HESPAN (Page 2 of 4)

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

Bilirubin Levels

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 HESPAN® (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 HESPAN® to patients with a history of liver disease.

Serum Amylase Levels

Elevated serum amylase levels may be observed temporarily following administration of HESPAN® 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 HESPAN®. Elevated serum amylase levels persist for longer periods of time in patients with renal impairment. Hetastarch has not been shown to increase serum lipase.

Hemodialysis

HESPAN® is not eliminated by hemodialysis. The utility of other extracorporeal elimination techniques has not been evaluated.

6 ADVERSE REACTIONS

The serious adverse events reported in clinical trials are increased mortality and renal replacement therapy renal in critically ill patients.

Most common adverse reactions are hypersensitivity, coagulopathy, hemodilution, circulatory overload and metabolic acidosis.

6.1 Clinical Trial 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.

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

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:

Mortality

Renal

need for renal replacement therapy

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 [see Warnings and Precautions (5.3)].

Cardiovascular reactions

including circulatory overload, congestive heart failure, and pulmonary edema [see Warnings and Precautions (5.4)].

Hematologic reactions

including intracranial bleeding, bleeding and/or anemia due to hemodilution [see Warnings and Precautions (5.4)] and/or Factor Vlll deficiency, acquired von Willebrand’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.

7 DRUG INTERACTIONS

HESPAN® 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.

8 USE IN SPECIFIC POPULATIONS

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.

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