Federal Register, Volume 85 Issue 148 (Friday, July 31, 2020)

[Federal Register Volume 85, Number 148 (Friday, July 31, 2020)]
[Notices]
[Pages 46126-46141]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-16649]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3240]

List of Bulk Drug Substances for Which There is a Clinical Need
Under Section 503B of the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is developing
a list of bulk drug substances (active pharmaceutical ingredients) for
which there is a clinical need (the 503B Bulks List). Drug products
that outsourcing facilities compound using bulk drug substances on the
503B Bulks List can qualify for certain exemptions from the Federal
Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are
met. This notice identifies four bulk drug substances that FDA has
considered and proposes to include on the 503B Bulks List:
Diphenylcyclopropenone (DPCP), glycolic acid, squaric acid dibutyl
ester (SADBE), and trichloroacetic acid (TCA). This notice also
identifies 19 bulk drug substances that FDA has considered and proposes
not to include on the list: Diazepam, dobutamine hydrochloride (HCl),
dopamine HCl, edetate calcium disodium, folic acid, glycopyrrolate,
hydroxyzine HCl, ketorolac tromethamine, labetalol HCl, mannitol,
metoclopramide HCl, moxifloxacin HCl, nalbuphine HCl, polidocanol,
potassium acetate, procainamide HCl, sodium nitroprusside, sodium
thiosulfate, and verapamil HCl. Additional bulk drug substances
nominated by the public for inclusion on this list are currently under
consideration and may be the subject of future notices.

DATES: Submit either electronic or written comments on the notice by
September 29, 2020.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before September 29, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of September 29, 2020. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2018-N-3240 for ``List of Bulk Drug Substances for Which There is a
Clinical Need Under Section 503B of the Federal Food, Drug, and
Cosmetic Act.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For

[[Page 46127]]

more information about FDA's posting of comments to public dockets, see
80 FR 56469, September 18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Elizabeth Hankla, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5216, Silver Spring, MD 20993, 240-402-
3359.

SUPPLEMENTARY INFORMATION:

I. Background

Section 503B of the FD&C Act (21 U.S.C. 353b) describes the
conditions that must be satisfied for drug products compounded by an
outsourcing facility to be exempt from section 505 (21 U.S.C. 355)
(concerning the approval of drugs under new drug applications (NDAs) or
abbreviated new drug applications (ANDAs)), section 502(f)(1) (21
U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate
directions for use), and section 582 (21 U.S.C. 360eee-1) (concerning
drug supply chain security requirements).\1\
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\1\ Section 503B(a) of the FD&C Act.
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Drug products compounded that meet the conditions in section 503B
are not exempt from current good manufacturing practice (CGMP)
requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C.
351(a)(2)(B)).\2\ Outsourcing facilities are also subject to FDA
inspections according to a risk-based schedule, specific adverse event
reporting requirements, and other conditions that help to mitigate the
risks of the drug products they compound.\3\ Outsourcing facilities may
or may not obtain prescriptions for identified individual patients and
can, therefore, distribute compounded drugs to healthcare practitioners
for ``office stock,'' to hold in their offices in advance of patient
need.\4\
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\2\ Compare section 503A(a) of the FD&C Act (21 U.S.C. 353a(a);
exempting drugs compounded in accordance with that section) with
section 503B(a) of the FD&C Act (not providing the exemption from
CGMP requirements).
\3\ Section 503B(b)(4) and (5) of the FD&C Act.
\4\ Section 503B(d)(4)(C) of the FD&C Act.
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One of the conditions that must be met for a drug product
compounded by an outsourcing facility to qualify for exemptions under
section 503B of the FD&C Act is that the outsourcing facility may not
compound a drug using a bulk drug substance unless: (1) The bulk drug
substance appears on a list established by the Secretary of Health and
Human Services identifying bulk drug substances for which there is a
clinical need (the 503B Bulks List) or (2) the drug compounded from
such bulk drug substances appears on the drug shortage list in effect
under section 506E of the FD&C Act (21 U.S.C. 356e) at the time of
compounding, distribution, and dispensing.\5\
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\5\ Section 503B(a)(2)(A) of the FD&C Act.
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Section 503B of the FD&C Act directs FDA to establish the 503B
Bulks List by: (1) Publishing a notice in the Federal Register
proposing bulk drug substances to be included on the list, including
the rationale for such proposal; (2) providing a period of not less
than 60 calendar days for comment on the notice; and (3) publishing a
notice in the Federal Register designating bulk drug substances for
inclusion on the list.\6\
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\6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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In March 2019, FDA published a notice that identified two bulk drug
substances, nicardipine hydrochloride and vasopressin, that were
nominated for inclusion on the 503B Bulks List, and that, after
consideration, FDA did not include on that list (84 FR 7383, March 4,
2019). The March 2019 notice stated that additional bulk drug
substances were under evaluation and that additional substances would
be the subject of future notices. This notice identifies 4 bulk drug
substances that FDA has considered and proposes to include on the 503B
Bulks List and 19 bulk drug substances that FDA has considered and
proposes not to include on the 503B Bulks List.
For purposes of section 503B of the FD&C Act, bulk drug substance
means an active pharmaceutical ingredient as defined in 21 CFR
207.1.\7\ Active pharmaceutical ingredient means any substance that is
intended for incorporation into a finished drug product and is intended
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body, but the term does not
include intermediates used in the synthesis of the
substance.^{8 9}
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\7\ 21 CFR 207.3.
\8\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
\9\ Inactive ingredients are not subject to section 503B(a)(2)
of the FD&C Act and will not be included in the 503B Bulks List
because they are not included within the definition of a bulk drug
substance. Pursuant to section 503B(a)(3), inactive ingredients used
in compounding must comply with the standards of an applicable U.S.
Pharmacopeia or National Formulary monograph, if a monograph exists.
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For further information about drug compounding and the background
for the 503B Bulks List, see 83 FR 43877 (August 28, 2018).

II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

FDA requested nominations for specific bulk drug substances for the
Agency to consider for inclusion on the 503B Bulks List in the Federal
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination
process in the Federal Register of July 2, 2014 (79 FR 37747) and
provided more detailed information on what FDA needs to evaluate
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency
opened a new docket, FDA-2015-N-3469, to provide an opportunity for
interested persons to submit new nominations of bulk drug substances or
to renominate substances with sufficient information.
As FDA evaluates bulk drug substances, it intends to publish
notices for public comment in the Federal Register that describe the
FDA's proposed position on each substance along with the rationale for
that position.\10\ After considering any comments on FDA's proposals
regarding whether to include nominated substances on the 503B Bulks
List, FDA intends to consider whether input from the Pharmacy
Compounding Advisory Committee (PCAC) on the nominations would be
helpful to the Agency in making its determination, and if so, it will
seek PCAC input.\11\ Depending on its review of the docket comments and
other relevant information before the Agency, FDA may finalize its
proposed determination without change, or it may finalize a
modification to its proposal to reflect new evidence or analysis
regarding clinical need. FDA will then publish in the Federal Register
a list identifying the bulk drug substances for

[[Page 46128]]

which it has determined there is a clinical need and FDA's rationale in
making that final determination. FDA will also publish in the Federal
Register a list of those substances it considered but found that there
is no clinical need to use in compounding and FDA's rationale in making
this decision.
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\10\ This is consistent with procedure set forth in section
503B(a)(2)(A)(i) of the FD&C Act. Although the statute only directs
FDA to issue a Federal Register notice and seek public comment when
it proposes to include bulk drug substances on the 503B Bulks List,
we intend to seek comment when the Agency has evaluated a nominated
substance and proposes either to include or not to include the
substance on the list.
\11\ Section 503B of the FD&C Act does not require FDA to
consult the PCAC before developing a 503B Bulks List.
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FDA intends to maintain a current list of all bulk drug substances
it has evaluated on its website, and separately identify bulk drug
substances it has placed on the 503B Bulks List and those it has
decided not to place on the 503B Bulks List. FDA will only place a bulk
drug substance on the 503B Bulks List where it has determined there is
a clinical need for outsourcing facilities to compound drug products
using the bulk drug substance. If a clinical need to compound drug
products using the bulk drug substance has not been demonstrated, based
on the information submitted by the nominator and any other information
considered by the Agency, FDA will not place a bulk drug substance on
the 503B Bulks List.
FDA intends to evaluate bulk drug substances nominated for the 503B
Bulks List on a rolling basis. FDA intends to evaluate and publish in
the Federal Register its proposed and final determinations in groups of
bulk drug substances until all nominated substances that were
sufficiently supported have been evaluated and either placed on the
503B Bulks List or identified as bulk drug substances that were
considered but determined not to be appropriate for inclusion on the
503B Bulks List (Ref. 1).\12\
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\12\ On January 13, 2017, FDA announced the availability of a
revised final guidance for industry that provides additional
information regarding FDA's policies for bulk drug substances
nominated for the 503B Bulks List pending our review of nominated
substances under the ``clinical need'' standard entitled ``Interim
Policy on Compounding Using Bulk Drug Substances Under Section 503B
of the Federal Food, Drug, and Cosmetic Act'' (``Interim Policy'');
available at https://www.fda.gov/media/94402/download.
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B. Analysis of Substances Nominated for the List

