in 0.9% Sodium Chloride Injection

Flexible Plastic Container

Rx only

DESCRIPTION

6% Hetastarch in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic solution for intravenous administration. Each 100 mL of 6% Hetastarch in 0.9% Sodium Chloride Injection contains hetastarch, 6 g and sodium chloride 0.9 g in water for injection. Total osmolar concentration is 308 mOsmol/liter (calc); pH 5.5 (3.5 to 7.0). May contain sodium hydroxide for pH adjustment. Electrolyte concentration per liter: Sodium (Na+) 154 mEq; Chloride (Cl‾) 154 mEq (not including ions for pH adjustment).

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.

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 and erythrocyte sedimenting agent.

Hetastarch is characterized by its molecular weight and molar substitution. The average molecular weight is approximately 670,000 (with a range of 550,000 − 800,000) and with 80% of the polymer units falling within the range of 20,000 − 2,500,000. The degree of substitution is 0.75 which means hetastarch has 75 hydroxyethyl groups for every 100 glucose units. 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 polymerized glucose units are joined primarily by 1-4 linkages with occasional 1-6 branching linkages. The degree of branching is approximately 1:20 which means that there is one 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 R2, R3, and R6 are H or CH2CH2OH, or R6 is a branching point in  the  starch  polymer  connected  through  a 1-6 linkage to additional alpha-D-glucopyranosyl units.

Hetastarch is an artificial colloid pharmacologically classified as a plasma volume expander; 0.9% Sodium Chloride Injection is a fluid and electrolyte replenisher.

6% Hetastarch in 0.9% Sodium Chloride Injection is a clear, pale yellow to amber solution. Exposure to prolonged adverse storage conditions (temperatures above 40°C or below freezing) 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.

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.

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.

Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

CLINICAL PHARMACOLOGY

The plasma volume expansion produced by 6% hetastarch approximates those of 5% human albumin. Intravenous infusion of hetastarch 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.

Hetastarch molecules below 50,000 molecular weight are rapidly eliminated by renal excretion. A single dose of approximately 500 mL of hetastarch injection (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 hetastarch injection 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, hetastarch is used to improve the efficiency of granulocyte collection by centrifugal means.

In randomized, controlled, comparative studies of hetastarch (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

INDICATIONS AND USAGE

Hetastarch injection is indicated in the treatment of hypovolemia when plasma volume expansion is desired. 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.

CONTRAINDICATIONS

6% hetastarch in 0.9% sodium chloride injection is contraindicated in patients with known hypersensitivity to hydroxyethyl starch. It is also contraindicated 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.

Patients with pre-existing coagulation or bleeding disorders should not be given 6% hetastarch in 0.9% sodium chloride injection.

WARNINGS

Life threatening anaphylactic/anaphylactoid reactions have been rarely reported with 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 hetastarch has been discontinued.

Usage in Plasma Volume Expansion

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.

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. However, this risk of bleeding diminished within hours.5-6

Hematocrit may be decreased and plasma proteins diluted excessively by administration of large volumes of hetastarch. Administration of packed red cells, platelets, and fresh frozen plasma should be considered if excessive dilution occurs.

Use over extended periods: 6% hetastarch in 0.9% sodium chloride injection has not been adequately evaluated to establish its safety in situations other than leukapheresis that require frequent use of colloidal solutions over extended periods. In some cases, 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 deficiency is identified. If a coagulopathy develops, it may take several days to resolve. Certain conditions may affect the safe use of hetastarch on a chronic basis. For example, in patients with subarachnoid hemorrhage where 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.7

Usage In Leukapheresis

Slight declines in platelet counts and hemoglobin levels have been observed in donors undergoing repeated leukapheresis procedures using hetastarch 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 hetastarch and saline may also result in 24 hour declines of total protein, albumin, calcium and fibrinogen values. None of these decreases are to a degree recognized to be clinically significant risks to healthy donors.

PRECAUTIONS

ADVERSE REACTIONS

Reported adverse reactions with hetastarch include:

General

Hypersensitivity (see WARNINGS).

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 (see PRECAUTIONS).

Hematologic

Intracranial bleeding, bleeding and/or anemia due to hemodilution (see WARNINGS) and/or, Factor VIII deficiency, acquired von Willebrand’s-like syndrome, and coagulopathy including rare cases of disseminated intravascular coagulopathy and hemolysis.

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.

DOSAGE 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.

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 higher doses have been reported in postoperative and trauma patients where severe blood loss has occurred (see WARNINGS and PRECAUTIONS).

Pediatric Patients: Adequate, well-controlled clinical trials to establish the safety and effectiveness of hetastarch in pediatric patients have not been conducted (see PRECAUTIONS, Pediatric Use).

Dosage in Leukapheresis

250 to 700 mL of 6% hetastarch in 0.9% sodium chloride injection to which citrate anticoagulant has been added is typically 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. 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.

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 seals are intact.

The safety and compatibility of other additives have not been established.

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.

HOW SUPPLIED

6% Hetastarch in 0.9% Sodium Chloride Injection is supplied in 500 mL single-dose flexible plastic containers (NDC No. 0409–7248–03).

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.

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.

To Open

Tear overwrap down at notch and remove solution container. Check for minute leaks 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 which is suspect should not be used.

Revised: April, 2009

Printed in USA

EN-2096

Hospira, Inc., Lake Forest, IL 60045 USA

IM-0581