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hydroxyethyl starch (130 kd/0.4 substitution) injection, solution
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia.
It is not a substitute for red blood cells or coagulation factors in plasma.
2 DOSAGE AND ADMINISTRATION
Voluven® is administered by intravenous infusion only. The daily dose and rate of infusion depend on the patient’s blood loss, on the maintenance or restoration of hemodynamics and on the hemodilution (dilution effect). Voluven® can be administered repetitively over several days. [see Warnings and Precautions (5)]
The initial 10 to 20 mL should be infused slowly, keeping the patient under close observation due to possible anaphylactoid reactions. [see General Warnings and Precautions (5.1)]
2.1 Adult Dose
Up to 50 mL of Voluven® per kg of body weight per day (equivalent to 3 g hydroxyethyl starch and 7.7 mEq sodium per kg of body weight). This dose is equivalent to 3500 mL of Voluven® for a 70 kg patient.
2.2 Pediatric Dose
Limited clinical data on the use of Voluven® in children are available. In 41 children including newborns to infants (< 2 years), a mean dose of 16 ± 9 mL/kg was administered. The dosage in children should be adapted to the individual patient colloid needs, taking into account the disease state, as well as the hemodynamic and hydration status. The safety and efficacy of Voluven® have not been established in the age group of 2 to 12 years. Use of Voluven® in children > 12 years is supported by evidence from adequate and well-controlled studies of Voluven® in adults and by data from children < 2 years old. [see Pediatric Use (8.4)]
2.3 Directions for Use of Voluven®
The safety and compatibility of additives have not been established.
Figure 1Figure 2Figure 3Figure 4Figure 5
3 DOSAGE FORMS AND STRENGTHS
500 mL freeflex® flexible plastic intravenous solution container are available. Each 100 mL contains 6 g hydroxyethyl starch 130/0.4 in isotonic sodium chloride injection.
The use of Voluven® is contraindicated in the following conditions:
5 WARNINGS AND PRECAUTIONS
5.1 General Warnings and Precautions
Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. 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. [see Adverse Reactions (6)]
Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction.
In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration.
Caution should be observed before administering Voluven® to patients with severe liver disease or severe bleeding disorders (e.g., severe cases of von Willebrand´s disease).
5.2 Monitoring: Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation.
5.3 Interference with Laboratory Tests
Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis.
At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit.
6 ADVERSE REACTIONS
6.1 Overall Adverse Reaction Profile
From the accumulated clinical development experience, expected adverse reactions after administration of Voluven® occurring in less than 10% of patients are as follows:
Immune system disorders (Rare, >0.01% to <0.1%): Products containing hydroxyethyl starch may lead to anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema). In the event of an intolerance reaction, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated. [see General Warnings and Precautions (5.1)]
Skin and subcutaneous tissue disorders (Common, >1 to <10%, dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is an undesirable effect observed with all hydroxyethyl starches.
Investigations (Common, >1% to <10%, dose dependent): The concentration of serum amylase can rise during administration of hydroxyethyl starch and can confound the diagnosis of pancreatitis. At high doses the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit. [see Interference with Laboratory Tests (5.3)]
6.2 Adverse Reactions in Clinical Trials
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug may not reflect the rates observed in practice.
During clinical development, 471 patients were exposed to Voluven®, and a total of 768 patients received the hydroxyethyl starch 130/0.4 drug substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative doses of several mL up to 66 L1). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.9 ± 3.3 days, mean cumulative doses were 3338 ± 3695 mL, and the longest follow-up period was 90 days.
In the US trial, 100 patients undergoing elective orthopedic surgery were treated either with Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative volume replacement. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch.
Adverse reactions observed in at least 1% of patients: In the US trial comparing Voluven® with hetastarch, a possible relationship to Voluven® was reported in five cases in a total of three patients (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to hetastarch was reported in five patients (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in patients receiving more than the labeled ceiling dose (20 mL/kg), whereas no serious coagulopathy occurred in the Voluven® group.