As noted above, the 503B Bulks List will include bulk drug
substances for which there is a clinical need. The Agency is currently
evaluating bulk drug substances that were nominated for inclusion on
the 503B Bulks List, proceeding case by case, under the clinical need
standard provided by the statute (Ref. 2).\13\ In applying this
standard to develop the proposals in this notice, FDA is interpreting
the phrase ``bulk drug substances for which there is a clinical need''
to mean that the 503B Bulks List may include a bulk drug substance if:
(1) There is a clinical need for an outsourcing facility to compound
the drug product and (2) the drug product must be compounded using the
bulk drug substance. FDA is not interpreting supply issues, such as
backorders, to be within the meaning of ``clinical need'' for
compounding with a bulk drug substance. Section 503B separately
provides for compounding from bulk drug substances under the exemptions
from the FD&C Act discussed above if the drug product compounded from
the bulk drug substance is on the FDA drug shortage list at the time of
compounding, distribution, and dispensing. Additionally, we are not
considering cost of the compounded drug product as compared with an
FDA-approved drug product to be within the meaning of ``clinical
need.''
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\13\ On March 4, 2019, FDA announced the availability of a final
guidance entitled ``Evaluation of Bulk Drug Substances Nominated for
Use in Compounding Under Section 503B of the Federal Food, Drug, and
Cosmetic Act'' (84 FR 7390); available at https://www.fda.gov/media/121315/download. This guidance describes FDA policies for developing
the 503B Bulks List and the Agency's interpretation of the phrase
``bulk drug substances for which there is a clinical need'' as it is
used in section 503B of the FD&C Act. The analysis under the
statutory ``clinical need'' standard described in this notice is
consistent with the approach described in FDA's guidance.
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Some of the bulk drug substances that we are addressing in this
notice are components of FDA-approved drug products,\14\ and we
therefore began our evaluation of these bulk drug substances by asking
one or both of the following questions:
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\14\ Specifically: Diazepam, dobutamine HCl, dopamine HCl,
edetate calcium disodium, folic acid, glycopyrrolate, hydroxyzine
HCl, ketorolac tromethamine, labetalol HCl, mannitol, metoclopramide
HCl, moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium
acetate, procainamide HCl, sodium nitroprusside, sodium thiosulfate,
and verapamil HCl.
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(1) Is there a basis to conclude, for each FDA-approved product
that includes the nominated bulk drug substance, that: (a) An attribute
of the FDA-approved drug product makes it medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and (b) the drug product proposed to be compounded is intended to
address that attribute?
(2) Is there a basis to conclude that the drug product proposed to
be compounded must be produced from a bulk drug substance rather than
from an FDA-approved drug product?
The reason for question 1 is that unless an attribute of the FDA-
approved drug is medically unsuitable for certain patients, and a drug
product compounded using a bulk drug substance that is a component of
the approved drug is intended to address that attribute, there is no
clinical need to compound a drug product using that bulk drug
substance. Rather, such compounding would unnecessarily expose patients
to the risks associated with drug products that do not meet the
standards applicable to FDA-approved drug products for safety,
effectiveness, quality, and labeling and would undermine the drug
approval process. The reason for question 2 is that to place a bulk
drug substance on the 503B Bulks List, FDA must determine that there is
a clinical need for outsourcing facilities to compound a drug product
using the bulk drug substance rather than starting with an FDA-approved
drug product.
If the answer to both of these questions is ``yes,'' there may be a
clinical need for outsourcing facilities to compound using the bulk
drug substance, and we would evaluate the substance further, applying
the factors described below. If the answer to either of these questions
is ``no,'' we generally would not include the bulk drug substance on
the 503B Bulks List, because there would not be a basis to conclude
that there may be a clinical need to compound drug products using the
bulk drug substance instead of administering or compounding starting
with an approved drug product. FDA did not answer ``yes'' to both of
the threshold questions for the 19 bulk drug substances that are
components of approved drug products that we are addressing in this
notice. Accordingly, as explained further below, we did not proceed
further in our evaluation of these substances and are proposing not to
include them on the 503B Bulks List.
With respect to four bulk drug substances we are addressing in this
notice that are not components of FDA-approved drug products,\15\ we
are conducting a balancing test with four factors, considering each
factor in the context of the others and balancing them, on a substance-
by-substance basis, to determine whether the statutory ``clinical
need'' standard has been met. The balancing test includes the following
factors:
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\15\ Specifically: DPCP, glycolic acid, SADBE, and TCA.
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(a) The physical and chemical characterization of the substance;
(b) Any safety issues raised by the use of the substance in
compounding;
(c) The available evidence of effectiveness or lack of
effectiveness of a drug product compounded with the substance, if any
such evidence exists; and

[[Page 46129]]

(d) Current and historical use of the substance in compounded drug
products, including information about the medical condition(s) that the
substance has been used to treat and any references in peer-reviewed
medical literature.
The discussion below reflects FDA's consideration of these four
factors where they are applicable and describes how they were applied
to develop FDA's proposal to include four bulk drug substances on the
503B Bulks List.

C. Inclusion of a Bulk Drug Substance on the 503B Bulks List

In preparing its proposal to include four substances on the 503B
Bulks List, FDA considered whether the clinical need for the bulk drug
substance is limited. For example, we considered whether there are
safety risks associated with a drug product compounded using the bulk
drug substance at a higher concentration that are not associated with
compounding at a lower concentration. Similarly, we considered whether
evidence that a compounded drug product may be effective is available
for only certain routes of administration or dosage forms. As
appropriate, and as explained further below, the Agency tailored its
proposed entries on the 503B Bulks List to reflect its findings related
to clinical need for each of the four bulk substances proposed for
inclusion on the list. Specifically, the proposed entries would
authorize use of these four bulk drug substances to compound drug
products for topical dermal use only, and one of them--glycolic acid--
would be authorized to compound drug products with a concentration of
not more than 70 percent.
In addition, we solicit comment on whether to include a further
limitation relating to the use of these bulk drug substances to
compound drug products containing more than one bulk drug substance.
In developing its proposal, the Agency has considered information
regarding the use of each of the four bulk drug substances to compound
a drug product containing a single active ingredient and did not review
information related to the use of these bulk drug substances in
combination with one or more other active ingredients. For each bulk
drug substance, FDA's evaluation of clinical need included a review of
the physical and chemical characteristics of the substance, any safety
issues raised by the use of the substance in compounding, the available
evidence of effectiveness or lack of effectiveness of a drug product
compounded with the substance, and the current and historical use of
the substance in compounded drug products. On this basis we have
identified a clinical need to compound certain topical dermal products
containing the bulk drug substances. These assessments regarding
clinical need could be affected if the bulk drug substances are used in
compounded products containing multiple active ingredients. In
particular, the use of certain active ingredients in combination with
other active ingredients in a compounded product could pose a safety
risk or affect the product's effectiveness. FDA's evaluation did not
take into consideration all of the possible drug products that could be
made with other ingredients or evaluate the clinical need for the bulk
substance in every possible combination with other substances.
We solicit comment on two options for listing the four bulk drug
substances we are proposing to include on the 503B Bulks List; either:
(1) To allow compounding of drug products containing only the listed
bulk drug substance and no other active ingredients; or (2) to allow
compounding of drug products that contain the listed bulk drug
substance without limits on compounding a drug product that contains
other active ingredients. Under option 2, the compounded drug product
would need to meet all of the conditions of section 503B; e.g., if the
outsourcing facility compounded a drug product using two bulk drug
substances, both of the bulk drug substances would have to meet the
conditions in section 503B(a)(2).

III. Substances Considered and Proposed for Inclusion on the 503B Bulks
List

Because the substances in this section are not components of FDA-
approved drug products, we applied the balancing test described above.
The four bulk drug substances that have been evaluated and that FDA is
proposing to place on the 503B Bulks List are DPCP, glycolic acid,
SADBE, and TCA. The reasons for FDA's proposals are included below
(Refs. 3 to 6).\16\
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\16\ In addition to the nominations for the 503B Bulks List, the
Agency considered data and information from its earlier evaluations
regarding the use of these bulk drug substances for the list of bulk
drug substances that can be used in compounding under section 503A
of the FD&C Act (the 503A Evaluations). FDA also considered a report
provided by the University of Maryland Center of Excellence in
Regulatory Science and Innovation and conducted a search for
relevant scientific literature and safety information, focusing on
materials published or submitted to FDA since the 503A Evaluations.
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A. Diphenylcyclopropenone (DPCP)

DPCP was nominated as a bulk drug substance for the 503B Bulks List
to compound drug products for topical use at variable concentrations,
usually 2 percent, in the treatment of alopecia areata.\17\ The
nominated bulk drug substance is not a component of an FDA-approved
drug product. We evaluated DPCP for potential inclusion on the 503B
Bulks List under the clinical need standard in section 503B of the FD&C
Act, considering data and information regarding the physical and
chemical characterization of DPCP, safety issues raised by use of this
substance in compounding, available evidence of effectiveness or lack
of effectiveness, and historical and current use in compounding (Ref.
3).
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\17\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-1363.
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DPCP is well characterized but there are concerns about stability
and consistency in product quality. Although there are still gaps in
the evidence for DPCP's safety and effectiveness, including a lack of
long-term safety data, substantial human safety data have been
collected and clinicians worldwide have gained experience in the use of
DPCP to treat alopecia areata. DPCP has been used for several decades
to compound drug products for dermatologists to treat alopecia areata
and continues to be used for this purpose. The reported adverse effects
are related to DPCP's mechanism of therapeutic action as a sensitizer,
causing allergic contact dermatitis in treated patients. Alopecia
areata may not respond adequately to available treatments. DPCP can be
a potentially effective agent for patients who have failed FDA-approved
and other therapies for this condition.
On balance, the physical and chemical characterization, safety,
effectiveness, and historical and current use of DPCP weigh in favor of
including this substance on the 503B Bulks List. Accordingly, we
propose adding DPCP to the 503B Bulks List for topical dermal use only.
Nominators did not submit, and we have not identified, significant
evidence to support use in other routes of administration.

B. Glycolic Acid

Glycolic acid was nominated as a bulk drug substance for the 503B
Bulks List to compound drug products for topical use at concentrations
ranging from 0.08 to 70 percent for the treatment of hyperpigmentation
and photodamaged

[[Page 46130]]

skin.\18\ The nominated bulk drug substance is not a component of an
FDA-approved drug product. We evaluated glycolic acid for potential
inclusion on the 503B Bulks List under the clinical need standard in
section 503B, considering data and information regarding the physical
and chemical characterization of glycolic acid, safety issues raised by
use of this substance in compounding, available evidence of
effectiveness or lack of effectiveness, and historical and current use
in compounding (Ref. 4).
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\18\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0035 and FDA-2015-N-3469-0123. One of the nominations also
states that prescribers may want glycolic acid compounds in other
formulations to treat other conditions but does not identify the
conditions or formulations. It also refers to the use of glycolic
acid in combination with other ingredients and, in particular, to
compounding a formulation containing hydroquinone 6 percent and
tretinoin 0.1 percent. Information submitted with this nomination
relevant to compounding with glycolic acid for the treatment of
hyperpigmentation disorders and photodamaged skin was considered.
FDA's evaluation does not consider whether there is a clinical need
for outsourcing facilities to compound drug products using the bulk
drug substances hydroquinone or tretinoin, or other bulk drug
substances.
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Glycolic acid, also known as hydroxyacetic acid, is physically and
chemically well characterized. When used in high concentrations,
glycolic acid causes local effects that are typical of a strong acid,
such as dermal and eye irritation. Reported adverse reactions were
generally limited in duration and readily manageable. There is no
information available on long-term outcomes. The available data on
short-term outcomes do not raise major safety concerns associated with
the topical use of glycolic acid.
Data from controlled clinical trials have shown consistently
positive results in the treatment of epidermal melasma or other forms
of hyperpigmentation. The available evidence suggests that there is a
role for glycolic acid in the treatment of melasma, typically as a
second line treatment. There is also some evidence indicating that
glycolic acid may be effective for the mitigation of manifestations of
photodamaged skin. Glycolic acid has been used for several decades to
compound drug products for dermatologists and continues to be used for
this purpose. Conclusions regarding each of these factors are for use
at concentrations up to 70 percent; data and evidence regarding use of
higher concentrations are very limited.
On balance, the physical and chemical characterization, safety,
effectiveness, and historical and current use of glycolic acid weigh in
favor of including this substance on the 503B Bulks List at
concentrations up to 70 percent. Accordingly, we propose adding
glycolic acid to the 503B Bulks List for topical dermal use in
concentrations up to 70 percent. Nominators did not submit, and we have
not identified, significant evidence to support use in other routes of
administration or higher concentrations.

