Our reference: NDA BN200952/55
Attention: Harold Waitz, PhD
1301 Harbor Bay Parkway
Alameda, CA 94502
Dear Dr. Waitz:
Please refer to your supplemental New Drug Application (sNDA) dated July 22, 2013, received July 24, 2013, submitted pursuant to 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA), for HEXTEND® (6% Hydroxyethyl Starch in Lactated Electrolyte Injection).
We acknowledge receipt of your amendments dated September 13, 2013; October 16, 2013; October 17, 2013; October 28, 2013; and October 29, 2013.
We also refer to our letter dated June 24, 2013, notifying you, under Section 505(o)(4) of the
FDCA, of new safety information that we have determined should be included in the labeling for Hydroxyethyl Starch products. This information pertains to the risk of increased mortality and renal replacement therapy (RRT) in critically ill adults including patients with sepsis; and increased risk of bleeding in patients undergoing open heart surgery in association with cardiopulmonary bypass. In addition, please refer to our e-mail dated October 28, 2013, notifying you of revisions to the final required safety labeling including the Adverse Reactions and Clinical study sections.
APPROVAL & LABELING
We have approved your sNDA for HEXTENDto include the following new safety information on the risk of increased mortality, risk of bleeding, and renal injury in the package insert:
RENAL REPLACEMENT THERAPY
- In critically ill adult patients, including patients with sepsis, use of hydroxyethyl starch (HES) products, including HEXTEND, increases risk of
- Renal replacement therapy
- Do not use HES products, including HEXTEND, in critically ill adult patients, including patients with sepsis
- Do not use hydroxyethyl starch (HES) products, including HEXTENDin critically ill adult patients, including patients with sepsis, due to increased risk of mortality and renal replacement therapy.
- Do not use HES products, including HEXTEND, in patients with severe liver disease.
---------------------------------WARNINGS and PRECAUTIONS--------------------------
- Avoid use in patients with pre-existing renal dysfunction.
- Discontinue use of HEXTENDat 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, including HEXTEND.
- 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 HEXTEND, at the first sign of coagulopathy.
- Monitor liver function in patients receiving HES products, including HEXTEND.
The Adverse Reactions and Clinical Study sections are revised accordingly.
We have completed our review of this supplemental application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
CONTENT OF LABELING
As soon as possible, but no later than 14 days from the date of this letter,submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert, text for the patient package insert, Medication Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed labeling.
Information on submitting SPL files using eList may be found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf
The SPL will be accessible from publicly available labeling repositories.
You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory comments, (2) the proposed materials in draft or mock-up form with annotated references, and (3) the package insert(s) to:
Food and Drug Administration
Center for Biologics Evaluation and Research
Advertising and Promotional Labeling Branch, HFM-602
1401 Rockville Pike
Rockville, MD 20852-1448
You must submit final promotional materials and package insert(s), accompanied by a Form FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html; instructions are provided on page 2 of the form.
All promotional materials that include representations about your drug product must be promptly revised to be consistent with the labeling changes approved in this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials should include prominent disclosure of the important new safety information that appears in the revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4) to the address above.
We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81).
If you have any questions, please contact Sonday L. Kelly, MS, RAC, Regulatory Project Manager at (301) 827-6162.
Basil Golding, MD
Division of Hematology
Office of Blood Research and Review
Center for Biologics
Evaluation and Research