6.3 Postmarketing Experience
The following adverse reactions have been identified during the post-approval use of Voluven® and other types of hydroxyethyl starch solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The safety profile from postmarketing experience of Voluven® is not different from the profile obtained from clinical trials performed using the product.
Based on spontaneous reporting of hypersensitivity reactions, urticaria, bronchospasm, or hypotension were the most frequently reported serious adverse drug reactions for patients treated with Voluven®.
With the administration of hydroxyethyl starch solutions, disturbances of blood coagulation can occur depending on the dosage2).
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
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. 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.
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 Toxicology (13.2.1)]
Fertility studies on directly exposed animals have not been conducted.
8.3 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.
8.4 Pediatric Use
In one trial, children including newborns to infants (< 2 years) 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/kg3).
Voluven® may be given to newborns only after a careful risk/benefit evaluation. The safety and efficacy of Voluven® have not been established in the age group of 2 to 12 years. Use of Voluven® in children > 12 years is supported by evidence from adequate and well-controlled studies of Voluven® in adults and by data from children < 2 years old. Dosage in children should be adapted to individual patient colloid needs, taking into account underlying disease, hemodynamics and hydration status. [see Pediatric Dose (2.2)]
8.5 Geriatric Use
Of the total number of subjects in clinical studies of Voluven® (N= 471), 32% were 65 years old and older while 7% were 75 and older. 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.
8.6 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)]
9 DRUG ABUSE AND DEPENDENCE
Voluven® is not considered to be a drug of abuse potential.
As with all plasma volume substitutes, overdosage can lead to overloading of the circulatory system (e.g. pulmonary edema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General Warnings and Precautions (5.1)]
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is a clear to slightly opalescent, colorless to slightly yellow, sterile, non-pyrogenic, isotonic solution for intravenous administration using sterile equipment.
Each 100 mL of the solution contains:
Electrolytes (mEq/L): Sodium 154, Chloride 154. pH 4 to 5.5. Calculated osmolarity 308 mOsmol/L.
The hydroxyethyl starch contained in Voluven® is a synthetic colloid for use in plasma volume replacement. The chemical name of hydroxyethyl starch is poly(O-2-hydroxyethyl) starch. The structural formula of hydroxyethyl starch is
Voluven® is packaged in 500 mL flexible plastic containers (freeflex®). Freeflex® is a flexible container made from coextruded polyolefin and is free of PVC, plasticizers, adhesives or latex (Non-DEHP, Latex-free). The freeflex® container offers an air-closed system and can be used with non-vented IV sets which prevent external air contamination. Freeflex® is collapsible and can be used in emergency cases for pressure infusion.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Voluven® contains hydroxyethyl starch in a colloidal solution which expands plasma volume when administered intravenously. This effect depends on the mean molecular weight (130,000 daltons; range 110,000 – 150,000 daltons), the molar substitution by hydroxyethyl groups (0.4; range 0.38 – 0.45) on glucose units of the starch, the pattern of hydroxyethyl substitution (C2/C6 ratio) of approximately 9:1, and the concentration (6%), as well as the dosage and infusion rate.
Hydroxyethyl starch is a derivative of thin boiling waxy corn starch, which mainly consists of a glucose polymer (amylopectin) predominately composed of α-1-4-connected glucose units with several α-1-6-branches. Substitution of hydroxyethyl groups on the glucose units of the polymer reduces the normal degradation of amylopectin by α-amylase in the body. The low molar substitution (0.4) is the main pharmacological determinant for the beneficial effects of Voluven® on pharmacokinetics, intravascular volume and hemodilution4). To describe the molecular weight and molar substitution characteristics of the hydroxyethyl starch in Voluven®, the compound is designated as hydroxyethyl starch 130/0.4.
After isovolemic exchange of blood with 500 mL of Voluven® in healthy volunteers, blood volume is maintained for at least 6 hours.
