Hextend

The plasma volume expansion produced by HEXTEND approximates that produced by 6% Hetastarch in 0.9% Sodium Chloride Injection and the plasma volume expansion of 6% Hetastarch in 0.9% Sodium Chloride Injection in turn approximates that of 5% Albumin (Human).1-4 In randomized, double-blind studies of HEXTEND versus control (6% Hetastarch in 0.9% Sodium Chloride Injection) for the treatment of hypovolemia in elective surgery, 60 patients were infused with a mean of 1596 mL of HEXTEND and 59 patients were infused with a mean of 1428 mL of 6% Hetastarch in 0.9% Sodium Chloride Injection without any serious related adverse events. 59% of the HEXTEND patients and 59% of the control patients required packed red blood cells and other blood-derived products either intraoperatively or postoperatively.

Intravenous infusion of 6% Hetastarch in 0.9% Sodium Chloride Injection 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. When administered intravenously, HEXTEND provides sources of water and electrolytes. Its electrolyte content resembles that of the principal ionic constituents of normal plasma.

Hetastarch molecules below 50,000 molecular weight are rapidly eliminated by renal excretion. A single dose of approximately 500 mL of 6% Hetastarch in 0.9% Sodium Chloride 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 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.

Clinical Studies

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 clinical 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 an HES product not licensed 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.9

Another trial (N=196) using a licensed HES product 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.10

A third trial (N=7000) using a licensed HES product in a heterogeneous population of ICU patients 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.11

REFERENCES

9. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis. N Eng J Med 2012; 367(2): 124-34

10. CRYSTMAS: Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 versus 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care 2012; 16(3): R94

11. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367(20): 1901-11

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 [see Postmarketing Experience and Clinical Studies]

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:

Renal: need for renal replacement therapy

Read the entire FDA prescribing information for Hextend (6% Hetastarch in Lactated Electrolyte Injection)

Hetastarch (hydroxyethyl starch) is made from natural sources of starch. Hetastarch increases the volume of blood plasma that can be lost from bleeding or severe injury. Plasma is needed to circulate red blood cells that deliver oxygen throughout the body.

Hetastarch is used to treat or prevent hypovolemia (decreased blood plasma volume, also called "shock") that may occur as a result of serious injury, surgery, severe blood loss, burns, or other trauma.

Hetastarch may also be used for purposes not listed in this medication guide.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers right away if you have:

• wheezing or gasping for breath, rapid breathing, sweating, and anxiety;

• a light-headed feeling, like you might pass out;

• weak pulse, slow breathing;

• chest pain, fever, chills, cough; or

• easy bruising, unusual bleeding, or any bleeding that will not stop.

Rare but serious side effects may include:

• severe headache, vision or speech problems, mental changes;

• drooping eyelids, loss of feeling in your face, tremors, trouble swallowing; or

• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Hetastarch can harm your kidneys. Call your doctor at once if you have any of these symptoms of kidney damage: swelling, rapid weight gain, unusual tiredness, nausea, vomiting, feeling short of breath, red or pink urine, painful or difficult urination, or little or no urinating.

Common side effects may include:

• mild itching or skin rash;

• mild headache;

• muscle pain; or

• swollen glands, mild flu symptoms.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• It is used to treat or prevent low blood volume.
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Any unexplained bruising or bleeding.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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

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 (see WARNINGS 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 (see WARNINGS AND PRECAUTIONS).

Hematologic

Intracranial bleeding, bleeding and/or anemia due to hemodilution (see WARNINGS 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.