[Federal Register Volume 86, Number 243 (Wednesday, December 22, 2021)]
[Notices]
[Pages 72606-72607]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-27696]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-P-0375]


Determination That Alcohol and Dextrose Injection, 5 Milliliters/
100 Milliliters, 5 Grams/100 Milliliters; and 10 Milliliters/100 
Milliliters, 5 Grams/100 Milliliters, Were Withdrawn From Sale for 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, Agency, or we) has 
determined that Alcohol and Dextrose Injection, 5 milliliters (mL)/100 
mL, 5 gram (g)/100 mL; and Alcohol and Dextrose Injection, 10 mL/100 
mL, 5 g/100 mL, were withdrawn from sale for reasons of safety or 
effectiveness. The Agency will not accept or approve abbreviated new 
drug applications (ANDAs) for Alcohol and Dextrose Injection, 5 mL/100 
mL, 5 g/100 mL; and 10 mL/100 mL, 5 g/100 mL.

FOR FURTHER INFORMATION CONTACT: Kaetochi Okemgbo, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6272, Silver Spring, MD 20993-0002, 240-
825-9944, [email protected].

SUPPLEMENTARY INFORMATION: Section 505(j) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)) allows the submission of 
an ANDA to market a generic version of a previously approved drug 
product. To obtain approval, the ANDA applicant must show, among other 
things, that the generic drug product: (1) Has the same active 
ingredient(s), dosage form, route of administration, strength, 
conditions of use, and, with certain exceptions, labeling as the listed 
drug, which is a version of the drug that was previously approved; and 
(2) is bioequivalent to the listed drug. ANDA applicants do not have to 
repeat the extensive clinical testing otherwise necessary to gain 
approval of a new drug application (NDA).
    Section 505(j)(7) of the FD&C Act 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 
known generally 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 (21 CFR 314.162).
    A person may petition the Agency to determine, or the Agency may 
determine on its own initiative, whether a listed drug was withdrawn 
from sale for reasons of safety or effectiveness. This determination 
may be made at any time after the drug has been withdrawn from sale, 
but must be made prior to approving an ANDA that refers to the listed 
drug (Sec.  314.161 (21 CFR 314.161)). FDA may not approve an ANDA that 
does not refer to a listed drug.
    Between 1938 and 1968, FDA evaluated NDAs solely on the basis of 
safety information. In 1962, the Kefauver-Harris Drug Amendments (Pub. 
L. 87-781) amended the FD&C Act to require that new drug products also 
be shown to be effective in order to obtain approval of an NDA. After 
the enactment of the Kefauver-Harris Drug Amendments, FDA initiated the 
Drug Efficacy Study Implementation (DESI) to evaluate the effectiveness 
of drug products that had been approved between 1938 and 1962 solely on 
the basis of safety.
    FDA introduced the concept of an ``abbreviated new drug 
application'' in 1968 as a vehicle for approval of certain drugs 
affected by the DESI review. When a drug product subject to the DESI 
review was determined to be effective for one or more indications, FDA 
would issue a Federal Register notice for that drug product describing 
the DESI review findings and stating whether abbreviated new drug 
applications that met specified criteria could be submitted to FDA (see 
generally 35 FR 11273 (July 14, 1970); 35 FR 6574 (April 24, 1970)) for 
products that had not been marketed under an NDA. Such a finding 
allowed manufacturers to submit an abbreviated new drug application in 
lieu of an NDA. For approval of these applications, which were 
submitted before the Drug Price Competition and Patent Term Restoration 
Act of 1984 (Hatch-Waxman Amendments) (Pub. L. 98-417) created the 
current ANDA pathway, FDA relied on the evidence of effectiveness that 
had been provided, reviewed, and accepted during the DESI process and 
evaluated the safety of these drug products on the basis of information 
included in NDAs submitted prior to 1962, as well as the subsequent 
marketing experience with the drugs. These applications are referred to 
as pre-Hatch-Waxman abbreviated new drug applications or ``PANDAs''.\1\ 
PANDAs were submitted under section 505(b) of the FD&C Act and approved 
for safety and effectiveness under section 505(c) of the FD&C Act (see 
86 FR 44731 at 44732 (August 13, 2021)).
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    \1\ See ``Drug Products Approved in Abbreviated New Drug 
Applications Before the Enactment of the Hatch-Waxman Amendments; 
Establishment of a Public Docket; Request for Comments,'' 86 FR 
44731 (August 13, 2021). Note that the scope of the referenced 
notice is limited to drug products approved in PANDAs under section 
505 of the FD&C Act prior to the Hatch-Waxman Amendments; the notice 
does not cover applications for antibiotic drug products that were 
originally submitted under section 507 of the FD&C Act (21 U.S.C. 
357).
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    As explained above, the current ANDA pathway is described in 
section 505(j) of the FD&C Act. Because of substantive differences in 
the application approval pathway for PANDAs, which were approved for 
safety and effectiveness under section 505(c) of the FD&C Act, compared 
to ANDAs approved under section 505(j) of the FD&C Act, FDA has 
determined that PANDA products can serve as reference listed drugs for 
505(j) ANDA applicants seeking to make generic versions of these 
products and that there is a finding of safety and effectiveness that 
may be relied upon for approval by applicants of 505(b)(2) 
applications.
    Alcohol and Dextrose Injection, 5 mL/100 mL, 5 g/100 mL; and 10 mL/
100 mL, 5 g/100 mL, is the subject of NDA 004589, held by B. Braun 
Medical Inc. The initial application, which included Alcohol and 
Dextrose Injection, 5 mL/100 mL, 5 g/100 mL, was allowed to take effect 
on February 21, 1942. Alcohol and Dextrose Injection, 10 mL/100 mL, 5 
g/100 mL, was allowed to take effect in a supplemental application on 
January 17, 1946. On July 28, 1972, FDA published a Federal Register 
notice regarding the DESI review of NDA 004589 (see 37 FR 15184). Under 
the DESI review, FDA concluded that there was substantial evidence of 
efficacy for two formulations of 5 percent Alcohol and 5 percent 
Dextrose for the indication ``for increasing caloric intake.'' Based on 
the Federal Register notice, FDA approved Alcohol and Dextrose 
Injection, 5 mL/100 mL, 5 g/100 mL in three PANDAs: ANDA 083263, held 
by Hospira, Inc. and initially approved on February 26, 1974; ANDA 
083483, held by Miles Laboratories Inc. and originally approved on 
November 22, 1974; and

