|contraindications=* Do not use hydroxyethyl starch (HES) products, including Voluven®, 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 Voluven®, in patients with severe liver disease.
Do not use HES products, including Voluven®, in patients with known hypersensitivity to hydroxyethyl starch [see GENERAL WARNINGS AND PRECAUTIONS (5.1)]
Do not use HES products in clinical conditions with volume overload.
Do not use HES products in patients with pre-existing coagulation or bleeding disorders.
Do not use HES products in patients with renal failure with oliguria or anuria not related to hypovolemia.
Do not use HES products in patients receiving dialysis treatment.
Do not use HES products in patients with severe hypernatremia or severe hyperchloremia.
Do not use HES products in patients with intracranial bleeding.
<!--Warnings-->
<!--Warnings-->
|warnings=* Description
|warnings=* Anaphylactoid Reactions
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)]
====Precautions====
5.2 Renal Dysfunction
Avoid use in patients with pre-existing renal dysfunction.
* Description
Discontinue use of Voluven® at the first sign of renal injury.
<!--Adverse Reactions-->
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.
<!--Clinical Trials Experience-->
5.3 Coagulopathy
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
Monitor the coagulation status of patients undergoing open heart surgery in association with cardiopulmonary bypass as excess bleeding has been reported with HES solutions in this population. Discontinue use of Voluven® at the first sign of coagulopathy.
=====Body as a Whole=====
5.4 Fluid Equilibrium
Avoid fluid overload; adjust dosage in patients with cardiac or renal dysfunction. 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.
5.5 Monitoring: Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, serum electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. Monitor liver function in patients receiving HES products, including Voluven®.
5.6 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.
=====Cardiovascular=====
At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit.
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=Overall Adverse Reaction Profile
Serious adverse reactions reported in clinical trials include increased mortality and increased use of RRT in critically ill subjects, including subjects with sepsis.
The most common adverse reactions after administration of Voluven® occurring in more than 1% of patients are: pruritus (itching; ≥1% to <10%), elevation of serum amylase (≥1% to <10%; interference with the diagnosis of pancreatitis), and dilutional effects that may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit (≥1% to <10%).
=====Digestive=====
Anaphylactoid reactions occur rarely in <0.1% after administration of hydroxyethyl starch solutions. Disturbances of blood coagulation beyond dilution effects can occur rarely in <0.1% depending on the dosage with the administration of hydroxyethyl starch solutions.1
6.2 Adverse Reactions in Clinical Trials
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 or another patient population and may not reflect the rates observed in clinical practice.
During clinical development, a total of 899 subjects 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 L.2 Of these 899 subjects, 602 were exposed to Voluven® (i.e., 6% hydroxyethyl startch 130/0.4). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.7 ± 3.1 days, mean cumulative doses were 3185 ± 3498 mL, and the longest follow-up period was 90 days.
=====Endocrine=====
In a randomized controlled trial (RCT) of subjects (N=100) undergoing elective orthopedic surgery, Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection; N=51) were administered for intraoperative volume replacement.3 Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch.
Adverse reactions observed in at least 1% of subjects: in the orthopedic surgery trial conducted in the U.S., no significant differences in serious adverse reactions were noted overall between the two treatment arms. A possible relationship to Voluven® was reported in five cases among three subjects (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus); a possible relationship to hetastarch was reported in five subjects (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in subjects receiving more than the labeled ceiling dose (20 mL/kg), which is known to increase the risk of bleeding, whereas no serious coagulopathy occurred in the Voluven® group. Since calculated red blood cell loss for the two treatment arms was not statistically different (95% confidence interval included unity), the difference observed for Factor VIII (see Table 1, 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) also must be viewed with caution.
=====Hematologic and Lymphatic=====
[[File:Hydroxyethyl Adv.png|None|400px]]
A safety profile for 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 were administered.
Trials in critically ill adult subjects
=====Metabolic and Nutritional=====
Three RCTs followed critically ill adult subjects treated with different HES products for 90 days.