The pharmacokinetic profile of hydroxyethyl starch is complex and largely dependent on its molar substitution as well as its molecular weight.4) When administered intravenously, molecules smaller than the renal threshold (60,000-70,000 daltons) are readily and rapidly excreted in the urine, while molecules with higher molecular weights are metabolized by plasma α-amylase prior to excretion via the renal route.
The mean in vivo molecular weight of Voluven® in plasma is 70,000 – 80,000 daltons immediately following infusion and remains above the renal threshold throughout the treatment period.
Following intravenous administration of 500 mL Voluven® to healthy volunteers, plasma levels of Voluven® remain at 75% of peak concentration at 30 minutes post-infusion and decrease to 14% at 6 hours post-infusion. Plasma levels of Voluven® return to baseline levels 24 hours following infusion. Plasma clearance, volume of distribution, and elimination half-life of Voluven® in healthy volunteers following IV administration of 500 mL were 31.4 mL/min, 5.9 liters, and 12 hours, respectively. Approximately 62 % of Voluven® was excreted as hydroxyethyl starch molecules in urine within 72 hours.
The pharmacokinetics of Voluven® are similar following single and multiple dose administration. No significant plasma accumulation occurred after daily administration of 500 mL of a 10% solution containing hydroxyethyl starch 130/0.4 over a period of 10 days. Approximately 70% of Voluven® was excreted as hydroxyethyl starch molecules in urine within 72 hours.
Following a single intravenous administration of Voluven® (500 mL) in subjects with varying degrees of renal dysfunction, the AUC and clearance of Voluven® increased by 73% and decreased by 42% in patients, respectively, with creatinine clearance <50 mL/min as compared to patients with creatinine clearance >50 mL/min. However, terminal half-life and peak hydroxyethyl starch concentration were not affected by renal impairment. Plasma levels of Voluven® returned to baseline levels 24 hours following infusion. Approximately 59 % and 51 % of Voluven® were excreted as hydroxyethyl starch molecules in urine within 72 hours in patients with creatinine clearance ≥30 mL/min and <30 mL/min, respectively.
There are no data available on the use of Voluven® in patients undergoing hemodialysis.
Pharmacokinetic data in patients with hepatic insufficiency or in pediatric or geriatric patients are not available. Effects of gender or race on the pharmacokinetics of Voluven® have not been studied.
13 NONCLINICAL TOXICOLOGY
13.1 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.
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 apparent 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) was observed to have no effect in studies assessing skin sensitization, antigenicity, and blood compatibility.
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 out6). 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.
14 CLINICAL STUDIES
Voluven® was studied in controlled clinical trials in adult and pediatric surgical patients and in patients in intensive care units. Clinical studies included patients undergoing various types of surgery (orthopedic, urologic, cardiac) and trauma intensive care for situations in which hypovolemia is treated (pre-, intra-, and postoperative) or prevented (autologous blood donation, acute normovolemic hemodilution, hypervolemic hemodilution before cardiac surgery). The safety and efficacy of Voluven® were compared to other colloidal plasma substitutes [pentastarch (6% hydroxyethyl starch 200/0.5), hetastarch (6% hydroxyethyl starch 450/0.7), gelatin solution or human serum albumin] in studies carried out in common clinical settings of volume replacement therapy. Perioperative fluid administration of Voluven® ranged from 500 to 4500 mL/day in surgical patients, and cumulatively, 6 to 66 L during stays in intensive care units following traumatic brain injury.
A prospective, controlled, randomized, double-blind, multi-center trial of 100 patients undergoing elective orthopedic surgery was conducted in the US evaluating Voluven® (N=49) compared to hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N =51) for intraoperative volume replacement therapy7). The primary efficacy variable, total volume of colloid solution required for intraoperative volume replacement therapy, was equivalent for the two treatment groups. Mean volume infused was 1613 ± 778 mL for Voluven® and 1584 ± 958.4 mL for hetastarch. The ratio Voluven®/hetastarch was estimated as 1.024 with a 95% confidence interval (0.84, 1.25), which was included within the equivalence range of (0.55, 1.82) prespecified in the study protocol. This indicated that Voluven® and hetastarch have similar efficacy as intraoperative volume replacement therapy in major orthopedic surgery.