C. Squaric Acid Dibutyl Ester (SADBE)

SADBE was nominated as a bulk drug substance for the 503B Bulks
List to compound drug products for topical use at variable
concentrations, ranging from 2 percent initially to 0.0001 percent to
0.001 percent for maintenance, for the treatment of alopecia areata and
warts.\19\ The nominated bulk drug substance is not a component of an
FDA-approved drug product. We evaluated SADBE for potential inclusion
on the 503B Bulks List under the clinical need standard in section
503B, considering data and information regarding the physical and
chemical characterization of SADBE, safety issues raised by use of this
substance in compounding, available evidence of effectiveness or lack
of effectiveness, and historical and current use in compounding (Ref.
5).
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\19\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-1363.
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SADBE is well-characterized but there are concerns about stability
and consistency in product quality. There is a lack of adequate
nonclinical data, long-term safety data, and safety information about
use in specific populations such as pregnant and lactating women.
Despite these data gaps, considerable human safety data have
accumulated over the past 40 years from its use in compounding drug
products for dermatologists to treat alopecia areata and resistant non-
genital warts and from reports for its use internationally. The
reported adverse effects are related to SADBE's mechanism of
therapeutic action as a sensitizer causing allergic contact dermatitis
in treated patients.
In addition, both alopecia areata and warts may not respond
adequately to available treatments. SADBE can be a potentially
effective agent for patients who have failed FDA-approved and other
therapies for these conditions. We recognize that treatment with SADBE
requires initial sensitization and typical protocols involve a SADBE
concentration of 2 percent, but lower concentrations may be used in
other patients.
On balance, the physical and chemical characterization, safety,
effectiveness, and historical and current use of SADBE weigh in favor
of including this substance on the 503B Bulks List. Accordingly, we
propose adding SADBE to the 503B Bulks List for topical dermal use
only. Nominators did not submit, and we have not identified,
significant evidence to support use in other routes of administration.

D. Trichloroacetic Acid (TCA)

TCA was nominated as a bulk drug substance for the 503B Bulks List
to compound drug products for topical use at concentrations ranging
from 6 percent to 20 percent as a chemical skin peeling agent for the
treatment of acne and melasma.\20\ The nominated bulk drug substance is
not a component of an FDA-approved drug product. We evaluated TCA for
potential inclusion on the 503B Bulks List under the clinical need
standard in section 503B, considering data and information regarding
the physical and chemical characterization of TCA, safety issues raised
by use of this substance in compounding, available evidence of
effectiveness or lack of effectiveness, and historical and current use
in compounding (Ref. 6).
---------------------------------------------------------------------------

\20\ See Docket No. FDA-2018-D-1067, document No. FDA-2018-D-
1067-0005.
---------------------------------------------------------------------------

TCA is well characterized in its physical and chemical properties.
Nonclinical evidence suggests that topical use of TCA does not raise
serious safety issues for humans. Although there have been no clinical
trials specifically designed to address the safety of TCA, safety
assessments were among the study procedures in several clinical trials
and reports of adverse reactions have included burning, pain, erythema,
hyperpigmentation, and hypopigmentation. More serious adverse reactions
reported were ulcerations, scarring, and pustules. Adverse events were
reported more frequently with higher concentrations. Several studies
indicate that TCA may be effective as a chemical peel for the treatment
of acne (Ref. 7) and melasma (Ref. 8), but there is a lack of evidence
comparing TCA to FDA-approved drug products for those uses. TCA has
been used, in the United States and worldwide, for dermatologic
conditions for over 40 years and for at least 20 years in pharmacy
compounding.
On balance, the physical and chemical characterization, safety,
effectiveness, and historical and current use of TCA weigh in favor of
including this substance on the 503B Bulks List. Accordingly, we
propose adding TCA to the 503B Bulks List for topical dermal use only.
Nominators did not submit,

[[Page 46131]]

and we have not identified, significant evidence to support use in
other routes of administration.

IV. Substances Evaluated and Not Proposed for Inclusion on the 503B
Bulks List

Because the substances in this section are components of FDA-
approved drug products, we considered one or both of the following
questions: (1) Is there is a basis to conclude that an attribute of
each FDA-approved drug product containing the bulk drug substance makes
each one medically unsuitable to treat certain patients for a condition
that FDA has identified for evaluation, and the drug product proposed
to be compounded is intended to address that attribute and (2) is there
a basis to conclude that the drug product proposed to be compounded
must be compounded using a bulk drug substance.
The 19 bulk drug substances that have been evaluated and that FDA
is proposing not to place on the list are as follows: Diazepam,
dobutamine HCl, dopamine HCl, edetate calcium disodium, folic acid,
glycopyrrolate, hydroxyzine HCl, ketorolac tromethamine, labetalol HCl,
mannitol, metoclopramide HCl, moxifloxacin HCl, nalbuphine HCl,
polidocanol, potassium acetate, procainamide HCl, sodium nitroprusside,
sodium thiosulfate, and verapamil HCl. The reasons for FDA's proposals
are included below.

A. Diazepam

Diazepam has been nominated for inclusion on the 503B Bulks List to
compound drug products that are used for alcohol withdrawal syndrome,
anxiety, and as premedication before surgery, endoscopic procedures,
and cardioversion, among other conditions.\21\ The proposed route of
administration is intravenous or intramuscular, the proposed dosage
form is a preserved solution, and the proposed concentration is 5
milligrams per milliliter (mg/mL). The nominators propose to compound a
preserved solution. However, they fail to acknowledge that there is an
FDA-approved formulation of diazepam that is preserved and do not
explain why that formulation would be medically unsuitable for certain
patients. The nominations state that diazepam might also be used to
compound other drug products but do not identify those products. The
nominated bulk drug substance is a component of FDA-approved drug
products (e.g., ANDA 072079). FDA-approved diazepam is available as a
preserved 10 mg/2 mL (5 mg/mL) and 50 mg/10 mL (5 mg/mL) solution for
intravenous or intramuscular administration.^{22 23 24}
---------------------------------------------------------------------------

\21\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\22\ See, e.g., ANDA 072079 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/4e800d0d-2181-49b1-a2c8-4c6c49edd83a/4e800d0d-2181-49b1-a2c8-4c6c49edd83a.xml.
\23\Per the label for ANDA 072079, each mL contains 5 mg
diazepam, 40 percent propylene glycol, 10 percent alcohol, 5 percent
sodium benzoate and benzoic acid added as buffers, and 1.5 percent
benzyl alcohol added as a preservative.
\24\ Diazepam is also approved as an oral tablet, oral
concentrate, oral solution, and rectal gel.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved preserved 5 mg/mL solution products is medically unsuitable
for certain patients or identify an attribute of the approved drug
products that the proposed compounded drug product (also a preserved 5
mg/mL solution) is intended to address. FDA finds no basis to conclude
that an attribute of the FDA-approved products makes them medically
unsuitable to treat certain patients for a condition that FDA has
identified for evaluation and that a proposed compounded product is
intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using diazepam and
approved drug products containing diazepam, there is nothing for FDA to
evaluate under question 2.

B. Dobutamine HCl

Dobutamine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products for ionotropic support in the short-term
treatment of adults with cardiac decompensation due to depressed
contractility resulting either from organic heart disease or from
cardiac surgical procedures.\25\ The proposed route of administration
is intravenous (IV), the proposed dosage form is an injection, and the
proposed concentrations are 1 mg/mL, 2 mg/mL, and 4 mg/mL in various
volumes of IV infusions (large volume parenterals). The nominated bulk
drug substance is a component of FDA-approved drug products (e.g., ANDA
074086 and NDA 020201). FDA has approved dobutamine drug products as EQ
50 mg base/100 mL (EQ 0.5 mg base/mL), EQ 100 mg base/100 mL (EQ 1 mg
base/mL), EQ 200 mg base/100 mL (EQ 2 mg base/mL), and EQ 400 mg base/
100 mL (EQ 4 mg base/mL) ready-to-administer forms (e.g., no further
dilutions needed) for intravenous administration and as an EQ 12.5mg
base/mL single-dose vial that must be diluted prior to
infusion.^{26 27}
---------------------------------------------------------------------------

\25\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0032.
\26\ See, e.g., ANDA 074086 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/7b9ea626-7073-2e77-e053-2a91aa0a9215/7b9ea626-7073-2e77-e053-2a91aa0a9215.xml.
\27\ See, e.g., NDA 020201 (ready-to-use version) labeling
available as the date of this notice at https://www.accessdata.fda.gov/spl/data/d1873a74-56e6-4a01-8e4d-875789e5e344/d1873a74-56e6-4a01-8e4d-875789e5e344.xml.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nomination does not explain why an attribute of each of the
FDA-approved EQ 12.5 mg base/mL solution for dilution for intravenous
administration products and each of the approved EQ 1 mg base/mL, EQ 2
mg base/mL, and EQ 4 mg base/mL ready-to-administer forms is medically
unsuitable for certain patients, or identify an attribute of the
approved drug products that the proposed compounded drug products are
intended to address. FDA finds no basis to conclude that an attribute
of the FDA-approved products makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nomination does not identify specific differences
between drug products that would be compounded using dobutamine HCl and
approved drug products containing dobutamine HCl, there is nothing for
FDA to evaluate under question 2.

C. Dopamine HCl

Dopamine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat cardiogenic shock, congestive
heart failure, decreased cardiac output, and renal failure, among other
conditions.\28\ The proposed route of administration is intravenous,
the proposed dosage form is a preservative-free solution, and the
proposed concentration is 80 mg/mL. The nominators proposed to compound

[[Page 46132]]

a preservative-free solution. However, they failed to acknowledge that
there is a preservative-free formulation of dopamine HCl available that
is FDA-approved or explain why that formulation would be medically
unsuitable for certain patients. The nominations state that dopamine
HCl might also be used to compound other drug products but do not
identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDA 207707). FDA-
approved dopamine HCl is available as a single-dose, preservative-free
40 mg/mL or 80 mg/mL solution for intravenous
administration.^{29 30}
---------------------------------------------------------------------------

\28\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\29\ See, e.g., ANDA 207707 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/d2927591-5fe5-4704-9091-82ab08bb792b/d2927591-5fe5-4704-9091-82ab08bb792b.xml.
\30\ According to the label for ANDA 207707, each mL contains
metabisulfite 9 mg added as an antioxidant, citric acid, anhydrous
10 mg, sodium citrate, and dihydrate 5 mg added as a buffer. May
contain additional citric acid and/or sodium citrate for pH
adjustment.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved preservative-free 80 mg/mL solution products is medically
unsuitable for certain patients or identify an attribute of the
approved drug products that the proposed compounded drug products are
intended to address. FDA finds no basis to conclude that an attribute
of the FDA-approved products makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using dopamine HCl and
approved drug products containing dopamine HCl, there is nothing for
FDA to evaluate under question 2.

