Volulyte 6%

Volulyte 6%^® 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 Volulyte 6%^® in leukapheresis has also been shown to be safe and efficacious in improving the harvesting and increasing the yield of granulocytes by centrifugal means.

Dosage For Acute Use In Plasma Volume Expansion

Volulyte 6%^® 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. Higher doses have been reported in postoperative and trauma patients where severe blood loss has occurred.

Leukapheresis

250 to 700 mL of Volulyte 6%^® (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 Volulyte 6%^® and citrate should be thoroughly mixed to assure effective anticoagulation of blood as it flows through the leukapheresis machine.

Direction For Use For Volulyte 6%^®

• 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. Discard unused portion.

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, Volulyte 6%^® 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 Volulyte 6%^®, 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 Volulyte 6%^®, in patients with severe liver disease
• Do not use HES products, including Volulyte 6%^®, in patients with known hypersensitivity to hydroxyethyl starch
• Do not use HES products, including Volulyte 6%^®, 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 Volulyte 6%^®, in patients with pre-existing coagulation or bleeding disorders

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Renal Dys function

• Avoid use in patients with pre-existing renal dysfunction
• Discontinue use of Volulyte 6%^® at the first sign of renal injury
• Continue to monitor renal function in hospitalized patients for at least 90 days as use of RRT has been reported up to 90 days after administration of HES products, including Volulyte 6%^®

Coagulopathy

• Volulyte 6%^® 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. Discontinue use of Volulyte 6%^® at first sign of coagulopathy^1-2

Volulyte 6%^® has not been adequately evaluated to establish its safety in uses over extended periods other than leukapheresis. Volulyte 6%^® has been associated with coagulation abnormalities in conjunction with an acquired, reversible von Willebrand’s-like syndrome and/or Factor Vlll deficiency when used over a period of days. Replacement therapy should be considered if a severe Factor Vlll deficiency is identified. If a coagulopathy develops, it may take several days to resolve. Certain conditions may affect the safe use of Volulyte 6%^® on a chronic basis. For example, in patients with subarachnoid hemorrhage where Volulyte 6%^® 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.³

Slight declines in platelet counts and hemoglobin levels have been observed in donors undergoing repeated leukapheresis procedures using Volulyte 6%^® 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 Volulyte 6%^® may also result in 24 hour declines of total protein, albumin, calcium, and fibrinogen levels. Regular and frequent clinical evaluation and complete blood counts (CBC) are necessary for proper monitoring of Volulyte 6%^® use during leukapheresis. If the frequency of leukapheresis is to exceed the guidelines for whole blood donation, you may wish to consider the following additional tests: total leukocyte and platelet counts, leukocyte differential count, hemoglobin and hematocrit, prothrombin time (PT), and partial thromboplastin time (PTT).

Hypersensitivity Reactions

Life threatening anaphylactic/anaphylactoid reactions including death have been rarely reported with Volulyte 6%^®. Patients may develop hypersensitivity reaction to corn starch from which this product is made. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved.

Circulatory Overload

Volulyte 6%^® has not been adequately evaluated to establish its safety in situations other than treatment of hypovolemia in elective surgery.

Large volumes of Volulyte 6%^® may transiently alter the coagulation mechanism due to hemodilution and a direct inhibitory action on Factor Vlll. Administration of volumes of Volulyte 6%^® 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 Volulyte 6%^® 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. Volulyte 6%^® 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.

Liver Function Test

• Monitor liver function in patients receiving HES products, including Volulyte 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 Volulyte 6%^® (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 Volulyte 6%^® to patients with a history of liver disease.

Serum Amylase Levels

Elevated serum amylase levels may be observed temporarily following administration of Volulyte 6%^® 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 Volulyte 6%^®. 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

Volulyte 6%^® is not eliminated by hemodialysis. The utility of other extracorporeal elimination techniques has not been evaluated.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Use In Specific Populations

Pregnancy Category C

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. Volulyte 6%^® 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 Volulyte 6%^® is administered to a nursing woman.

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 Volulyte 6%^® in pediatric patients have not been conducted.

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.

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.

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

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.

Cardiovascular Reactions

including circulatory overload, congestive heart failure, and pulmonary edema.

Hematologic Reactions

including intracranial bleeding, bleeding and/or anemia due to hemodilution 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 starchassociated pruritus has been reported in some patients with deposits of hydroxyethyl starch in peripheral nerves.

No Information Provided

Volulyte 6%^® 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 Volulyte 6%^® (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 Volulyte 6%^® 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, Volulyte 6%^® is used to improve the efficiency of granulocyte collection by centrifugal means.