Voluven FDA Alerts

FDA Safety Communication: Labeling Changes on Mortality, Kidney Injury, and Excess Bleeding with Hydroxyethyl Starch Products

July 7, 2021 -- The U.S. Food and Drug Administration (FDA) is requiring safety labeling changes to the prescribing information for the class of hydroxyethyl starch products to amend the Boxed Warning to warn about the risk of mortality, kidney injury, and excess bleeding. FDA is also requiring related changes to the Indications and Usage, Contraindications, Warnings and Precautions, and Adverse Reactions sections.

Summary of Safety Issues

Hydroxyethyl starch (HES) products are approved for the treatment of hypovolemia (low blood volume). Recent data have associated administration of these products with certain serious risks.

FDA as completed a review of data and information on the safety of HES products, including data from randomized clinical trials, meta-analyses, and observational studies.
These data and information reflect the following serious risks associated with use of HES products:

1. mortality, acute kidney injury (AKI) (including need for renal replacement therapy (RRT), and excess bleeding in surgical patients who are treated with HES products; and
2. mortality and AKI in blunt trauma patients who are treated with HES products.

FDA has concluded that changes to the Boxed Warning are warranted to highlight the risk of mortality, kidney injury, and excess bleeding, as well as to include a statement that HES products should not be used unless adequate alternative treatment is unavailable. In addition,

FDA has determined that changes should be made to other sections of the prescribing information for HES products, including the Indications and Usage, Contraindications, Warnings and Precautions, and Adverse Reactions sections.

Recommendation for Patients

Patients should be aware of the risks associated with the use of HES products and discuss these risks with their healthcare provider.

• Be aware that death, kidney injury, and excess bleeding have been associated with the use of HES products.
• Be sure to follow up with your healthcare provider as requested and follow all instructions. Report any unusual symptoms immediately.
• Symptoms of kidney injury can include:
  
  • Change in the frequency, amount, or color of urine
  • Blood in the urine
  • Difficulty urinating
  • Swelling of the legs, ankles, feet, face, or hands
  • Unusual weakness or fatigue
  • Nausea and vomiting
  • Shortness of breath

Information for Health Professionals

Do not use HES products unless adequate alternative treatment is unavailable.

Data Summary

There are currently three FDA-approved innovator HES products: HESPAN (6% hetastarch in 0.9% sodium chloride injection; B. Braun Medical Inc.), HEXTEND (6% hetastarch in Lactated Electrolyte Injection; BioTime, Inc.), and Voluven (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection; Fresenius Kabi). HESPAN and HEXTEND are indicated for “treatment of hypovolemia when plasma volume expansion is desired,” and Voluven is indicated for “treatment and prophylaxis of hypovolemia in adults and children.” There is also currently one approved generic version of HESPAN that is distributed in the U.S. (6% hetastarch in 0.9% sodium chloride injection; Hospira, Inc.).

Data from a randomized controlled trial (RCT), a meta-analysis, and observational studies collectively show an increased risk of mortality, AKI, and excess bleeding in surgical patients who are treated with HES products, as well as an increased risk of mortality and AKI in blunt trauma patients who are treated with HES products.

Mortality and AKI in surgical and blunt trauma patients

Surgical patients

Data from a meta-analysis and observational studies collectively show increased risk of mortality and AKI (including need for RRT) in surgical patients who are treated with HES products.

• A meta-analysis of 15 RCTs (HES vs. crystalloids/non-HES colloids) conducted in cardiac, noncardiac, hepatic and renal transplant patients (N=4409) found a safety signal for RRT.¹
• A single-center, three-arm retrospective study in 796 high-risk vascular surgery patients found safety signals for mortality and need for renal replacement therapy (RRT).²
• A single-center, three-arm retrospective study in 1442 thoracic surgery patients found a safety signal for AKI using the AKIN criteria.³ A single-center, two-arm (HES with crystalloids vs. crystalloids alone) retrospective study with propensity score matching in 29,360 noncardiac surgery patients found a safety signal for AKI.⁴
• A single-center, two-arm retrospective study in 606 cardiac surgery patients found safety signals for AKI and coagulopathy.⁵
• A multicenter prospective observational study in 529 kidney transplant donors who received HES found a safety signal for RRT.⁶
• A single-center, three-arm, prospective, observational, sequential study in 6,478 post-cardiac surgery patients found a safety signal for RRT.⁷

Blunt trauma patients

Data from observational studies show increased risk of mortality and AKI in blunt trauma patients who are treated with HES products.

• A single-center, two arm retrospective study (N=1410) of blunt (N=959) and penetrating (N=451) trauma patients found safety signals for mortality and AKI in blunt trauma.⁸
• A single-center, single arm, retrospective cohort study of blunt (89%) and penetrating (11%) trauma patients admitted to the ICU (N=413) found safety signals for mortality and AKI.⁹

Excess bleeding in surgical patients

Data from an RCT and an observational study show increased risk of excess bleeding in surgical patients who are treated with HES products.