D. Edetate Calcium Disodium

Edetate calcium disodium dihydrate has been nominated for inclusion
on the 503B Bulks List to compound drug products that treat
cardiovascular disease, diabetes, hypercholesterolemia, arthritis,
cancer, and chronic renal failure, among other conditions.\31\ The
proposed route of administration is slow intravenous, the proposed
dosage form is a preservative-free injection, and the proposed
concentration is 200 mg/mL. The nominators proposed to compound a
preservative-free solution. However, they failed to acknowledge that
there is a preservative-free formulation of edetate calcium disodium
available that is FDA-approved or explain why that formulation would be
medically unsuitable for certain patients. The nominated bulk drug
substance is a component of an FDA-approved drug product (NDA
008922).\32\ FDA-approved edetate calcium disodium is available as a
preservative-free 200 mg/mL injection for intravenous and intramuscular
administration.^{33 34}
---------------------------------------------------------------------------

\31\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2302, FDA-2013-N-1524-2301, FDA-2013-N-1525-0225, FDA-2013-N-
1524-2305, and FDA-2013-N-1524-2297.
\32\ In the nominations, the name of the nominated substance is
listed as ``edetate calcium disodium dihydrate.'' Since the
nominated dosage form is an injection, ``edetate calcium disodium''
and ``edetate calcium disodium dihydrate'' result in the same entity
when in solution.
\33\ See NDA 008922 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/143830d7-46a5-49a3-b8b2-457a59533008/143830d7-46a5-49a3-b8b2-457a59533008.xml.
\34\ Per the label for NDA 008922, edetate calcium disodium
dihydrate is available in a preservative-free ampule. Each 5 ml
ampule contains 1,000 mg of edetate calcium disodium (equivalent to
200 mg/ml) in water for injection.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of the FDA-approved
preservative-free 200 mg/mL injection is medically unsuitable for
certain patients or identify an attribute of the approved drug product
that the proposed compounded drug product is intended to address. FDA
finds no basis to conclude that an attribute of the FDA-approved
product makes it medically unsuitable to treat certain patients for a
condition that FDA has identified for evaluation and that a proposed
compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using edetate calcium
disodium and the approved drug product containing edetate calcium
disodium, there is nothing for FDA to evaluate under question 2.

E. Folic Acid

Folic acid has been nominated for inclusion on the 503B Bulks List
to compound drug products that treat megaloblastic and macrocytic
anemias.\35\ The proposed routes of administration are intravenous,
intramuscular, and subcutaneous, the proposed dosage forms are
injection solutions, and the proposed concentration is 5 mg/mL. The
nomination states that folic acid might also be used to compound other
drug products but does not identify those products. The nominated bulk
drug substance is a component of FDA-approved drug products (e.g., ANDA
089202). FDA-approved folic acid is available as a 50 mg/10 mL (5 mg/
mL) solution for intravenous, intramuscular, and subcutaneous
administration.^{36 37}
---------------------------------------------------------------------------

\35\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
\36\ See, e.g., ANDA 089202 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26.xml.
\37\ Folic acid is also approved in as a single ingredient as an
oral tablet.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nomination does not explain why an attribute of each of the
FDA-approved 5 mg/mL solution products for intravenous, intramuscular,
and subcutaneous administration is medically unsuitable for certain
patients or identify an attribute of the approved drug products that
the proposed compounded drug product is intended to address. FDA finds
no basis to conclude that an attribute of the FDA-approved products
makes them medically unsuitable to treat certain patients for a
condition that FDA has identified for evaluation and that a proposed
compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nomination does not identify specific differences
between drug products that would be compounded using folic acid and
approved drug products containing folic acid, there is nothing for FDA
to evaluate under question 2.

F. Glycopyrrolate ³⁸
---------------------------------------------------------------------------

\38\ One nominator nominated ``Glycopyrrolate, USP'' and the
other nominator nominated ``Glycopyrrolate Bromide.'' The UNII code
for both nominations (V92SO9WP2I) corresponds to the chemical
formula for glycopyrrolate bromide (C19H28NO3.Br). The official FDA
and USP nonproprietary name for glycopyrrolate bromide is
``glycopyrrolate.'' Therefore, if finalized, glycopyrrolate (not
glycopyrrolate bromide) will not be added to the 503B Bulks List.
---------------------------------------------------------------------------

Glycopyrrolate bromide has been nominated for inclusion on the 503B

[[Page 46133]]

Bulks List to compound drug products that treat cardiac dysrhythmia,
surgically induced or drug-induced vagal reflex, and peptic ulcer
disease, among other conditions.\39\ The proposed route of
administration is intravenous, the proposed dosage forms are both a
preservative-free and a preserved solution, and the proposed
concentration is 0.2 mg/mL. The nominators proposed to compound a
preservative-free solution. However, they failed to acknowledge that
there is a preservative-free formulation of glycopyrrolate available
that is FDA-approved or explain why that formulation would be medically
unsuitable for certain patients. The nominations state that
glycopyrrolate might also be used to compound other drug products but
do not identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., NDA 210997). FDA-
approved glycopyrrolate is available as a 0.2 mg/mL in 1 mL or 2 mL
preserved and preservative-free, single-dose vials for intramuscular or
intravenous administration.\40\ \41\ \42\
---------------------------------------------------------------------------

\39\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\40\ See, e.g., NDA 210997 and ANDA 208973 labeling available as
of the date of this notice at https://www.accessdata.fda.gov/spl/data/6a379327-0f29-44a4-ba4f-54cb9379f854/6a379327-0f29-44a4-ba4f-54cb9379f854.xml and https://www.accessdata.fda.gov/spl/data/fdebc248-87d3-4afd-a5ed-592fcaddab1c/fdebc248-87d3-4afd-a5ed-592fcaddab1c.xml.
\41\ Per the label for NDA 210997, glycopyrrolate is available
in a preservative-free, single-dose vial. Per the label for ANDA
208973, glycopyrrolate is available in preserved, single-dose and
multiple-dose vials.
\42\ Glycopyrrolate is also approved oral tablet, oral solution,
and for inhalation as a single ingredient.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of the FDA-approved
0.2 mg/mL preservative-free and the FDA-approved preserved solutions
for intramuscular or intravenous administration are medically
unsuitable for certain patients or identify an attribute of the
approved drug products that the proposed compounded drug products are
intended to address. FDA finds no basis to conclude that an attribute
of the FDA-approved products makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using glycopyrrolate and
approved drug products containing glycopyrrolate, there is nothing for
FDA to evaluate under question 2.

G. Hydroxyzine HCl

Hydroxyzine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat alcohol withdrawal syndrome,
analgesia in labor, pre- and postpartum reduction of narcotic use, and
relief of anxiety, among other conditions.\43\ The proposed route of
administration is intramuscular, the proposed dosage form is a
preserved solution, and the proposed concentration is 50 mg/mL. The
nominators proposed to compound a preserved solution. However, they
failed to acknowledge that there is a preserved formulation of
hydroxyzine HCl available that is FDA-approved or explain why that
formulation would be medically unsuitable for certain patients. The
nominations state that hydroxyzine HCl might also be used to compound
other drug products but do not identify those products. The nominated
bulk drug substance is a component of FDA-approved drug products (e.g.,
ANDA 087408). FDA-approved hydroxyzine HCl is available as a preserved
50 mg/mL solution for intramuscular administration.^{44 45 46}
---------------------------------------------------------------------------

\43\ See Docket No FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\44\ See, e.g., ANDA 087408 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/4d9d37b0-7fa0-47e1-8414-c2b86f83fe73/4d9d37b0-7fa0-47e1-8414-c2b86f83fe73.xml.
\45\ Per the label for ANDA 087408, each mL contains hydroxyzine
HCl 25 mg or 50 mg, benzyl alcohol 0.9 percent, and water for
injection q.s. pH is adjusted with sodium hydroxide and/or
hydrochloric acid.
\46\ Hydroxyzine HCl is also approved as an oral tablet and as
an oral syrup.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of the FDA-approved
preserved 50 mg/mL hydroxyzine HCl solution for intramuscular
administration is medically unsuitable for certain patients or identify
an attribute of the approved drug products that the proposed compounded
drug product is intended to address. FDA finds no basis to conclude
that an attribute of the FDA-approved products makes them medically
unsuitable to treat certain patients for a condition that FDA has
identified for evaluation and that a proposed compounded product is
intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using hydroxyzine HCl
and the approved drug product containing hydroxyzine HCl, there is
nothing for FDA to evaluate under question 2.

H. Ketorolac Tromethamine

Ketorolac tromethamine has been nominated for inclusion on the 503B
Bulks List to compound drug products for seasonal allergic
conjunctivitis, short-term pain, pain in the eye, and extraction of
cataract.\47\ The proposed route of administration is intravenous and
intramuscular, the proposed dosage form is a preserved solution, and
the proposed concentration is 30 mg/mL. The nominators proposed to
compound a preserved solution. However, they failed to acknowledge that
there is a preserved formulation of ketorolac tromethamine available
that is FDA-approved or explain why that formulation would be medically
unsuitable for certain patients. The nominations state that ketorolac
tromethamine might also be used to compound other drug products but do
not identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDA 209900). FDA-
approved ketorolac tromethamine is available as a 15 mg/mL or 30 mg/mL
solution for intravenous and intramuscular
administration.^{48 49 50}
---------------------------------------------------------------------------

\47\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\48\ See, e.g., ANDA 209900 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/f7e12067-6ba2-48d8-abac-7b4d9a6822f3/f7e12067-6ba2-48d8-abac-7b4d9a6822f3.xml.
\49\ According to the label for ANDA 209900, the solution
contains 10 percent (w/v) alcohol USP, and 6.68 mg, 4.35 mg, and
8.70 mg, respectively, of sodium chloride in sterile water. The pH
range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or
hydrochloric acid.
\50\ Ketorolac tromethamine is also approved as a single
ingredient in an ophthalmic drop, a nasal spray, and an oral tablet.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved preserved 30 mg/mL solution products is medically unsuitable
for

[[Page 46134]]

certain patients or identify an attribute of the approved drug products
that the proposed compounded drug product is intended to address. FDA
finds no basis to conclude that an attribute of the FDA-approved
products makes them medically unsuitable to treat certain patients for
a condition that FDA has identified for evaluation and that a proposed
compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using ketorolac
tromethamine and approved drug products containing ketorolac
tromethamine, there is nothing for FDA to evaluate under question 2.

