 6% Hetastarch in 0.9% Sodium Chloride Injection is indicated in the treatment of hypovolemia when plasma volume expansion is desired in settings where adequate alternative treatment is unavailable. 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.

• 6% Hetastarch in 0.9% Sodium Chloride Injection is a hetastarch indicated for treatment of hypovolemia when plasma volume expansion is desired in settings where adequate alternative treatment is unavailable. ( 1 )
• 6% Hetastarch in 0.9% Sodium Chloride Injection in leukapheresis has shown to be safe and efficacious in improving the harvesting and increasing the yield of granulocytes by centrifugal means. ( 1 )

AND 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. For intravenous use only.

Recommended Dosage Dose

Adults ( 2.1 ) 500 to 1000 mL Leukapheresis ( 2.2 ) 250 to 700 mL of 6% Hetastarch in 0.9% Sodium Chloride Injection with citrate anticoagulant is added to the input line of the centrifugation apparatus.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span>.

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

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 Hospira, Inc. at 1-800-441-4100 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 &gt;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&apos;s, administration of HES reduced clot strength (Maximum Amplitude; p&lt;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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>. Cardiovascular reactions including circulatory overload, congestive heart failure, and pulmonary edema <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>. Hematologic reactions including intracranial bleeding, bleeding and/or anemia due to hemodilution <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> and/or Factor VIII deficiency, acquired von Willebrand&apos;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.

WARNINGS AND PRECAUTIONS

• Increased risk of mortality and acute kidney injury (AKI) in critically ill patients, including patients with sepsis; surgical patients; and blunt trauma patients
• Avoid use in patients with pre-existing renal dysfunction
• Discontinue use of HEXTEND at the first sign of renal injury
• Continue to monitor renal function for at least 90 days as use of renal replacement therapy (RRT) has been reported up to 90 days after administration of HES products
• Monitor the coagulation status of surgery patients, as excess bleeding has been reported with HES solutions in this population. Discontinue use of HEXTEND at the first sign of coagulopathy
• Monitor liver function in patients receiving HES products, including HEXTEND Solutions containing calcium should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. Life threatening anaphylactic/anaphylactoid reactions have been rarely reported with solutions containing hetastarch; death has occurred, but a causal relationship has not been established. Patients who develop severe anaphylactic/anaphylactoid reactions may need continued supportive care until symptoms have resolved. Hypersensitivity reactions can occur even after solutions containing hetastarch have been discontinued. Solutions which contain potassium should be used with great care, if at all, in patients with hyperkalemia and severe renal failure and in situations in which potassium retention is present. Solutions containing sodium ions should be used with great care, if at all, in patients with congestive heart failure and severe renal insufficiency and in clinical states in which edema with sodium retention occurs. In patients with diminished renal function, administration of solutions containing sodium or potassium ions may result in sodium or potassium retention. Solutions containing lactate ions should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be performed with great care when dealing with conditions in which an increased level or an impaired utilization of these ions occurs, such as severe hepatic insufficiency. DO NOT USE IN LEUKAPHERESIS. Usage in Plasma Volume Expansion Large volumes of isotonic solutions containing 6% hetastarch (HEXTEND or 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. Hemodilution by isotonic solutions containing 6% hetastarch may also result in a 24 hour decline of total protein, albumin, and fibrinogen levels and in transient prolongation of prothrombin, activated partial thromboplastin, clotting, and bleeding times. Increased bleeding has been reported in patients undergoing open heart surgery in association with cardiopulmonary bypass following the use of 6% Hetastarch in 0.9% Sodium Chloride Injection. 5,6 Although the electrolyte content of HEXTEND resembles that of the principal ionic constituents of normal plasma, its 6% Hetastarch component is identical to that of 6% Hetastarch in 0.9% Sodium Chloride Injection and has a direct inhibitory action on Factor VIII. There are no retrospective studies similar to those with 6% Hetastarch in 0.9% Sodium Chloride Injection that compare HEXTEND to albumin in cardiopulmonary bypass surgery nor have any adequate and well-controlled clinical studies been performed. Hematocrit may be decreased and plasma proteins diluted excessively by administration of large volumes of isotonic solutions containing 6% hetastarch. Administration of packed red cells, platelets, and fresh frozen plasma should be considered if excessive dilution occurs. In randomized, controlled, comparative studies of 6% Hetastarch in 0.9% Sodium Chloride Injection (n = 92) and Albumin (n = 85) in surgical patients, no patient in either treatment group had a bleeding complication and no significant difference was found in the amount of blood loss between the treatment groups. 1-4 HEXTEND has not been adequately evaluated to establish its safety in situations other than treatment of hypovolemia in elective surgery. In some cases, the use of isotonic solutions containing 6% hetastarch 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 or von Willebrand deficiency is identified. If a coagulopathy develops, it may take several days to resolve. Certain conditions may affect the safe use of isotonic solutions containing 6% hetastarch on a chronic basis. For example, in patients with subarachnoid hemorrhage where an isotonic solution containing 6% hetastarch 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 with the use of 6% Hetastarch in 0.9% Sodium Chloride Injection. 7 The possibility of circulatory overload should be kept in mind. Caution should be used when the risk of pulmonary edema and/or congestive heart failure is increased. Special care should be exercised in patients who have impaired renal clearance since this is the principal way in which hetastarch is eliminated and in clinical states in which edema with sodium retention occurs. 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 isotonic solutions containing 6% hetastarch to patients with a history of liver disease. If a hypersensitivity effect occurs, administration of the drug should be discontinued and appropriate treatment and supportive measures should be undertaken (see WARNINGS AND PRECAUTIONS ). Caution should be used when administering solutions containing hetastarch to patients allergic to corn because such patients can also be allergic to hetastarch. HEXTEND should be used with caution in patients who have been anticoagulated with other drugs that negatively influence the coagulation system. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus. Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotropin. Potassium containing solutions should be used with caution in the presence of cardiac disease, particularly in digitalized patients or in the presence of renal disease. Solutions containing lactate ions should be used with caution as excess administration may result in metabolic alkalosis. Elevated serum amylase levels may be observed temporarily following administration of solutions containing hetastarch 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 solutions containing hetastarch. Elevated serum amylase levels persist for longer periods of time in patients with renal impairment. Solutions containing hetastarch have not been shown to increase serum lipase. One report suggests that in the presence of renal glomerular damage, larger molecules of hetastarch can leak into the urine and elevate the specific gravity. The elevation of specific gravity can obscure the diagnosis of renal failure. Hetastarch is not eliminated by hemodialysis. The utility of other extracorporeal elimination techniques has not been evaluated. If administration is by pressure infusion, all air should be withdrawn or expelled from the bag through the medication port prior to infusion. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies of animals have not been performed to evaluate the carcinogenic potential of hetastarch.