A second objective of the trial was to show superiority for safety between Voluven® and hetastarch. Four safety endpoints were prospectively defined and compared in a sequential manner (in order to preserve the type–1 error rate, i.e., observing a difference where none actually exists). Per protocol, if there was no difference found between treatment arms for the first safety endpoint (EBL), the remaining endpoints were to be considered exploratory analyses requiring additional studies for confirmation.
Overall, no significant differences in serious adverse events were noted between the two treatment arms, but three cases of serious coagulopathy occurred in the hetastarch treatment arm. All three subjects received high doses (>3000 mL; labeled ceiling dose = 20 mL/kg) of the product, which are known to increase the risk of bleeding. Since EBL for the two treatment arms was not statistically different (95% confidence interval includes unity), the difference observed for Factor VIII (see table, below) must be interpreted with caution. An exploratory analysis of total erythrocyte volume transfused (8.0 mL/kg vs. 13.8 mL/kg, Voluven® vs hetastarch, respectively) must also be viewed with caution.
There was no statistically significant difference between the two treatment groups with respect to the secondary efficacy endpoints of hemodynamic stability, body temperature, hemodynamic parameters, blood pressure, central venous pressure, heart rate, fibrinogen and platelet count.
In addition to the US trial, three non-US trials were conducted with the primary objective of showing equivalency (based on mean difference rather than mean ratio as in the US study) between Voluven® and pentastarch in maintaining or restoring hemodynamic parameters. The largest of the three trials (N=100) met the prespecified boundary (-500 mL, 500 mL), but the two smaller studies (N=52 and N=59) did not.
In exploratory analyses, the effect of Voluven® on coagulation parameters (von Willebrand factor, Factor VIII, and Ristocetin cofactor) was shown to be significantly lower than pentastarch at one or more time points (US and non-US trials). These findings are consistent with the lower molar substitution, lower average molecular weight and narrower molecular weight distribution of Voluven® as compared to pentastarch resulting in a lower in vivo molecular weight and increased elimination from the circulation.
A safety profile of Voluven® at least as favorable as for pentastarch was also demonstrated in studies where Voluven® was administered at doses higher (up to 50 mL/kg or 3 g/kg) than for pentastarch (up to 33 mL/kg or 2 g/kg) in clinical settings where large or repetitive doses are administered. [see Adverse Reactions (6)]
1) 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
2) Kozek-Langenecker S. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology 2005; 103 (3): 654-60
3) Lochbühler H, Galli C, Hagemann H. Hydroxyethyl starch HES 130/0.4 in paediatric surgery: results of an explorative, controlled, multicenter safety study. Crit Care 2003; 7 (Suppl 1):, P107
4) Jungheinrich C, Neff T. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinetik 2005; 44 (7): 681-699
5) 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
6) 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
7) 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; 106:1120–1127
16 HOW SUPPLIED/STORAGE AND HANDLING
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is supplied in the following primary container and carton sizes:
Polyolefin bag (freeflex®) with overwrap: 500 mL
Carton of 15 x 500 mL
Store at 15° to 25°C (59° to 77°F). Do not freeze.
17 PATIENT COUNSELING INFORMATION
Because this product is not used directly by patients, patient counseling or instructions for use by patients is not considered necessary.
Manufactured by: Fresenius Kabi Norge AS,
P.O. Box 430,
NO-1753 Halden, Norway
Distributed by: Hospira, Inc.
275 North Field Drive
Lake Forest, Illinois 60045 USA
Made in Norway EN-2475
Revised: 07/2010 Hospira Inc.
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2017
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