I. Labetalol HCl

Labetalol HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that control blood pressure in severe
hypertension.\51\ The proposed route of administration is intravenous,
the proposed dosage form is an injection solution, and the proposed
concentration is 5 mg/mL. The nomination states that labetalol HCl
might also be used to compound other drug products but do not identify
those products. The nominated bulk drug substance is a component of
FDA-approved drug products (e.g., ANDA 075240). FDA-approved labetalol
hydrochloride is available as a 100 mg/20 mL (5 mg/mL) and 200 mg/40 mL
(5 mg/mL) solution for dilution for intravenous
administration.^{52 53}
---------------------------------------------------------------------------

\51\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
\52\ See, e.g., ANDA 075240 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/d92ec06a-794d-4951-8173-b7fa7c9a66bd/d92ec06a-794d-4951-8173-b7fa7c9a66bd.xml.
\53\ Labetalol hydrochloride is also approved as an oral tablet.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved 5 mg/mL solution for dilution products is medically unsuitable
for certain patients or identify an attribute of the approved drug
products that the proposed compounded drug product is intended to
address. FDA finds no basis to conclude that an attribute of the FDA-
approved products makes them medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using labetalol HCl and
approved drug products containing labetalol HCl, there is nothing for
FDA to evaluate under question 2.

J. Mannitol

Mannitol has been nominated for inclusion on the 503B Bulks List to
compound drug products for treatment of acute renal failure, inhalation
bronchial challenge testing, and irrigation of the urinary bladder,
among other conditions.\54\ The proposed route of administration is
intravenous, the proposed dosage form is a preservative-free solution,
and the proposed concentration is 25 percent. The nominators proposed
to compound a preservative-free solution. However, they failed to
acknowledge that there is a preservative-free formulation of mannitol
available that is FDA-approved or explain why that formulation would be
medically unsuitable for certain patients. The nominations state that
mannitol might also be used to compound other drug products but do not
identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., NDA 016269). FDA-
approved mannitol is available as a preservative-free solution in water
for injection in various concentrations, including a 25 percent
concentration in a flip-top vial for administration by intravenous
infusion only.^{55 56 57}
---------------------------------------------------------------------------

\54\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\55\ See, e.g., NDA 016269 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/785b3a4e-c632-48c6-9fc9-b1b4e7d5d885/785b3a4e-c632-48c6-9fc9-b1b4e7d5d885.xml.
\56\ Per the label for NDA 016269, the solutions contain no
bacteriostat, antimicrobial agent or added buffer (except for pH
adjustment) and each is intended only as a single-dose injection.
\57\ Mannitol is also approved as a single ingredient as a
solution for irrigation and as a powder for inhalation.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved 25 percent preservative-free solution products is medically
unsuitable for certain patients or identify an attribute of the
approved drug product that the proposed compounded drug product is
intended to address. FDA finds no basis to conclude that an attribute
of the FDA-approved products makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using mannitol and
approved drug products containing mannitol, there is nothing for FDA to
evaluate under question 2.

K. Metoclopramide HCl

Metoclopramide HCl has been nominated for inclusion on the 503B
Bulks List to compound drug products that treat chemotherapy-induced
nausea and vomiting, diabetic gastroparesis, gastroesophageal reflux
disease, and postoperative nausea and vomiting, among other
conditions.\58\ The proposed routes of administration are intravenous
and intramuscular, the proposed dosage forms are both a preservative-
free and a preserved suspension and the proposed concentration is 5 mg/
mL. The nominators proposed to compound both preservative-free and
preserved suspensions. However, they failed to acknowledge that there
is a preservative-free formulation of metoclopramide HCl available that
is FDA-approved or explain why that formulation would be medically
unsuitable for certain patients. The nominations state that
metoclopramide HCl might also be used to compound other drug products
but do not identify those products. The nominated bulk drug substance
is a component of FDA-approved drug products (e.g., ANDA 073118). FDA-
approved metoclopramide HCl is available as a preservative-free 10 mg/2
mL (5 mg/mL) solution for intravenous or intramuscular
administration.^{59 60 61}
---------------------------------------------------------------------------

\58\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\59\ See, e.g., ANDA 073118 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/93db98f7-b687-432f-810a-5c4da6d874ab/93db98f7-b687-432f-810a-5c4da6d874ab.xml.
\60\ Per the label for ANDA 073118, the solution is
preservative-free and is intended for intravenous or intramuscular
administration.
\61\ Metoclopramide is also approved as an oral solution and as
a tablet.

---------------------------------------------------------------------------

[[Page 46135]]

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved preservative-free 10 mg/2 mL (5 mg/mL) solution products for
intravenous or intramuscular administration is medically unsuitable for
certain patients or identify an attribute of the approved drug products
that the proposed compounded drug product is intended to address. In
particular, the nominations do not identify any data or information
indicating that there are some patients who need a preserved product
rather than the approved preservative-free products. In addition, the
nominations do not identify any data or information indicating that
there are some patients who need a suspension rather than a solution
for intravenous and intramuscular administration. FDA finds no basis to
conclude that an attribute of the FDA-approved products makes them
medically unsuitable to treat certain patients for a condition that FDA
has identified for evaluation and that a proposed compounded product is
intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations have not identified a population for whom
the approved products would be medically unsuitable, FDA has not
evaluated whether the proposed preserved drug products containing
metoclopramide HCl must be compounded from bulk drug substances rather
than using the approved drug product.

L. Moxifloxacin HCl

Moxifloxacin HCl has been nominated for inclusion on the 503B Bulks
List in combination with other bulk drug substances, including
triamcinolone acetonide and vancomycin HCl, as a topical ophthalmic and
as an intravitreal injection in patients who undergo cataract
surgery.\62\ According to the nomination, the compounded products are
as follows:
---------------------------------------------------------------------------

\62\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0004.
---------------------------------------------------------------------------

(1) Moxifloxacin hydrochloride (0.2ml-0.3ml; 1mg/ml in combination
with other compounds);
(2) Moxifloxacin hydrochloride in a formulation with triamcinolone
``acetonidenide'' \63\ (0.1 mg/mL to 50.0 mg/ml 165 mcg injection); and
---------------------------------------------------------------------------

\63\ We assume this refers to triamcinolone acetonide.
---------------------------------------------------------------------------

(3) Moxifloxacin hydrochloride in a formulation with triamcinolone
``aceton[id]e'' and vancomycin hydrochloride (0.1 mg/mL to 50.0 mg/ml
165 mcg injection).\64\
---------------------------------------------------------------------------

\64\ The nomination did not propose to compound drug products
using moxifloxacin as a single active ingredient, and FDA's
evaluation does not consider such uses.
---------------------------------------------------------------------------

The nominated bulk drug substance is a component of FDA-approved
drug products. FDA-approved moxifloxacin HCl is available as an EQ 0.5
percent base ophthalmic solution under two separate NDAs (Vigamox, NDA
021598; Moxexa, NDA 022428) and various ANDAs.\65\ In addition, FDA-
approved moxifloxacin HCl is available as an EQ 400 mg base/250 mL (EQ
1.6 mg base/mL) solution for intravenous administration (e.g. ANDA
205833).^{66 67}
---------------------------------------------------------------------------

\65\ See, NDA 021598 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/f9febc6f-db6d-44e8-9730-f7c1a2354d71/f9febc6f-db6d-44e8-9730-f7c1a2354d71.xml.
\66\ See, ANDA 205833 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/840eeb54-1874-4831-8c55-38efa1099c69/840eeb54-1874-4831-8c55-38efa1099c69.xml.
\67\ Moxifloxacin is also available as a single ingredient as an
oral tablet.
---------------------------------------------------------------------------

The nomination proposes to combine moxifloxacin HCl with two other
bulk drug substances, both of which are components of FDA-approved
products. Triamcinolone acetonide (Triesence, NDA 022048) is available
as a 40 mg/mL suspension for intravitreal
administration.^{68 69} Vancomycin HCl is available as an
intravenous solution and as a lyophilized powder for preparing
intravenous infusions in various strengths (e.g. ANDA
205694).^{70 71}
---------------------------------------------------------------------------

\68\ See, NDA 022048 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/5561cb6d-1ddb-4b3a-a131-efc210f35e6b/5561cb6d-1ddb-4b3a-a131-efc210f35e6b.xml.
\69\ Triamcinolone acetonide is also available as a single
ingredient in topical, injectable, nasal, and dental products.
\70\ ANDA 205694 is available as a preservative free lyophilized
powder, for preparing intravenous infusions, in vials each
containing vancomycin HCl EQ 500 mg base/vial and EQ 1 gram base/
vial. See, ANDA 205694 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/028f4949-396d-d15b-8fc3-2bf69daf67f2/028f4949-396d-d15b-8fc3-2bf69daf67f2.xml.
\71\ Vancomycin HCl is also available as a single ingredient as
an oral capsule and powder for oral solution.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
a. Moxifloxacin HCl in Combination With ``other compounds''
The proposal to combine moxifloxacin HCl with ``other compounds''
will not be considered further. The nomination does not identify the
``other compounds'' \72\ that the nominator proposes to combine with
moxifloxacin HCl in a compounded drug product, or other attributes of
those products (e.g., proposed dosage strength(s)). Nor does the
nomination identify any attribute of the FDA-approved drug products
that makes them medically unsuitable to treat certain patients for a
condition and that the proposed compounded drugs are intended to
address.
---------------------------------------------------------------------------

\72\ We understand the term ``other compounds'' to refer to
other bulk drug substances that would be contained in the compounded
drug.
---------------------------------------------------------------------------

b. Moxifloxacin HCl in Combination With Triamcinolone Acetonide for
Injection
The nomination states that the FDA-approved products are drops, and
that a compounded intravitreal product is needed for patients
recovering from cataract surgery. Specifically, the nomination states
that ``intravitreal placement of the compounded drug'' during surgery,
relative to the post-surgical installation of ``a number of'' topical
medications, ``avoids confusion of post-operative treatment to patients
who undergo cataract surgery.'' The nomination states, further, that
``the length of a typical postoperative drop regimen is further
complicated by the different daily dosing regiments of various
medications, which can cause confusion for patients because age [sic]
and physical handicaps. '' Thus, the proposed clinical need for
compounding from bulk moxifloxacin HCl and triamcinolone acetonide is
to prepare an intraoperative injection for patients who would have
difficulty with topical administration of the approved topical products
post-operatively.
The nomination does not provide supporting data or information for
its statement about the medical unsuitability of FDA-approved topical
products to treat patients post-operatively.\73\ We take no position at
this time on whether any such unsuitability exists. To the extent there
may be patients for whom the FDA-approved topical dosage forms are
medically unsuitable post-operatively, the nomination does not
acknowledge that there are FDA-approved products containing
moxifloxacin HCl and triamcinolone acetonide that are available as
intravitreal injections or could be used to prepare such injections for
patients undergoing cataract surgery.