One trial using Voluven® in severe sepsis subjects (N=196) reported no difference in mortality (relative risk, 1.20; 95% CI, 0.83 to 1.74; p=0.33) and a trend for increased use of RRT (relative risk, 1.83; 95% CI, 0.93 to 3.59; p=0.06) in HES subjects.4
=====Musculoskeletal=====
Another trial using Voluven® in a heterogeneous population of critically ill subjects admitted to the ICU (N=7000) 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 subjects.5 A third trial in severe sepsis subjects (N=804) using an HES product not licensed in the U.S. (HES 130/0.42) reported increased mortality (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03) and increased use of RRT (relative risk, 1.35; 95% CI, 1.01 to 1.80; p=0.04) in HES subjects.6
|postmarketing=* Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to product exposure.
Among the very rarely occurring serious adverse drug reactions in patients treated with Voluven®, anaphylactic/anaphylactoid/hypersensitivity reactions or hypotension/shock/ circulatory collapse were most frequently reported.
The following adverse reactions have been identified and reported during the post-approval use of different HES products in critically ill adult patients, including patients with sepsis:
=====Neurologic=====
Mortality
Renal: use of RRT
|drugInteractions=* The safety and compatibility of other additives have not been established.
<!--Use in Specific Populations-->
|FDAPregCat=C
|useInPregnancyFDA=* 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.
=====Respiratory=====
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.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=* Information on the use of Voluven® during labor or delivery is unknown. Use if clearly needed.
|useInNursing=* 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.
|useInPed=* 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
=====Skin and Hypersensitivy Reactions=====
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.
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
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.
=====Respiratory=====
|useInGeri=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.
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInRenalImpair=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.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
Line 211:
Line 175:
<!--Administration and Monitoring-->
<!--Administration and Monitoring-->
|administration=* Oral
|administration=* Intravenous
|monitoring=* 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
* Intravenous
* Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, serum electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. Monitor liver function in patients receiving HES products, including Voluven®.
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
<!--Overdosage-->
|overdose====Acute Overdose===
|overdose=* 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.
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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Black Box Warning
WARNING:
See full prescribing information for complete Boxed Warning.
MORTALITY RENAL REPLACEMENT THERAPY:
In critically ill adult patients, including patients with sepsis, use of hydroxyethyl starch (HES) products, including Voluven®, increases risk of
Mortality
Renal replacement therapy
Do not use HES products, including Voluven®, in critically ill adult patients, including patients with sepsis.
Overview
Hydroxyethyl starch is a plasma volume substitute that is FDA approved for the treatment of hypovolemia in adults and children. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, elevated serum amylase, hemodilution.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
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.
Dosage
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.
Directions for Use of Voluven
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyethyl starch in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroxyethyl starch in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
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.
Dosage
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.
In 41 newborns to infants (< 2 years), a mean dose of 16 ± 9 mL/kg was administered. In 31 children from 2 to 12 years of age a mean dose of 36 ± 11 mL/kg was administered. The dose in adolescents > 12 is the same as the adult dose.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyethyl starch in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroxyethyl starch in pediatric patients.
Contraindications
Do not use hydroxyethyl starch (HES) products, including Voluven®, 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 Voluven®, in patients with severe liver disease.
Do not use HES products, including Voluven®, in patients with known hypersensitivity to hydroxyethyl starch [see GENERAL WARNINGS AND PRECAUTIONS (5.1)]
Do not use HES products in clinical conditions with volume overload.
Do not use HES products in patients with pre-existing coagulation or bleeding disorders.
Do not use HES products in patients with renal failure with oliguria or anuria not related to hypovolemia.
Do not use HES products in patients receiving dialysis treatment.
Do not use HES products in patients with severe hypernatremia or severe hyperchloremia.
Do not use HES products in patients with intracranial bleeding.
Warnings
WARNING:
See full prescribing information for complete Boxed Warning.
MORTALITY RENAL REPLACEMENT THERAPY:
In critically ill adult patients, including patients with sepsis, use of hydroxyethyl starch (HES) products, including Voluven®, increases risk of
Mortality
Renal replacement therapy
Do not use HES products, including Voluven®, in critically ill adult patients, including patients with sepsis.
Anaphylactoid Reactions
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)]
5.2 Renal Dysfunction
Avoid use in patients with pre-existing renal dysfunction.
Discontinue use of Voluven® 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.
5.3 Coagulopathy
Monitor the coagulation status of patients undergoing open heart surgery in association with cardiopulmonary bypass as excess bleeding has been reported with HES solutions in this population. Discontinue use of Voluven® at the first sign of coagulopathy.
