Voluven

Third-generation hydroxyethyl starch (HES) (tetrastarch); a nonprotein synthetic colloid used as a plasma volume expander.1 107

Hypovolemia

Prevention or treatment of hypovolemia.1

Not a substitute for RBCs or coagulation factors in plasma.1

Comparable with 6% hetastarch in 0.9% sodium chloride injection as a plasma volume expander in patients undergoing major elective orthopedic surgery.1 2

Provides no mortality benefit over normal saline (0.9% sodium chloride injection) when used in patients admitted to the intensive care unit (ICU) and may be associated with an increased risk of severe renal injury (i.e., requirement for renal replacement therapy).1 4 Contraindicated in critically ill adults, including those with sepsis.1 104 (See Contraindications and also see Increased Mortality and Severe Renal Injury under Cautions.)

• Third-generation HES (tetrastarch);107 synthetic colloid derived from thin boiling waxy corn starch composed mainly of amylopectin.1 107

• Average molecular weight is approximately 130 (range: 110–150); molar substitution is 0.4 (approximately 40% of the glucose units of the starch are hydroxyethylated).1 107

• Exhibits colloidal oncotic effects,107 resulting in plasma volume expansion.1 Plasma volume expansion comparable to that of hetastarch.1

• If you have an allergy to tetrastarch or any other part of Voluven (tetrastarch).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Bleeding in the brain, bleeding problems, blood clotting problems, heart failure, high blood volume, high chloride levels, high sodium levels, kidney disease, or liver disease.
• If you are not able to pass urine.
• If you are on dialysis, talk with your doctor.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Voluven with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use Voluven as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Voluven, please talk with your doctor, nurse, pharmacist, or other health care provider.
• 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.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Voluven. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Voluven (tetrastarch).

Review Date: October 4, 2017

Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia in adults and children. It is not a substitute for red blood cells or coagulation factors in plasma.

Pregnancy

Pregnancy Category C. Voluven® has been shown to cause embryocidal or other adverse effects in rats and rabbits when given in doses 1.7 times the human dose.

The type of hydroxyethyl starch present in Voluven® had no teratogenic properties in rats or rabbits. At 5 g/kg of body weight per day, administered as a bolus injection, fetal retardations and embryolethal effects were observed in rats and rabbits, respectively. In rats, a bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. All adverse effects were seen exclusively at maternal toxic doses due to fluid overload. [see Animal Pharmacology and/or Toxicology (13.2)]

Fertility studies on directly exposed animals have not been conducted.

There are no adequate and well-controlled studies in pregnant women. Voluven® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

Information on the use of Voluven® during labor or delivery is unknown.  Use if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Voluven® is administered to a nursing woman.

Pediatric Use

In one trial, newborns and infants < 2 years of age undergoing elective surgery were randomized to receive Voluven® (N=41) or 5% albumin (N=41). The mean dose of Voluven® administered was 16 ± 9 mL/kg.7

In an additional trial, children from 2 - 12 years of age undergoing cardiac surgery were randomized to receive Voluven® (N=31) or 5% albumin (N=30). The mean dose administered was 36 ± 11 mL/kg.

Use of Voluven® in adolescents > 12 years is supported by evidence from adequate and well-controlled studies of Voluven® in adults.

Dosage in children should be adapted to individual patient colloid needs, taking into account underlying disease, hemodynamics and hydration status.

Studies conducted in children have not been of sufficient size or follow-up duration to assess the risks of renal injury and mortality in this patient population. [See Pediatric Dose (2.2)]

Geriatric Use

Of the total number of subjects in clinical studies of Voluven® (N=471), 32% were ≥ 65 years old while 7% were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

Voluven® is mainly excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Volume status, infusion rate, and urine output should be closely monitored. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. [see Pharmacokinetics (12.3)]

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of Voluven® have not been performed. No mutagenic effects were observed with hydroxyethyl starch 130/0.4 (10% solution) in the following tests on mutagenic activity: Salmonella typhimurium reverse mutation assay (in vitro), mammalian cells in the in vitro gene mutation assay, assessment of the clastogenic activity in cultured human peripheral lymphocytes (in vitro), bone marrow cytogenetic test in Sprague-Dawley rats.

Fertility studies on directly exposed animals have not been performed.