[[Page 46136]]

Nor does the nomination explain how the drugs it proposes to compound
from bulk drug substances are intended to address an attribute of these
approved drugs.
---------------------------------------------------------------------------

\73\ For example, the nomination did not provide supporting data
or information to demonstrate a medical unsuitability for certain
patients, or to identify which patients might find the topical
products medically unsuitable and under what conditions.
---------------------------------------------------------------------------

Specifically, the nomination does not acknowledge that there is an
FDA-approved triamcinolone acetonide product for intravitreal injection
(Triescence, NDA 022048), nor does it identify an attribute of this
approved product that would make it medically unsuitable for the
proposed use. Nor does the nomination identify an attribute of the FDA-
approved drug products that contain moxifloxacin HCl (e.g., Vigamox NDA
021598 or moxifloxacin HCl solution for intravenous administration
(e.g., ANDA 205833)) that would make them medically unsuitable for the
proposed use. For example, if there are patients for whom products for
topical administration would be medically unsuitable, the nomination
does not explain or provide support for the view that the approved
products, or drug products prepared using the approved products, could
not be injected sequentially during cataract surgery to address the
same clinical condition.^{74 75 76} Further, the nomination
does not explain or provide support for the view that compounding a
drug product for injection that contains both moxifloxacin HCl and
triamcinolone acetonide, in a single solution, is intended to change
some attribute of the approved drugs that makes the approved drugs
medically unsuitable to treat certain patients who have cataract
surgery. In general, the combination of two or more active ingredients
to allow for the administration of fewer drug products is not likely to
constitute clinical need, and we are not aware of a basis to conclude
that there is clinical need to make the combination proposed by this
nomination.
---------------------------------------------------------------------------

\74\ In making this observation, we do not suggest that the
approved drug products, or products prepared from them, are approved
for the use proposed by the nomination. Here we are asking a
limited, threshold question to determine whether there might be
clinical need for a compounded drug product, by asking what
attributes of the approved drug the proposed compounded drug would
change, and why. Asking this question helps ensure that if a bulk
drug substance is included on the 503B Bulks List, it is to compound
drugs that include a needed change to an approved drug product
rather than to produce drugs without such a change. Because our
answer to question (1) is ``no'', we do not evaluate the available
evidence of effectiveness or lack of effectiveness of a drug product
compounded with moxifloxacin HCl and triamcinolone acetonide.
Vigamox and moxifloxacin HCl for injection have not been
demonstrated to be safe and effective as an intravitreal injection
to treat any condition or disease. FDA-approved Triesence is an
intravitreal injection product, approved for a different use than
what is proposed in the nomination.
\75\ In 2020, based on FDA's review of safety data and
information, the Agency approved a supplemental application to
remove a warning from the Vigamox labeling against intraocular
injection.
\76\ Typically, endotoxin testing is not required for topically
administered ophthalmic products (e.g., Vigamox). See USP General
Chapter <771> Ophthalmic Products-Quality Tests. Under CGMP
requirements for outsourcing facilities each shipment of each lot of
components must be tested to verify identity and evaluated for
conformity with appropriate specifications before use (see 21 CFR
211.84). Appropriate specifications for components in products
intended for intravitreal use include bacterial endotoxin level.
---------------------------------------------------------------------------

Accordingly, with respect to the moxifloxacin HCl with
triamcinolone acetonide for intraocular injection products proposed to
be compounded, FDA finds no basis to conclude that an attribute of the
FDA-approved products make them medically unsuitable to treat certain
patients who undergo cataract surgery and that the proposed compounded
drugs are intended to address.
c. Moxifloxacin HCl With Triamcinolone Acetonide and Vancomycin HCl for
Injection
The nomination states that there is a clinical need for the
proposed compounded drug products to prepare an intraoperative
injection for patients who would have difficulty with topical
administration of the approved products post-operatively. As discussed
above, the nomination does not identify an attribute of the FDA-
approved products containing moxifloxacin HCl and triamcinolone
acetonide that would make them medically unsuitable for the proposed
use. The nomination also does not acknowledge the availability of FDA-
approved vancomycin HCl for injection products (e.g., ANDA 62663), or
identify an attribute of the FDA-approved products that would make them
medically unsuitable for the proposed use. For example, if there are
patients for whom products for topical administration would be
medically unsuitable, the nomination does not explain or provide
support for the view that the approved products, or drug products
prepared using the approved products, could not be injected
sequentially during cataract surgery.\77\ Further, the nomination does
not explain or provide support for the view that compounding a drug
product for injection that contains moxifloxacin HCl, triamcinolone
acetonide, and vancomycin HCl, in a single solution, is intended to
address any attribute of the approved drugs that make them medically
unsuitable to treat certain patients who have cataract surgery.\78\
---------------------------------------------------------------------------

\77\ In noting this issue, we do not mean to suggest or imply
that the approved drug products, or products prepared from them, are
approved for the use proposed by the nomination. See fn. 71 above.
\78\ See fn. 73, above.
---------------------------------------------------------------------------

Accordingly, with respect to the moxifloxacin HCl with
triamcinolone acetonide and vancomycin HCl for injection product
proposed to be compounded, FDA finds no basis to conclude that there
are attributes of the FDA-approved products that make them medically
unsuitable to treat certain patients who undergo cataract surgery.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because we are proposing not to include moxifloxacin HCl on the
503B Bulks list for the reasons described above, we do not consider
whether there is a basis to conclude that the drug products proposed to
be compounded must be produced from a bulk drug substance rather than
from an FDA-approved drug product.
3. Additional Comments
For the reasons stated above, we did not evaluate this nomination
using the factors that we considered for our evaluation in section II.B
above. However, we note that the nomination provided no data or support
regarding the evidence or lack of evidence of efficacy for the drug
products it proposed to compound using bulk drug substances, or
regarding the evidence of safety. The nomination also did not provide
information regarding the extent of historic and current use of the
drug products it proposed to compound.
Further, the prophylactic use of intraocular vancomycin, alone or
in a compounded drug combining multiple active ingredients, during
cataract surgery is associated with the risk of hemorrhagic occlusive
retinal vasculitis (HORV),\79\ a rare, potentially blinding
postoperative complication that has been observed after intraocular
injection of vancomycin formulations toward the end of otherwise
uncomplicated cataract surgeries.\80\ On September 28, 2017, FDA
approved a supplemental new drug application that adds a subsection
about HORV to the WARNINGS section in the labeling of Vancomycin
Injection, USP. The warning states:
---------------------------------------------------------------------------

\79\ See FDA's compounding risk alert current as of June 21,
2018, at https://www.fda.gov/drugs/human-drug-compounding/case-hemorrhagic-occlusive-retinal-vasculitis-horv-following-intraocular-injections-compounded.
\80\ Id.
---------------------------------------------------------------------------

Hemorrhagic occlusive retinal vasculitis, including permanent loss
of vision, occurred in patients receiving intracameral or intravitreal

[[Page 46137]]

administration of vancomycin during or after cataract surgery. The
safety and efficacy of vancomycin administered by the intracameral or
the intravitreal route have not been established by adequate and well-
controlled trials. Vancomycin is not indicated for prophylaxis of
endophthalmitis.
Most of the bulk drug substance nominations FDA has evaluated to
date have only proposed to compound drug products containing a single
active ingredient. This nomination proposed to compound drug products
containing more than one active ingredient. If FDA finalizes its
proposal not to include moxifloxacin HCl on the 503B Bulks List, we
intend to remove the substance from Category 1 for purposes of the
Interim Policy, which would mean that drug products compounded using
the bulk drug substance moxifloxacin HCl, including the proposed
compounded products addressed in this notice, would fall outside the
enforcement discretion described in the Interim Policy. However, if the
proposal not to include moxifloxacin HCl on the 503B Bulks List is
finalized, FDA would not remove triamcinolone acetonide or vancomycin
HCl from Category 1 at that time as a result, because we are not
currently in the process of reviewing nominations for those substances
or any supporting data or information they contain. Nominations for
vancomycin and triamcinolone acetonide, if they are not withdrawn,
remain the subject of future evaluations. Finally, if FDA determines
there is a clinical need for outsourcing facilities to use bulk drug
substances to compound the proposed drug products, we would include
each substance, as appropriate, on the 503B Bulks List at the time that
final determination is made.

M. Nalbuphine HCl

Nalbuphine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that are used for general anesthesia and
to treat moderate to severe pain as a preoperative, postoperative, and
obstetrical analgesia.\81\ The proposed routes of administration are
intravenous, intramuscular, and subcutaneous, the proposed dosage form
is a preservative-free solution, and the proposed concentrations are 10
mg/mL and 20 mg/mL. The nominators proposed to compound a preservative-
free solution. However, they failed to acknowledge that there is a
preservative-free formulation of nalbuphine HCl available that is FDA-
approved or explain why that formulation would be medically unsuitable
for certain patients. The nominations state that nalbuphine HCl might
also be used to compound other drug products but do not identify those
products. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDA 070914). FDA-approved nalbuphine HCl
is available as a preservative-free 10 mg/mL and 20 mg/mL solution for
intravenous, intramuscular, and subcutaneous
administration.^{82 83}
---------------------------------------------------------------------------

\81\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2298 and FDA-2013-N-1524-2292.
\82\ See, e.g., ANDA 070914 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/96944c71-2337-47f2-bab6-f46ad01499f3/96944c71-2337-47f2-bab6-f46ad01499f3.xml.
\83\ Per the label for ANDA 070914, single-dose products contain
no bacteriostat or antimicrobial agent and unused portions must be
discarded.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved preservative-free 10 mg/mL and 20 mg/mL nalbuphine HCl
solutions for intravenous, intramuscular, and subcutaneous
administration makes them medically unsuitable for certain patients or
identify an attribute of the approved drug products that the proposed
compounded drug products are intended to address. FDA finds no basis to
conclude that an attribute of the FDA-approved products makes them
medically unsuitable to treat certain patients for a condition that FDA
has identified for evaluation and that a proposed compounded product is
intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using nalbuphine HCl and
approved drug products containing nalbuphine HCl, there is nothing for
FDA to evaluate under question 2.

N. Polidocanol

Polidocanol was nominated for inclusion on the 503B Bulks List to
compound drug products for the treatment of v[a]ricose and spider
veins.\84\ The proposed route of administration is intravenous, the
proposed dosage form is an injection solution, and the proposed
concentration is 1 percent to 5 percent. The nominated bulk drug
substance is a component of FDA-approved drug products. FDA-approved
polidocanol (Asclera) is available as a 0.5 percent (5 mg/mL) and 1
percent (10 mg/mL) solution for intravenous administration.\85\ In
addition, FDA-approved polidocanol (Varithena) is available as a 1
percent (10 mg/mL) solution for intravenous administration that must be
activated before use.\86\
---------------------------------------------------------------------------

\84\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
\85\ See, NDA 021201 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/fe391849-9f70-4c3b-8698-39b243647727/fe391849-9f70-4c3b-8698-39b243647727.xml.
\86\ See, NDA 205098 labeling available as of the date of this
notice at https://www.accessdata.fda.gov/spl/data/5cfae95c-e866-4c37-857c-ab72e7a0fb40/5cfae95c-e866-4c37-857c-ab72e7a0fb40.xml.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nomination proposes polidocanol solution for the 503B Bulks
List at a concentration of 1 percent to 5 percent. The nomination does
not identify an attribute of the approved products that makes them
medically unsuitable to treat certain patients and that the proposed
compounded drug products are intended to address. Specifically, the
nomination does not explain why the FDA-approved 1 percent solution
products are medically unsuitable to treat certain patients for
varicose veins or spider veins. While FDA is aware that higher
concentrations of polidocanol have sometimes been used to treat
patients with larger spider veins and varicose veins, FDA is not aware
of patients who would need concentrations above 1 percent for this
purpose. Varithena, approved in 2013, demonstrated safety and efficacy
based on adequate and well-controlled studies in veins above 12 mm in
diameter.
FDA finds no basis to conclude that an attribute of each FDA-
approved product makes it medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because we are proposing not to include polidocanol on the 503B
Bulks list for the reasons described above, we do not consider whether
there is a basis to conclude that the drug product proposed to be
compounded must be produced from a bulk drug substance rather than from
an FDA-approved drug product.