[[Page 72607]]

ANDA 083256, held by Baxter Healthcare Corp. and initially approved on 
March 12, 1976.\2\
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    \2\ The Orange Book refers to the Alcohol and Dextrose 
Injection, 5 mL/100 mL, 5 g/100 mL products in the three PANDAs 
(i.e., ANDA 083263, ANDA 083483, and ANDA 083256) as Alcohol ``in'' 
Dextrose, but these products contain the same concentrations of 
alcohol and dextrose as Alcohol and Dextrose Injection, 5 mL/100 mL, 
5 g/100 mL, approved under NDA 004589. Our findings are limited to 
these products, which contain both alcohol and dextrose, and we make 
no findings about the safety or effectiveness of any product that 
may contain only one of the active ingredients.
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    All Alcohol and Dextrose Injection products have been discontinued 
and moved to the ``Discontinued Product List'' section of the Orange 
Book. In a letter dated June 23, 1999, Miles Laboratories Inc. notified 
FDA that Alcohol and Dextrose Injection, 5 mL/100 mL, 5 g/100 mL, the 
subject of ANDA 083483, was being discontinued, and FDA moved the drug 
product to the ``Discontinued Drug Product List'' section of the Orange 
Book. In the Federal Register of September 22, 1999, FDA announced it 
was withdrawing approval of ANDA 083256, effective September 22, 1999 
(see 64 FR 51325). Approval of ANDA 083256 was withdrawn upon request 
of Baxter Healthcare Corp. under Sec.  314.150(c) (21 CFR 314.150(c)) 
because the product was no longer being marketed. In the Federal 
Register of June 19, 2014, FDA announced it was withdrawing approval of 
ANDA 083263, effective July 21, 2014 (see 79 FR 35170). Approval of 
ANDA 083263 was withdrawn upon request of Hospira, Inc., under Sec.  
314.150(c) because the product was no longer being marketed. In the 
Federal Register of October 13, 2015, FDA announced it was withdrawing 
approval of NDA 004589, effective November 15, 2015 (see 80 FR 61426). 
Approval of NDA 004589 was withdrawn upon request of B. Braun Medical 
Inc. under Sec.  314.150(c) because the products were no longer being 
marketed.
    Celerity Pharmaceuticals, LLC submitted a citizen petition dated 
April 12, 2021 (Docket No. FDA-2021-P-0375), under 21 CFR 10.30, 
requesting that the Agency determine whether B. Braun Medical Inc.'s 
Alcohol and Dextrose Injection, 10 mL/100 mL, 5 g/100 mL, NDA 004589, 
was withdrawn from sale for reasons of safety or effectiveness. 
Although the citizen petition did not address the 5 mL/100 mL, 5 g/100 
mL strength or the PANDAs, that strength and the PANDAs have also been 
withdrawn from sale. On our own initiative, we have also determined 
whether the 5 mL/100 mL, 5 g/100 mL strength under NDA 004589 and the 
PANDAs were withdrawn from sale for safety or effectiveness reasons.
    The petitioner has identified no data or other information 
suggesting that Alcohol and Dextrose Injection, 5 mL/100 mL, 5 g/100 
mL; or 10 mL/100 mL, 5 g/100 mL, were withdrawn for reasons of safety 
or effectiveness. Specifically, the petitioner states that the Alcohol 
and Dextrose Injection, 10 mL/100 mL, 5 g/100 mL, was discontinued for 
unknown reasons. The petitioner also included a letter published on 
November 15, 2005, in the American Journal of Health-System Pharmacy, 
which describes the use of Alcohol and Dextrose Injection as a 
treatment for ethylene glycol and methanol poisonings.
    We have carefully reviewed our files for records concerning the 
withdrawal of Alcohol and Dextrose Injection, 5 mL/100 mL, 5 g/100 mL; 
and 10 mL/100 mL, 5 g/100 mL, from sale. We have also independently 
