[Federal Register Volume 75, Number 86 (Wednesday, May 5, 2010)]
[Notices]
[Pages 24710-24711]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-10559]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-P-0284]


Determination That BREVIBLOC (Esmolol Hydrochloride) Injection, 
250 Milligrams/Milliliter, 10-Milliliter Ampule, Was Withdrawn From 
Sale for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) has determined that 
BREVIBLOC (esmolol hydrochloride (HCl)) Injection, 250 milligrams (mg)/
milliliter (mL), 10-mL ampule, was withdrawn from sale for reasons of 
safety or effectiveness. This determination means the agency will not 
accept or approve abbreviated new drug applications (ANDAs) for esmolol 
HCl injection, 250 mg/mL, 10-mL ampule.

FOR FURTHER INFORMATION CONTACT: Olivia A. Pritzlaff, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 6308, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION: In 1984, Congress enacted the Drug Price 
Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 
(the 1984 amendments), which authorized the approval of duplicate 
versions of drug products approved under an ANDA procedure. ANDA 
applicants must, with certain exceptions, show that the drug for which 
they are seeking approval contains the same active ingredient in the 
same strength and dosage form as the ``listed drug,'' which is a 
version of the drug that was previously approved under a new drug 
application (NDA). ANDA applicants do not have to repeat the extensive 
clinical testing otherwise necessary to gain approval of an NDA. The 
only clinical data required in an ANDA are data to show that the drug 
that is the subject of the ANDA is bioequivalent to the listed drug.
    The 1984 amendments include what is now section 505(j)(7) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(j)(7)), 
which requires FDA to publish a list of all approved drugs. FDA 
publishes this list as part of the ``Approved Drug Products With 
Therapeutic Equivalence Evaluations,'' which is generally known as the 
``Orange Book.'' Under FDA regulations, drugs are removed from the list 
if the agency withdraws or suspends approval of the drug's NDA or ANDA 
for reasons of safety or effectiveness, or if FDA determines that the 
listed drug was withdrawn from sale for reasons of safety or 
effectiveness (section 505(j)(7)(C) of the act; 21 CFR 314.162).
    FDA will not approve an ANDA if the listed drug has been withdrawn 
from sale for safety or effectiveness reasons (section 505(j)(4)(I) of 
the act). Under Sec.  314.161(a)(1) (21 CFR 314.161(a)(1)), the agency 
must determine whether a listed drug was withdrawn from sale for 
reasons of safety or effectiveness before an ANDA that refers to that 
listed drug may be approved. A drug that has been withdrawn from the 
market for safety or effectiveness reasons is not a listed drug (21 CFR 
314.3(b)). FDA may not approve an ANDA that does not refer to a listed 
drug.
    BREVIBLOC (esmolol HCl)) Injection is the subject of NDA 19-386, 
held by Baxter Healthcare Corp. (Baxter). BREVIBLOC is a 
beta1-selective adrenergic receptor-blocking agent with a 
short duration of action. BREVIBLOC is approved for the treatment of 
supraventricular tachycardia. BREVIBLOC is also indicated for treatment 
of intraoperative and postoperative tachycardia and/or hypertension.
    Baxter currently markets 4 product presentations of BREVIBLOC 
Injection--10-mg/mL and 20-mg/mL ready-to-use vials and 10-mg/mL and 
20-mg/mL premixed injection bags. Baxter has discontinued marketing the 
following two product presentations of BREVIBLOC (esmolol HCl) 
Injection:
     In 2003, Baxter discontinued BREVIBLOC (esmolol HCl) 
Injection, 10 mg/mL (formulation without sodium chloride), and FDA 
determined that this presentation of BREVIBLOC Injection was not 
withdrawn from sale for reasons of safety or effectiveness (69 FR 
47155, August 4, 2004).
     In 2007, Baxter discontinued BREVIBLOC (esmolol HCl) 
Injection, 250 mg/mL, 10-mL ampule. In a letter dated June 28, 2007, 
Baxter informed the agency that the company had decided to cease 
manufacture and distribution of BREVIBLOC (esmolol HCl) Injection, 250 
mg/mL, 10-mL ampule, because the product demonstrated a higher risk of 
medication errors that may potentially result in serious outcomes. 
Baxter observed that serious adverse events were associated with the 
following medication errors:
     Mixups between the ready-to-use 10-mg/mL vial and the 250-
mg/mL, 10-mL ampule concentrate;
     Use of undiluted 250-mg/mL, 10-mL ampule concentrate;
     Dilution calculation errors with the 250-mg/mL, 10-mL 
ampule concentrate; and
     Administration of the wrong drug.
    In a Dear Healthcare Professional letter dated August 20, 2007, 
Baxter stated that their decision to cease manufacture of BREVIBLOC 
(esmolol HCl) Injection, 250 mg/mL, 10-mL ampule, was made after 
thorough review of adverse event reports, clinical usage studies, input 
from clinicians, and initiatives to reduce medication errors.
    In a citizen petition dated March 27, 2008 (Docket No. FDA-2008-P-
0284), submitted under 21 CFR 10.30 and in accordance with 21 CFR 
314.122 and 314.161, Bedford Laboratories (Bedford) requested that the 
agency determine

[[Page 24711]]

whether BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 10-mL ampule, was 
withdrawn from sale for reasons of safety or effectiveness. Bedford 
noted that Baxter has publicly stated that the product was discontinued 
due to safety issues surrounding medication errors and asked the agency 
to determine the cause of the discontinuation.
    We have carefully reviewed our files for records concerning the 
withdrawal from sale of BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 
10-mL ampule, including the NDA file for this drug product. We have 
also independently evaluated relevant literature and data for possible 
postmarketing adverse event reports. FDA's review shows that the 
product was withdrawn from sale because of reports of serious adverse 
events, including deaths.
    Although the application holder has made several labeling revisions 
(including a warning sticker on the ampule) and issued Dear Healthcare 
Provider letters to reduce the potential for medication errors, there 
have been additional reports of medication errors. In addition, 
alternative presentations of the product are available that are not 
associated with the same potential for medication errors.
    After considering the citizen petition (and comments submitted) and 
reviewing agency records concerning the drug product, analyses of 
adverse event reports, and relevant literature, FDA has determined 
under Sec.  314.161 that BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 
10-mL ampule, was withdrawn from sale for reasons of safety or 
effectiveness. FDA has reviewed the latest approved labeling for 
BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 10-mL ampule, and has 
determined that this labeling is inadequate to reduce medication errors 
to an acceptable level. FDA has determined that Human Factors studies 
(i.e., Failure Mode and Effects Analysis and usability studies to test 
the product in a typical practice setting) are necessary before this 
product could be considered for reintroduction to the market.
    Therefore, the agency has determined, under Sec.  314.161, that 
BREVIBLOC (esmolol HCl) Injection, 250 mg/mL, 10-mL ampule, was 
withdrawn from sale for reasons of safety. BREVIBLOC (esmolol HCl) 
Injection, 250 mg/mL, 10-mL ampule, will be removed from the list of 
drug products published in the Orange Book. FDA will not accept or 
approve ANDAs that refer to BREVIBLOC (esmolol HCl) Injection, 250 mg/
mL, 10-mL ampule.

    Dated: April 30, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-10559 Filed 5-4-10; 8:45 am]
BILLING CODE 4160-01-S