[[Page 46138]]

3. Additional Comments
For the reasons stated above, we did not evaluate this nomination
using the factors that we considered for our evaluation in section II.B
above. However, we note that polidocanol products that are of higher
concentrations than the approved product would deliver higher doses if
used in the same volume, potentially posing greater risk to patients.

O. Potassium Acetate

Potassium acetate has been nominated for inclusion on the 503B
Bulks List to compound drug products that facilitate electrolyte
management.\87\ The proposed route of administration is intravenous,
the proposed dosage form is a preservative-free solution, and the
proposed concentration is 2 milliequivalents per milliliter (mEq/mL).
The nominators proposed to compound a preservative-free solution.
However, they failed to acknowledge that there is a preservative-free
formulation of potassium acetate available that is FDA-approved or
explain why that formulation would be medically unsuitable for certain
patients. The nominations state that potassium acetate might also be
used to compound other drug products but do not identify those
products. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., NDA 018896). FDA-approved potassium
acetate is available as a 40 mEq/20 mL (2 mEq/mL) preservative-free
solution for intravenous administration.^{88 89}
---------------------------------------------------------------------------

\87\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\88\ See, e.g., NDA 018896 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/fed21ec1-a0e2-457e-9b7d-c9a04f5d8871/fed21ec1-a0e2-457e-9b7d-c9a04f5d8871.xml.
\89\ Per the label for NDA 018896, the potassium acetate
solution contains no bacteriostat, antimicrobial agent or added
buffer but may contain acetic acid for pH adjustment.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved 2 mEq/mL preservative-free solution products is medically
unsuitable for certain patients or identify an attribute of the
approved drug products that the proposed compounded drug product is
intended to address. FDA finds no basis to conclude that an attribute
of the FDA-approved products makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using potassium acetate
and approved drug products containing potassium acetate, there is
nothing for FDA to evaluate under question 2.

P. Procainamide HCl

Procainamide HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat ventricular arrhythmia.\90\
The proposed routes of administration are intramuscular and
intravenous, the proposed dosage form is a preserved solution, and the
proposed concentrations are 100 mg/mL and 500 mg/mL. The nominators
proposed to compound a preserved solution. However, they failed to
acknowledge that there is a preserved formulation of procainamide HCl
available that is FDA-approved or explain why that formulation would be
medically unsuitable for certain patients. The nominations state that
procainamide HCl might also be used to compound other drug products but
do not identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDA 089069). FDA-
approved procainamide HCl is available as a 100 mg/mL and 500 mg/mL
preserved solution for intramuscular and intravenous
administration.^{91 92}
---------------------------------------------------------------------------

\90\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\91\ See, e.g., ANDA 089069 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/0ddcc43e-3d9c-4a79-ab19-790d8c0043cd/0ddcc43e-3d9c-4a79-ab19-790d8c0043cd.xml.
\92\ Per the label for ANDA 089069, each milliliter of the 2 mL
vial contains procainamide hydrochloride 500 mg; methylparaben 1 mg
and sodium metabisulfite 1.8 mg added in water for injection and may
contain hydrochloric acid and/or sodium hydroxide for pH adjustment.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved 100 mg/mL and 500 mg/mL preserved solutions makes them
medically unsuitable for certain patients or identify an attribute of
the approved drug products that the proposed compounded drug products
are intended to address. FDA finds no basis to conclude that an
attribute of the FDA-approved products makes them medically unsuitable
to treat certain patients for a condition that FDA has identified for
evaluation and that a proposed compounded product is intended to
address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using procainamide HCl
and approved drug products containing procainamide HCl, there is
nothing for FDA to evaluate under question 2.

Q. Sodium Nitroprusside

Sodium nitroprusside has been nominated for inclusion on the 503B
Bulks List to compound drug products to treat acute decompensated heart
failure and acute hypertension.\93\ The proposed route of
administration is a sterile, injectable solution, the proposed dosage
form is a diluted injection, and the proposed concentration is 12.5 mg/
mL. The nomination states that sodium nitroprusside might also be used
to compound other drug products but does not identify those products.
The nominated bulk drug substance is a component of FDA-approved drug
products (e.g., ANDA 209493). FDA-approved sodium nitroprusside is
available as a 50 mg/2 mL (25 mg/mL) solution that must be diluted
prior to injection.^{94 95}
---------------------------------------------------------------------------

\93\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0238.
\94\ See, e.g., ANDA 209493 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/61245426-5d5a-4788-b060-33671152b526/61245426-5d5a-4788-b060-33671152b526.xml.
\95\ Sodium nitroprusside is also approved as a solution for
intravenous administration.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nomination does not explain why an attribute of each of the
FDA-approved 50 mg/2 mL solution for dilution products are medically
unsuitable for certain patients or identify an attribute of the
approved drug products that the proposed compounded drug product is
intended to address. FDA finds no basis to conclude that an attribute
of the FDA-approved products makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.

[[Page 46139]]

2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nomination does not take the position or provide support for
the position that drug products containing sodium nitroprusside must be
compounded from bulk drug substances rather than using the approved
drug product. FDA finds no basis to conclude that the sodium
nitroprusside drug products proposed in the nomination must be
compounded using a bulk drug substance rather than using the approved
drug product.

R. Sodium Thiosulfate

Sodium thiosulfate has been nominated for inclusion on the 503B
Bulks List for the treatment of calciphylaxis, cyanide toxicity,
extravasation, Malassezia furfur, and nephrotoxicity prophylaxis.\96\
Sodium thiosulfate was nominated as a 250 mg/mL injectable, for
intravenous, intradermal, intramuscular, and subcutaneous
administration, and in a topical dosage form at an unknown
concentration. The nominated bulk drug substance is a component of an
FDA-approved drug product (NDA 203923). FDA-approved sodium thiosulfate
is available as a 12.5 g/50 mL (250 mg/mL) solution for intravenous
administration.^{97 98}
---------------------------------------------------------------------------

\96\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0173.
\97\ See, e.g., NDA 203923 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/29449d76-f4c7-4571-b7bb-5c2a55f637b5/29449d76-f4c7-4571-b7bb-5c2a55f637b5.xml.
\98\ Sodium thiosulfate is also approved for sequential use with
sodium nitrite for intravenous administration.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
Sodium thiosulfate was nominated for injectable (intravenous,
intradermal, intramuscular, subcutaneous) and topical administration
\99\ for the treatment of calciphylaxis, cyanide toxicity,
extravasation, Malassezia furfur, and nephrotoxicity prophylaxis.
---------------------------------------------------------------------------

\99\ The topical route of administration will not be considered
further because the nomination does not identify a condition that
this formulation is intended to address. The nomination also did not
identify an attribute of the approved intravenous drug product that
makes it medically unsuitable to treat patients with the conditions
for which the bulk drug substance was nominated.
---------------------------------------------------------------------------

a. Calciphylaxis
The nominator proposes to remove potassium chloride from the
proposed injectable compounded product used in the treatment of
calciphylaxis. The nominator asserts that the safety of the approved
product is of concern because the potassium level of the product is too
high for patients with renal disease or impairment. This assertion is
inaccurate because the amount of potassium in the approved 12.5 g/50 mL
(250 mg/mL) solution for intravenous administration is small (440 mg or
~6 mEq potassium chloride per dose), and when it is used off-label for
the treatment of calciphylaxis, to the best of our knowledge, the
product is generally administered during hemodialysis, which allows for
removal of the excess potassium.\100\
---------------------------------------------------------------------------

\100\ Even in circumstances where it is not administered during
dialysis, the amount of potassium in the approved product is small
and potassium levels could be monitored for safety. (See, e.g.,
Nigwekar, S.U., S.M. Brunelli, D. Meade, et al., 2013, ``Sodium
Thiosulfate Therapy for Calcific Uremic Arteriolopathy, '' Clinical
Journal of the American Society of Nephrology, 8(7):1162-1170
(providing, ``The median dose of STS treatment was 25 g administered
intravenously in 100 ml of normal saline given over the last half-
hour of each HD session''); Generali, J.A. and D.J. Cada, 2015,
``Sodium Thiosulfate: Calciphylaxis,'' Hospital Pharmacy,
50(11):975-977 (studying dialysis patients on ``25 grams
intravenously diluted in 100 mL of sodium chloride 0.9 percent
administered over 30 to 60 minutes 3 times per week during the last
hour or after the hemodialysis session.'')).
---------------------------------------------------------------------------

The nomination proposes to make a 250 mg/mL injectable, as well as
unspecified higher concentrations. The nomination states that it may be
necessary to compound a product with a greater concentration than is
commercially available, but the nomination does not identify specific
higher concentrations that the nominator proposes to compound or
provide any data or information supporting the need for a higher
concentration. In addition, FDA is not aware of patients who would need
concentrations above 250 mg/mL. The approved product is available as a
concentrated solution (12.5 g/50 mL). Although the product is generally
diluted in normal saline before administration to minimize potential
complications associated with the intravenous infusion of a hypertonic
solution, presumably, a concentrated, compounded sodium thiosulfate
product would also need to be diluted before administration. In
addition, when used for the treatment of calciphylaxis in hemodialysis
patients, the product is administered during dialysis, which allows for
removal of excess fluid (Refs. 9 to 11) (discussing how sodium
thiosulfate is generally used to treat calciphylaxis).
Accordingly, FDA finds no basis to conclude that an attribute of
the FDA-approved product makes it medically unsuitable to treat
patients with calciphylaxis and that the sodium thiosulfate drug
products proposed to be compounded are intended to address.\101\
---------------------------------------------------------------------------