Animal Pharmacology and/or Toxicology

Toxicology 

Three-month repeat infusion toxicology studies were conducted in rats and dogs in which three groups of animals were administered daily intravenous infusion over three hours. Dosing volumes of either 60 or 90 mL/kg body weight of hydroxyethyl starch 130/0.4 (10% solution) or 90 mL/kg 0.9% sodium chloride injection were studied. Observed toxicity following repeat infusion of hydroxyethyl starch is consistent with the oncotic properties of the solution resulting in hypervolemia in the animals. There were no gender-related effects on toxicity following repeat administration of hydroxyethyl starch 130/0.4 in rats or dogs.

In reproduction studies in rats and rabbits, hydroxyethyl starch 130/0.4 (10% solution) had no teratogenic properties. Embryolethal effects were observed in rabbits at 5 g/kg body weight/day. In rats, bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. Signs of fluid overload were seen in the dams. Hydroxyethyl starch 130/0.4 (10% solution) had no effect in studies assessing skin sensitization, antigenicity, and blood compatibility.

Pharmacology

The pharmacodynamic effect of Voluven® was examined in a hemorrhagic shock model in conscious rats and a hemodilution model in dogs. In both studies the control group received pentastarch (6% hydroxyethyl starch 200/0.5).

Voluven® was as effective as pentastarch in maintaining cardiopulmonary function during isovolemic hemodilution in beagle dogs. In the three-hour follow-up period no additional administration of colloid was necessary.

There were no differences in long-term survival of rats after a single administration of Voluven® and pentastarch solutions following induced hemorrhagic shock (67% and 50% blood loss). In the 67% induced bleeding group receiving Voluven® (N=6), the survival rate was 83% which is within the normal range for this type of experiment. In the corresponding pentastarch group, survival was 100%. Infusion of Ringer's lactate resulted in a 50% survival rate after a 50% blood loss and a 0% survival after a 67% blood loss.

After multiple intravenous infusions of 0.7 g per kg body weight per day of 10% hydroxyethyl starch 130/0.4 or 10% hydroxyethyl starch 200/0.5 solution during 18 consecutive days, the plasma hydroxyethyl starch concentration in rats treated with hydroxyethyl starch 130/0.4 was lower compared to rats treated with hydroxyethyl starch 200/0.5. Hydroxyethyl starch 130/0.4 was eliminated faster than hydroxyethyl starch 200/0.5. In both groups, clear signs of hydroxyethyl starch tissue storage were detected in lymph nodes and spleen. Numerous empty vacuoles in macrophages were observed. Only minimal cellular vacuolization was found in the liver and kidney. Histochemical differences between the groups were not observed.

A study with 10% radiolabeled 14C-hydroxyethyl starch 130/0.4 and 10% 14C- hydroxyethyl starch 200/0.5 solutions was carried out.10  In animals treated with hydroxyethyl starch 130/0.4, radioactivity decreased from 4.3% of the total administered dose (2.6 g hydroxyethyl starch 130/0.4 per animal) on day 3 to 0.65% on day 52. In animals treated with hydroxyethyl starch 200/0.5, the 14C-activity decreased from 7.7% of the total administered dose (2.7 g hydroxyethyl starch 200/0.5 per animal) on day 3 to 2.45% on day 52. These results confirm the faster elimination and lower persistence of hydroxyethyl starch 130/0.4 in tissue.

1. Kozek-Langenecker S. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology 2005; 103 (3): 654-60.
2. Neff TA, Doelberg M, Jungheinrich C, et al. Repetitive large-dose infusion of the novel hydroxyethyl starch HES 130/0.4 in patients with severe head injury. Anest Analg 2003; 96 (5): 1453-9.
3. Gandhi SD, Weiskopf RB, Jungheinrich C et al. Volume replacement therapy during major orthopedic surgery using Voluven® (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology 2007; 106(6):1120-7.
4. 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.
5. 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.
6. 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.
7. Standl T, Lochbuehler H, Galli C, et al. HES 130/0.4 (Voluven®) or human albumin in children younger than 2 yr undergoing non-cardiac surgery.   A prospective, randomized, open label, multicentre trial. Eur J Anaesthesiol 2008; 25(6): 437-45.
8. Jungheinrich C, Neff T. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinetik 2005; 44 (7): 681-99.
9. Jungheinrich C, Scharpf R, Wargenau M, et al. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesth Analg 2002; 95 (3): 544-51.
10. Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F. Tissue storage of 14C-labeled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 2003; 4 (6): 331-8.