Hextend

HEXTEND (6% Hetastarch in Lactated Electrolyte Injection) is supplied sterile and nonpyrogenic in 500 mL single-dose flexible plastic infusion containers.

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C/77°F); however, brief exposure up to 40°C does not adversely affect the product.

To Open

Tear overwrap down at notch and remove solution container. Check for any leakage by squeezing solution container firmly. If leaks are found, discard solution as sterility may be impaired.

Invert container and carefully inspect the solution in good light for cloudiness, haze, or particulate matter. Any container that is suspect should not be used.

Manufactured and Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA. Under license from BioTime, Inc., Alameda, CA 94502, USA. Revised: Nov 2014

HEXTEND (6% Hetastarch in Lactated Electrolyte Injection) is indicated in the treatment of hypovolemia when plasma volume expansion is desired. It is not a substitute for blood or plasma.

Dosage For Acute Use In Plasma Volume Expansion

HEXTEND 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 as well as age, weight, and clinical condition of the patient.

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 although doses of isotonic solutions containing 6% hetastarch up to 1500 mL have been used during major surgery generally without a need for blood or blood products. Volumes in excess of 1500 mL per day have been used where severe blood loss has occurred although generally only in conjunction with the administration of blood and blood products (see WARNINGS AND PRECAUTIONS).

Pediatric Patients

Adequate, well controlled clinical trials to establish the safety and effectiveness of HEXTEND in pediatric patients have not been conducted (seeWARNINGS AND PRECAUTIONS, Pediatric Use).

General Recommendations

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.

This solution is intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours.

Use only if solution is clear and container and seals are intact.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

If administration is by pressure infusion, all air should be withdrawn or expelled from the bag through the medication port prior to infusion.

The safety and compatibility of other additives have not been established. This product contains calcium and should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation (see WARNINGS AND PRECAUTIONS).

The solution contains no bacteriostat or antimicrobial agent and is intended only for single-dose injection. When smaller doses are required, the unused portion should be discarded.

• Do not use hydroxyethyl starch (HES) products, including HEXTEND, in critically ill adult patients, including patients with sepsis, due to increased risk of mortality and renal replacement therapy.
• Do not use HES products, including HEXTEND, in patients with severe liver disease
• Do not use HES products, including HEXTEND, in patients with known hypersensitivity to hydroxyethyl starch
• Do not use HES products in clinical conditions where volume overload is a potential problem
• Do not use HES products in patients with pre-existing coagulation or bleeding disorders
• Solutions containing hetastarch should not be used in renal disease with oliguria or anuria not related to hypovolemia
• Do not use in the treatment of lactic acidosis as HEXTEND contains lactate

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

• 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 in hospitalized patients 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 patients undergoing open heart surgery in association with cardiopulmonary bypass 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 (seeWARNINGS 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

Pregnancy Category C

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 ½ 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.

REFERENCES

1. Diehl J, et al., Clinical Comparison of Hetastarch and Albumin in Postoperative Cardiac Patients. The Annals of Thoracic Surgery, 1982;34(6):674-679.

2. Gold M, et al., Comparison of Hetastarch to Albumin for Perioperative Bleeding in Patients Undergoing Abdominal Aortic Aneurysm Surgery, Annals of Surgery, 1990;211(4):482-485.

3. Kirklin J, et al., Hydroxyethyl Starch versus Albumin for Colloid Infusion Following Cardiopulmonary Bypass in Patients Undergoing Myocardial Revascularization, The Annals of Thoracic Surgery, 1984;37(1):40-46.

4. Moggio RA, et al., Hemodynamic Comparison of Albumin and Hydroxyethyl Starch in Postoperative Cardiac Surgery Patients, Critical Care Medicine, 1983;11(12):943-945.

5. Knutson, JE, et al., Does Intraoperative Hetastarch Administration Increase Blood Loss and Transfusion Requirements After Cardiac Surgery? Anesthesia Analg., 2000;90: 801-7.

6. Cope, JT, et al., Intraoperative Hetastarch Infusion Impairs Hemostasis After Cardiac Operations, The Annals of Thoracic Surgery, 1997;63: 78-83.

7. Damon L, Intracranial Bleeding During Treatment with Hydroxyethyl Starch, New England Journal of Medicine, 1987; 317(15):964-965.

8. Brutocao D, et al., Comparison of Hetastarch with Albumin for Postoperative Volume Expansion in Children After Cardiopulmonary Bypass, Journal of Cardiothoracic and Vascular Anesthesia, 1996;10(3):348-351.

SIDE EFFECTS

Serious adverse reactions (ARs) observed in clinical trials of critically ill adult patients include:

• Increased mortality in severe sepsis and other conditions requiring ICU admission
• Increased need for renal replacement therapy in severe sepsis and other conditions requiring ICU admission

In clinical trials comparing the plasma volume expanding properties of HEXTEND (n=60) with those of 6% Hetastarch in 0.9% Sodium Chloride Injection (n=59), there were no significant differences in the number of adverse or serious adverse events between the two groups.

Reported adverse reactions with isotonic solutions containing 6% hetastarch include:

General

Hypersensitivity (seeWARNINGS AND PRECAUTIONS).

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.

Cardiovascular

Circulatory overload, congestive heart failure, and pulmonary edema (seeWARNINGS AND PRECAUTIONS).

Hematologic

Intracranial bleeding, bleeding and/or anemia due to hemodilution (seeWARNINGS AND PRECAUTIONS) and/or Factor VIII deficiency, acquired von Willebrand's-like syndrome, and coagulopathy including rare cases of disseminated intravascular coagulopathy and hemolysis. With extensive clinical use of 6% Hetastarch in 0.9% Sodium Chloride Injection, rare cases of disseminated intravascular coagulopathy and hemolysis have been observed.

Metabolic

Metabolic acidosis.

Other

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.

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 other HES products in critically ill adult patients, including patients with sepsis:

Mortality

Renal: need for renal replacement therapy

DRUG INTERACTIONS

No Information Provided

Serious adverse reactions (ARs) observed in clinical trials of critically ill adult patients include:

• Increased mortality in severe sepsis and other conditions requiring ICU admission
• Increased need for renal replacement therapy in severe sepsis and other conditions requiring ICU admission

In clinical trials comparing the plasma volume expanding properties of HEXTEND (n=60) with those of 6% Hetastarch in 0.9% Sodium Chloride Injection (n=59), there were no significant differences in the number of adverse or serious adverse events between the two groups.

Reported adverse reactions with isotonic solutions containing 6% hetastarch include:

General

Hypersensitivity (seeWARNINGS AND PRECAUTIONS).

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.

Cardiovascular

Circulatory overload, congestive heart failure, and pulmonary edema (seeWARNINGS AND PRECAUTIONS).

Hematologic

Intracranial bleeding, bleeding and/or anemia due to hemodilution (seeWARNINGS AND PRECAUTIONS) and/or Factor VIII deficiency, acquired von Willebrand's-like syndrome, and coagulopathy including rare cases of disseminated intravascular coagulopathy and hemolysis. With extensive clinical use of 6% Hetastarch in 0.9% Sodium Chloride Injection, rare cases of disseminated intravascular coagulopathy and hemolysis have been observed.

Metabolic

Metabolic acidosis.

Other

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.

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 other HES products in critically ill adult patients, including patients with sepsis:

Mortality

Renal: need for renal replacement therapy

No Information Provided