\101\ In making this observation, we do not suggest that the
approved drug product, or products prepared from it, are approved
for the use proposed by the nomination. Here we are asking a
limited, threshold question to determine whether there might be
clinical need for a compounded drug product, by asking what
attributes of the approved drug the proposed compounded drug would
change, and why. Asking this question helps ensure that if a bulk
drug substance is included on the 503B Bulks List it is to compound
drugs that include a needed change to an approved drug product
rather than to produce drugs without such a change. Because our
answer to question (1) is ``no'', we do not evaluate the available
evidence of effectiveness or lack of effectiveness of a drug product
compounded with sodium thiosulfate for the treatment of
calciphylaxis. We note that the references cited by the nominator
appear to be general reviews of potassium homeostasis and studies in
other populations showing associations between potassium excretion
or potassium levels and clinical outcomes. None of these references
address whether there is a risk of the amount of potassium in the
approved product to patients receiving sodium thiosulfate for the
treatment of calciphylaxis.
---------------------------------------------------------------------------

b. Cyanide Toxicity
The nomination also proposes to combine sodium thiosulfate with
sodium nitroprusside to reduce the risk of cyanide toxicity during
sodium nitroprusside administration. Sodium thiosulfate is FDA-approved
for sequential use with sodium nitrite for treatment of acute cyanide
poisoning that is judged to be serious or life-threatening. The
nomination states that sodium thiosulfate is commonly administered with
sodium nitroprusside, but the nomination does not identify the final
product formulation proposed to be compounded (e.g., dosage form and
strength of each ingredient).\102\ Sodium nitroprusside was also
nominated separately (see FDA's analysis at section IV.Q. above), but
that nomination does not mention the use of sodium nitroprusside in
combination with sodium thiosulfate.
---------------------------------------------------------------------------

\102\ While the nomination does not provide final product
formulation information, it does include an article (Ref. 12), which
reports on the stability of a 1:10 sodium nitroprusside: sodium
thiosulfate admixture stored up to 48 hours when compounded from the
approved products.
---------------------------------------------------------------------------

The nomination states that providing sodium thiosulfate and sodium
nitroprusside in a combined compounded preparation would allow for
faster administration in the clinical setting and fewer human
manipulations, thus reducing the rate of error. We do not consider the
risk that a clinician may mishandle the approved product to be an
indicator of clinical need. Further, the approved labeling for sodium
nitroprusside states that no other drugs should be administered in the
same solution with sodium nitroprusside. The

[[Page 46140]]

nomination has not identified any patients for whom co-administration
of both approved drug products would not be medically appropriate, and
for whom compounding a drug product with both active ingredients in one
solution would address an unmet medical need.
Accordingly, with respect to the combination sodium thiosulfate and
sodium nitroprusside drug products proposed to be compounded, FDA finds
no basis to conclude that an attribute of the FDA-approved products
makes them medically unsuitable to treat certain patients.
c. Extravasation, Malassezia furfur, and Nephrotoxicity Prophylaxis
The nomination does not identify an attribute of the approved
products that makes them medically unsuitable for the conditions listed
above and that the proposed compounded injectable drug products are
intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because we are proposing not to include sodium thiosulfate on the
503B Bulks list for the reasons described above, we do not consider
whether there is a basis to conclude that the drug products proposed to
be compounded must be produced from a bulk drug substance rather than
from an FDA-approved drug product.

S. Verapamil HCl

Verapamil HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat atrial fibrillation and
flutter, hypertension, and paroxysmal supraventricular tachycardia,
among other conditions.\103\ The proposed route of administration is
intravenous, the proposed dosage form is a preservative-free solution,
and the proposed concentration is 2.5 mg/mL. The nominators proposed to
compound a preservative-free solution. However, they failed to
acknowledge that there is a preservative-free formulation of verapamil
HCl available that is FDA-approved or explain why that formulation
would be medically unsuitable for certain patients. The nominations
state that verapamil HCl might also be used to compound other drug
products but do not identify those products. The nominated bulk drug
substance is a component of FDA-approved drug products (e.g., ANDA
070737). FDA-approved verapamil HCl is available as a preservative-free
5 mg/2 mL (2.5 mg/mL) solution for intravenous
administration.^{104 105 106}
---------------------------------------------------------------------------

\103\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2298 and FDA-2013-N-1524-2292.
\104\ See, e.g., ANDA 070737 labeling available as of the date
of this notice at https://www.accessdata.fda.gov/spl/data/3d8f6e3e-444b-44e3-b60c-a725948085b6/3d8f6e3e-444b-44e3-b60c-a725948085b6.xml.
\105\ Per the label for ANDA 070737, the solution contains no
bacteriostat or antimicrobial agent and is intended for single-dose
intravenous administration and may contain hydrochloric acid for pH
adjustment.
\106\ Verapamil hydrochloride is also approved as oral extended
release tablet.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nominations do not explain why an attribute of each of the FDA-
approved preservative-free 5 mg/2 mL (2.5 mg/mL) solution products for
intravenous administration is medically unsuitable for certain patients
or identify an attribute of the approved drug products that the
proposed compounded drug products are intended to address. FDA finds no
basis to conclude that an attribute of the FDA-approved products makes
them medically unsuitable to treat certain patients for a condition
that FDA has identified for evaluation and that a proposed compounded
product is intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using verapamil HCl and
approved drug products containing verapamil HCl, there is nothing for
FDA to evaluate under question 2.

V. Other Issues Raised in Nominations

Some of the bulk drug substance nominations included in this notice
state that there could be a benefit gained from using a bulk drug
substance contained in an approved drug product to compound drug
products that do not require dilution or reconstitution prior to
administration. As explained above, when a bulk drug substance is a
component of an approved drug, we considered whether there is a basis
to conclude that an attribute of each approved drug product makes each
one medically unsuitable to treat certain patients for their condition,
an interpretation that protects patients and the integrity of the drug
approval process. The nominations proposing to compound drug products
in ready-to-use form containing bulk drug substances in one or more
FDA-approved drug products do not show that the approved drug product,
when not manufactured in the ready-to-use form, is medically unsuitable
for certain patients. Nor do the nominations establish that drug
products in the relevant concentrations, including ready-to-use
products, cannot be prepared from the approved drug products. Rather,
they propose to compound a ready-to-use product from bulk drug
substances to seek improved efficiency for prescribers or healthcare
providers, or to address the possibility that the approved drug might
be mishandled by a medical professional, neither of which falls within
the meaning of clinical need to compound a drug product using a bulk
drug substance.
Some of the nominations for the substances in this notice include
statements that these substances should be added to the 503B Bulks List
because compounding from the bulk drug substance could help outsourcing
facilities address drug shortages and supply disruptions of approved
drugs. As noted above, section 503B of the FD&C Act contains a separate
provision for compounding from bulk drug substances to address a drug
shortage, and we do not interpret the other price- and supply-related
issues advanced by the nominations to be within the meaning of
``clinical need'' for compounding with a bulk drug substance.\107\
---------------------------------------------------------------------------

\107\ Please see the final guidance entitled ``Evaluation of
Bulk Drug Substances Nominated for Use in Compounding Under Section
503B of the Federal Food, Drug, and Cosmetic Act'' (84 FR 7390)
(Ref. 2) and the Federal Register notice entitled ``List of Bulk
Drug Substances for Which There Is a Clinical Need Under Section
503B of the Federal Food, Drug, and Cosmetic Act'' available at
https://www.federalregister.gov/documents/2019/03/04/2019-03810/list-of-bulk-drug-substances-for-which-there-is-a-clinical-need-under-section-503b-of-the-federal.
---------------------------------------------------------------------------

Some of the nominations for the substances in this notice assert
that it would be preferable to compound a drug product using a bulk
drug substance rather than using an approved drug product; however,
they do not take the position or provide support for the position that
a bulk drug substance must be used to prepare these
concentrations.\108\
---------------------------------------------------------------------------

\108\ For example, the nominations do not take the position or
provide support for the position that a drug product prepared by
starting with the approved drug would be unsuitable for
administration.
---------------------------------------------------------------------------

VI. Conclusion

For the reasons stated above, we tentatively conclude that there is
a clinical need for outsourcing facilities to compound drug products
using the bulk drug substances DPCP, glycolic acid,

[[Page 46141]]

SADBE, and TCA, and we therefore propose to include them on the 503B
Bulks List as described in this notice.
At this time, we find no basis to conclude that there is a clinical
need for outsourcing facilities to compound drug products using the
bulk drug substances diazepam, dobutamine HCl, dopamine HCl, edetate
calcium disodium, folic acid, glycopyrrolate, hydroxyzine HCl,
ketorolac tromethamine, labetalol HCl, mannitol, metoclopramide HCl,
moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium acetate,
procainamide HCl, sodium nitroprusside, sodium thiosulfate, and
verapamil HCl. We therefore propose not to include these bulk drug
substances on the 503B Bulks List.

VII. References

The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they are also available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.

*1. FDA, Guidance for Industry, ``Interim Policy on Compounding
Using Bulk Drug Substances Under Section 503B of the Federal Food,
Drug, and Cosmetic Act,'' January 2017 (available at https://www.fda.gov/media/94402/download).
*2. FDA, Guidance for Industry, ``Evaluation of Bulk Drug
Substances Nominated for Use in Compounding Under Section 503B of
the Federal Food, Drug, and Cosmetic Act,'' March 2019 (available at
https://www.fda.gov/media/121315/download).
*3. FDA Memorandum to File, Clinical Need for
Diphenylcyclopropenone (DPCP) in Compounding Under Section 503B of
the FD&C Act, July 2020.
*4. FDA Memorandum to File, Clinical Need for Glycolic Acid in
Compounding Under Section 503B of the FD&C Act, July 2020.
*5. FDA Memorandum to File, Clinical Need for Squaric Acid
Dibutyl Ester (SADBE) in Compounding Under Section 503B of the FD&C
Act, July 2020.
*6. FDA Memorandum to File, Clinical Need for Trichloroacetic
Acid (TCA) in Compounding Under Section 503B of the FD&C Act, July
2020.
7. Leheta, T.M., A. El Tawdy, R.M. Abdel Hay, and S. Farid,
2011, ``Percutaneous Collagen Induction Versus Full-Concentration
Trichloroacetic Acid in the Treatment of Atrophic Acne Scars,''
Dermatologic Surgery, 37(2):207-216.
8. Kumari, R. and D.M. Thappa, 2010, ``Comparative Study of
Trichloroacetic Acid Versus Glycolic Acid Chemical Peels in the
Treatment of Melasma,'' Indian Journal of Dermatology, Venereology
and Leprology, 76:447, available at http://www.ijdvl.com/text.asp?2010/76/4/447/66602.
9. Nigwekar, S.U., S.M. Brunelli, D. Meade, et al., 2013,
``Sodium Thiosulfate Therapy for Calcific Uremic Arteriolopathy,''
Clinical Journal of the American Society of Nephrology, 8(7):1162-
1170.
10. Generali, J.A. and D.J. Cada, 2015, ``Sodium Thiosulfate:
Calciphylaxis,'' Hospital Pharmacy, 50(11):975-977.
*11. Udomkarnjananun, S., K. Kongnatthasate, K. Praditpornsilpa,
et al., 2019, ``Treatment of Calciphylaxis in CKD: A Systematic
Review and Meta-Analysis,'' Kidney International Reports, 4(2):231-
244.
*12. Schulz, L.T., E.J. Elder, Jr, K.J. Jones, et al., 2010,
``Stability of Sodium Nitroprusside and Sodium Thiosulfate 1:10
Intravenous Admixture,'' Hospital Pharmacy, 45(10):779-784.

Dated: July 28, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-16649 Filed 7-30-20; 8:45 am]
BILLING CODE 4164-01-P