HESPAN (Page 3 of 4)

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.

11 DESCRIPTION

HESPAN® (6% hetastarch in 0.9% sodium chloride injection) is a sterile, nonpyrogenic solution for intravenous administration.

Each 100 mL contains:

Hetastarch………………………………………….. 6 g

Sodium Chloride, USP…………………………. 0.9 g

Water for Injection, USP……………………….. qs

pH adjusted with Sodium Hydroxide, NF if necessary

Concentration of Electrolytes (mEq/L): Sodium 154, Chloride 154

pH: approximately 5.9 with negligible buffering capacity

Calc. Osmolarity: approximately 309 mOsM

Hetastarch is a synthetic 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. 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 600,000 with a range of 450,000 to 800,000 and with at least 80% of the polymers falling within the range of 20,000 to 2,600,000. 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 chemical name for hetastarch is hydroxyethyl starch.

The structural formula is as follows:

HESPAN structural formula

Amylopectin derivative in which R2 and R3 are H or CH2 CH2 OH and R6 is H, CH2 CH2 OH, or a branching point in the starch polymer connected through an α-1,6 link to additional D-glucopyranosyl units.

HESPAN® 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.

Not made with natural rubber latex, PVC or DEHP.

The plastic container is made from a multi-layered film specifically developed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. 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.

12 CLINICAL PHARMACOLOGY

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 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

Surgical Patients Comparative Studies

In randomized, controlled, comparative studies of HESPAN® (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.7-10

Pediatric Postoperative Volume Expander Study

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 HESPAN® 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 HESPAN®. 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 HESPAN®, an increase in prothrombin time was demonstrated (p=0.006).11 There were no neonates included in this study [see Use in Specific Populations (8.4)].

Adult Critically Ill Studies

Three randomized controlled trials (RCTs) followed critically ill adult patients treated with different HES products for 90 days.

One 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 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 third 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

15 REFERENCES

  1. Knutson JE., et al., Does Intraoperative Hetastarch Administration Increase Blood Loss and Transfusion Requirements After Cardiac Surgery? Anesthesia Analg., 2000;90:801-7.
  2. Cope JT., et al., Intraoperative Hetastarch Infusion Impairs Hemostasis After Cardiac Operations. The Annals of Thoracic Surgery , 1997;63:78-83.
  3. Damon L., Intracranial Bleeding During Treatment with Hydroxyethyl Starch. New England Journal of Medicine , 1987;317(15):964-965.
  4. Perner A, et al., Hydroxyethyl starch 130/0.42 versus Ringer”s acetate in severe sepsis patients. The New England Journal of Medicine , 2012 July 12;367(2):124-34.
  5. Guidet B, et al., Assessment of hemodynamic efficacy and safety of 6% hydroxyethyl starch 130/0.4 vs 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS Study. Critical Care , 2012 May 24;16(3):R94.
  6. Myburgh JA, et al., Hydroxyethyl starch or saline for fluid resuscitation in intensive care. The New England Journal of Medicine , 2012 November 15;367(20):1901-11.
  7. Diehl J., et al., Clinical Comparison of Hetastarch and Albumin in Postoperative Cardiac Patients. The Annals of Thoracic Surgery , 1982;34(6):674-679.
  8. 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.
  9. 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.
  10. Moggio RA., et al., Hemodynamic Comparison of Albumin and Hydroxyethyl Starch in Postoperative Cardiac Surgery Patients. Critical Care Medicine , 1983;11(12):943-945.
  11. 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.

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