evaluated relevant literature and data for possible postmarketing 
adverse events. Based on a thorough evaluation of the information we 
have available to us and an evaluation of the latest version of the 
drug products' approved labeling, we have determined that the drug 
products would not be considered safe and effective if they were 
reintroduced to the market today. Therefore, after considering the 
citizen petition and reviewing Agency records and based on the 
information we have at this time, FDA has determined under Sec.  
314.161 that Alcohol and Dextrose Injection, 5 mL/100 mL, 5 g/100 mL; 
and Alcohol and Dextrose Injection, 10 mL/100 mL, 5 g/100 mL were 
withdrawn for reasons of safety or effectiveness.
    Alcohol and Dextrose Injection is indicated to provide increased 
caloric intake. The use of Alcohol and Dextrose raises several safety 
concerns because there are many risks associated with the exposure to 
alcohol. Alcohol is contraindicated for use in patients with neurologic 
disorders, such as seizures, who have current or past substance abuse 
problems or who are pregnant. It can cause intoxication, respiratory 
depression, and disturbances in serum glucose levels. FDA-approved 
alternatives for intravenous calorie supplementation that do not 
include alcohol were approved after these Alcohol and Dextrose products 
and are available today.
    In addition to the safety considerations, we have concerns about 
the appropriateness of Alcohol and Dextrose Injection to provide 
intravenous nutrition. Alcohol and Dextrose Injection was developed 
prior to the advent of more physiologically complete intravenous 
nutrition options. Parenteral nutrition, delivered intravenously, is 
used as a source of nutrition when oral or enteral nutrition cannot be 
administered. Parenteral nutrition is an admixture of solutions 
containing dextrose, amino acids, electrolytes, vitamins, minerals, and 
trace elements. Lipid emulsions are infused separately or added to the 
mixture, which allows for high energy supply with iso-osmolar 
solutions. Providing an adequate proportion of the energy needs as 
lipids obviates the need for high glucose infusion rates and, 
therefore, can contribute to the prevention of hepatic steatosis and 
hyperglycemia. Lipid emulsions are also necessary to supply essential 
fatty acids. Today, there are several FDA-approved parenteral products 
that are alternatives to Alcohol and Dextrose for increasing caloric 
intake and that also address other nutritional needs.
    Because new clinical studies would first need to be conducted to 
address the concerns described above, FDA has determined that these 
Alcohol and Dextrose products would not be considered safe and 
effective if they were reintroduced to the market. Therefore, under 
Sec.  314.161, FDA has determined that Alcohol and Dextrose Injection, 
5 mL/100 mL, 5 g/100 mL; and 10 mL/100 mL, 5 g/100 mL were withdrawn 
for safety and effectiveness reasons. Accordingly, the Agency will 
remove B. Braun Medical Inc.'s NDA 004589 for Alcohol and Dextrose 
Injection, 5 mL/100 mL, 5 g/100 mL; and 10 mL/100 mL, 5 g/100 mL; Miles 
Laboratory Inc.'s ANDA 083483 for Alcohol and Dextrose Injection, 5 mL/
100 mL, 5 g/100 mL; Baxter Healthcare Corp's ANDA 083256 for Alcohol 
and Dextrose Injection, 5 mL/100 mL, 5 g/100 mL; and Hospira, Inc.'s 
ANDA 083263 for Alcohol and Dextrose Injection, 5 mL/100 mL, 5 g/100 mL 
from the list of drug products published in the Orange Book. FDA will 
not accept or approve ANDAs that refer to these drug products.

    Dated: December 15, 2021.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2021-27696 Filed 12-21-21; 8:45 am]
BILLING CODE 4164-01-P