• A single-center, two-arm RCT of 33 cystectomy patients found a coagulopathy safety signal.¹⁰
• A single-center, two-arm retrospective study in 606 cardiac surgery patients found safety signals for AKI and coagulopathy.⁵

Based on these data and information, FDA has determined that information on mortality, AKI (including RRT), and excess bleeding in surgical patients, and mortality and AKI in blunt trauma patients, must be added to the Black Box, Contraindications, and other portions of HES products’ prescribing information.

Contact FDA
Center for Biologics Evaluation and Research
Food and Drug Administration
ocod@fda.hhs.gov
800-835-4709
240-402-8010

References

1. Wilkes MM, Navickis RJ. Postoperative renal replacement therapy after hydroxyethyl starch infusion: a meta-analysis of randomized trials. Neth J Crit Care 2014; 18:4-9.
2. Green RS, Butler MB, Hicks SD, et al. Effect of hydroxyethyl starch on outcomes in high-risk vascular surgery patients: A retrospective analysis. J Cardiothorac Vasc Anesth 2016; 30(4):967-72.
3. Ahn HJ, Kim JA, Lee AR, et al. The risk of acute kidney injury from fluid restriction and hydroxyethyl starch in thoracic surgery. Anesth Analg 2016; 122(1):186-193.
4. Kashy BK, Podolyak A, Makarova N, et al. Effect of hydroxyethyl starch on postoperative kidney function in patients having noncardiac surgery. Anesthesiology 2014; 121 (4):730-9.
5. Lagny MG, Roediger L, Koch JN, et al. Hydroxyethyl starch 130/0.4 and the risk of acute kidney injury after cardiopulmonary bypass: A single-center retrospective study. J of Cardiothorac and Vasc Anesth 2016: 30(4):869-75.
6. Patel MS, Niemann CU, Sally MB, et al. The impact of hydroxyethyl starch use in deceased organ donors on the development of delayed graft function in kidney transplant recipients: A Propensity-Adjusted Analysis. Am J of Transplant 2015; 15 (8):2152-8.
7. Bayer O, Schwarzkopf D, Doenst T, et al. Perioperative fluid therapy with tetrastarch and gelatin in cardiac surgery – a prospective sequential analysis. Crit Care Med 2013; 41(11):2532-42.
8. Allen CJ, Valle EJ, Jouria JM, et al. Differences between blunt and penetrating trauma after resuscitation with HES. J Trauma Acute Care Surg 2014; 77(6):859-64.
9. Eriksson M, Brattström O, Mårtensson J, et al. Acute kidney injury following severe trauma: Risk factors and long-term outcome. J Trauma Acute Care Surg 2015; 79(3):407-12.
10. Rasmussen KC, Johansson PI, Højskov M, et al. Hydroxyethyl starch reduces coagulation competence and increases blood loss during major surgery: results from a randomized controlled trial. Ann Surg 2014; 259 (2):249-54.

Source: FDA

Hydroxyethyl Starch Solutions: FDA Safety Communication - Boxed Warning on Increased Mortality and Severe Renal Injury and Risk of Bleeding

ISSUE: FDA has analyzed recent data that indicate an increased risk of (i) mortality and renal injury requiring renal replacement therapy in critically ill adult patients, including patients with sepsis and those admitted to the ICU; and (ii) excess bleeding particularly in patients undergoing open heart surgery in association with cardiopulmonary bypass. Refer to the FDA Safety Communication for more details about the data analysis. 

FDA has concluded that HES solutions should not be used in critically ill adult patients, including patients with sepsis and those admitted to the ICU, and a Boxed Warning to include the risk of mortality and severe renal injury is warranted. In addition, FDA has reviewed a meta-analysis of studies conducted in patients undergoing open heart surgery in association with cardiopulmonary bypass and has determined that an additional warning about excessive bleeding is needed in the Warnings and Precautions Section of the package insert.

BACKGROUND:  Hydroxyethyl starch (HES) solutions are used for the treatment of hypovolemia (low blood volume) when plasma volume expansion is desired. Recent data have associated the use of these products with an increased risk of severe adverse events when used in certain patient populations.

RECOMMENDATION: Patients should be aware of the risks associated with the use of HES solutions and discuss these risks with their healthcare provider (refer to the FDA Safety Communication for detailed recommendations for patients). 

Recommendations for Health Professionals include the following:

• Do not use HES solutions in critically ill adult patients including those with sepsis, and those admitted to the ICU.
• Avoid use in patients with pre-existing renal dysfunction.
• Discontinue use of HES at the first sign of renal injury.
• Need for renal replacement therapy has been reported up to 90 days after HES administration. Continue to monitor renal function for at least 90 days in all patients.
• Avoid use in patients undergoing open heart surgery in association with cardiopulmonary bypass due to excess bleeding.
• Discontinue use of HES at the first sign of coagulopathy.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[06/24/2013 - FDA Safety Communication - FDA]