Document ID: FDA-2018-N-3240-0054
Agency: fda
Document Type: Notice
Title: List of Bulk Drug Substances for Which There is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act
Posted Date: 2020-07-31T04:00Z

[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.
---------------------------------------------------------------------------

    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.

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[[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