5.4 Fluid Equilibrium
Avoid fluid overload; adjust dosage in patients with cardiac or renal dysfunction. 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.
5.5 Monitoring: Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, serum electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. Monitor liver function in patients receiving HES products, including Voluven®.
5.6 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.
Adverse Reactions
Clinical Trials Experience
Overall Adverse Reaction Profile
Serious adverse reactions reported in clinical trials include increased mortality and increased use of RRT in critically ill subjects, including subjects with sepsis.
The most common adverse reactions after administration of Voluven® occurring in more than 1% of patients are: pruritus (itching; ≥1% to <10%), elevation of serum amylase (≥1% to <10%; interference with the diagnosis of pancreatitis), and dilutional effects that may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit (≥1% to <10%).
Anaphylactoid reactions occur rarely in <0.1% after administration of hydroxyethyl starch solutions. Disturbances of blood coagulation beyond dilution effects can occur rarely in <0.1% depending on the dosage with the administration of hydroxyethyl starch solutions.1
6.2 Adverse Reactions in Clinical Trials
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 or another patient population and may not reflect the rates observed in clinical practice.
During clinical development, a total of 899 subjects 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 L.2 Of these 899 subjects, 602 were exposed to Voluven® (i.e., 6% hydroxyethyl startch 130/0.4). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.7 ± 3.1 days, mean cumulative doses were 3185 ± 3498 mL, and the longest follow-up period was 90 days.
In a randomized controlled trial (RCT) of subjects (N=100) undergoing elective orthopedic surgery, Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection; N=51) were administered for intraoperative volume replacement.3 Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch.
Adverse reactions observed in at least 1% of subjects: in the orthopedic surgery trial conducted in the U.S., no significant differences in serious adverse reactions were noted overall between the two treatment arms. A possible relationship to Voluven® was reported in five cases among three subjects (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus); a possible relationship to hetastarch was reported in five subjects (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in subjects receiving more than the labeled ceiling dose (20 mL/kg), which is known to increase the risk of bleeding, whereas no serious coagulopathy occurred in the Voluven® group. Since calculated red blood cell loss for the two treatment arms was not statistically different (95% confidence interval included unity), the difference observed for Factor VIII (see Table 1, 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) also must be viewed with caution.
A safety profile for 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 were administered.
Trials in critically ill adult subjects
Three RCTs followed critically ill adult subjects treated with different HES products for 90 days.
One trial using Voluven® in severe sepsis subjects (N=196) reported no difference in mortality (relative risk, 1.20; 95% CI, 0.83 to 1.74; p=0.33) and a trend for increased use of RRT (relative risk, 1.83; 95% CI, 0.93 to 3.59; p=0.06) in HES subjects.4
Another trial using Voluven® in a heterogeneous population of critically ill subjects admitted to the ICU (N=7000) 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 subjects.5 A third trial in severe sepsis subjects (N=804) using an HES product not licensed in the U.S. (HES 130/0.42) reported increased mortality (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03) and increased use of RRT (relative risk, 1.35; 95% CI, 1.01 to 1.80; p=0.04) in HES subjects.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 or establish a causal relationship to product exposure.
Among the very rarely occurring serious adverse drug reactions in patients treated with Voluven®, anaphylactic/anaphylactoid/hypersensitivity reactions or hypotension/shock/ circulatory collapse were most frequently reported.
The following adverse reactions have been identified and reported during the post-approval use of different HES products in critically ill adult patients, including patients with sepsis:
Mortality
Renal: use of RRT
Drug Interactions
The safety and compatibility of other additives have not been established.
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.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroxyethyl starch in women who are pregnant.
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.
Geriatic 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.
Gender
There is no FDA guidance on the use of Hydroxyethyl starch with respect to specific gender populations.
Race
There is no FDA guidance on the use of Hydroxyethyl starch with respect to specific racial populations.
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.
Hepatic Impairment
There is no FDA guidance on the use of Hydroxyethyl starch in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hydroxyethyl starch in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Hydroxyethyl starch in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
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
Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, serum electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. Monitor liver function in patients receiving HES products, including Voluven®.
IV Compatibility
There is limited information regarding IV Compatibility of Hydroxyethyl starch in the drug label.
Overdosage
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.
Pharmacology
There is limited information regarding Hydroxyethyl starch Pharmacology in the drug label.