Teratogenic Effects

6% Hetastarch in 0.9% Sodium Chloride Injection 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

6% Hetastarch in 0.9% Sodium Chloride Injection 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. HEXTEND should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 HEXTEND is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of HEXTEND in pediatric patients have not been established. Adequate, well-controlled clinical trials to establish the safety and effectiveness of HEXTEND in pediatric patients have not been conducted. However, in one small double-blind study, 47 infants, children, and adolescents (ages 1 year to 15.5 years) scheduled for repair of congenital heart disease with moderate hypothermia were randomized to receive either 6% Hetastarch in 0.9% Sodium Chloride Injection or Albumin as a postoperative volume expander during the first 24 hours after surgery. Thirty-eight children required colloid replacement therapy, of which 20 children received 6% Hetastarch in 0.9% Sodium Chloride Injection. No differences were found in the coagulation parameters or in the amount of replacement fluids required in the children receiving 20 mL/kg or less of either colloid replacement therapy. In children who received greater than 20 mL/kg of 6% Hetastarch in 0.9% Sodium Chloride Injection, an increase in prothrombin time was demonstrated (p = 0.006). 8 There were no neonates included in this study.

Geriatric

Use Of the total number of patients in clinical trials of HEXTEND (n=119), 30% were 65 or older while 12% were 70 or older. Other reported experience with 6% Hetastarch in 0.9% Sodium Chloride Injection has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

INTERACTIONS 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.
• Use with caution with drugs that negatively influence the coagulation system. ( 7 )
• The safety and compatibility of other additives have not been established. ( 7 )