Document ID: FDA-2018-N-3240-0369
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: 2022-11-23T05:00Z

[Federal Register Volume 87, Number 225 (Wednesday, November 23, 2022)]
[Notices]
[Pages 71642-71652]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-25549]

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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 two bulk drug substances that FDA has 
considered and proposes to include on the 503B Bulks List to compound 
three categories of compounded drug products: arginine hydrochloride 
(HCl) for oral use, lysine HCl for oral use, and lysine HCl for 
intravenous use in combination with FDA-approved, single-ingredient 
arginine HCl for intravenous use. This notice identifies three bulk 
drug substances that FDA has considered and proposes not to include on 
the 503B Bulks List: etomidate, furosemide, and rocuronium bromide. 
Additional bulk drug substances nominated for inclusion on this list 
are under consideration and may be the subject of future notices.

DATES: Either electronic or written comments on the notice must be 
submitted by January 23, 2023.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of January 23, 2023. 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.

[[Page 71643]]

     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 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: Tracy Rupp, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Silver Spring, MD 20993, 301-796-3100.

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 of the FD&C Act (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 of the FD&C 
Act (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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    Compounded drug products 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 from 
CGMP requirements) with section 503B(a) of the FD&C Act (not 
providing an 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 the 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 
the bulk drug substance 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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    FDA has published a series of Federal Register notices addressing 
bulk drug substances nominated for inclusion on the 503B Bulks List.\7\ 
This notice identifies two bulk drug substances that FDA has considered 
and proposes to include on the 503B Bulks List and three bulk drug 
substances that FDA has considered and proposes not to include on the 
503B Bulks List.
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    \7\ See Federal Register of August 28, 2018 (83 FR 43877), March 
4, 2019 (84 FR 7383), September 3, 2019 (84 FR 46014), July 31, 2020 
(85 FR 46126), and March 24, 2021 (86 FR 15673). The comment period 
for the July 2020 notice was reopened for 30 days on January 8, 2021 
(86 FR 1515), to allow interested parties an additional opportunity 
to comment. FDA has not yet reached a final determination on whether 
the substances evaluated in the September 2019, July 2020, or March 
2021 notices will be added to the 503B Bulks List. In addition, 
bumetanide, which was considered in the August 2018 notice, remains 
under consideration by the Agency.
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    For purposes of section 503B of the FD&C Act, bulk drug substance 
means an active pharmaceutical ingredient as defined in Sec.  207.1 (21 
CFR 207.1).\8\ 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.9 10
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    \8\ See section 503B(a)(2) of the FD&C Act, which defines bulk 
drug substances used in compounding under section 503B according to 
21 CFR 207.3(a)(4) ``or any successor regulation.'' Section 207.1 is 
the successor regulation.
    \9\ Section 503B(a)(2) of the FD&C Act and Sec.  207.1.
    \10\ 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) of the FD&C Act, 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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[[Page 71644]]

II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

    In the Federal Register of December 4, 2013 (78 FR 72838), FDA 
requested nominations for specific bulk drug substances for the Agency 
to consider for inclusion on the 503B Bulks List. 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. In the Federal Register of 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 or submit comments on nominated substances.
    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.\11\ 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.\12\ 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 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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    \11\ 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.
    \12\ 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 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. This list is available at https://www.fda.gov/media/120692/download. FDA will only place a bulk drug 
substance on the 503B Bulks List when 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 is evaluating 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).

B. Analysis of Substances Nominated for the List

    As noted above, the 503B Bulks List includes bulk drug substances 
for which the Agency has determined there is a clinical need. The 
Agency is 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 
interprets 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 does not interpret supply 
issues, such as backorders, to be within the meaning of ``clinical 
need'' for compounding with a bulk drug substance. Section 503B of the 
FD&C Act separately provides for compounding from a bulk drug substance 
under the exemptions 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, FDA 
does not consider convenience in administering a particular drug 
product (e.g., a ready-to-use form) or the cost of the compounded drug 
product as compared with an FDA-approved drug product when assessing 
``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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    All 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 the bulk drug substances by asking 
one or both, as applicable, of the following questions:
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    \14\ Specifically, arginine HCl, etomidate, furosemide, lysine 
HCl, and rocuronium bromide.
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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. When it is feasible to compound a drug

[[Page 71645]]

product by starting with an approved drug product, there are certain 
benefits of doing so over starting with a bulk drug substance, 
including that approved drugs have undergone premarket review for 
safety, effectiveness, and quality, and are manufactured by a facility 
that is subject to premarket assessment, including site inspection, as 
well as routine post-approval risk-based inspections. In contrast, FDA 
does not conduct a premarket review of the quality standards, 
specifications, and controls for bulk drug substances used in 
compounding and does not conduct a premarket assessment of the 
manufacturer of the bulk drug substance.
    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 an approved drug or 
compounding starting with an approved drug product. FDA answered 
``yes'' to both of the threshold questions for two of the bulk drug 
substances that are components of approved drug products that we are 
addressing in this notice. Accordingly, as explained further below, we 
proceeded further in our evaluation of these substances by conducting a 
balancing test and are proposing to include those substances on the 
503B Bulks List.
    We are conducting a balancing test using four factors. 
Specifically, on a substance-by-substance basis, we consider available 
data relevant to each factor in the context of the other factors and 
balance all four factors to determine whether the statutory ``clinical 
need'' standard has been met. The balancing test includes the following 
factors:
     The physical and chemical characterization 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, if any 
such evidence exists; and
     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 three entries addressing two bulk 
drug substances on the 503B Bulks List.
    In this notice, FDA evaluated certain nominated bulk drug 
substances for potential inclusion on the 503B Bulks List either alone 
or in combination with other bulk drug substances. FDA will not 
consider comments raising different combinations of bulk drug 
substances than those evaluated by FDA in this notice to be within the 
scope of this notice. New nominations may be submitted to docket FDA-
2015-N-3469 for combinations of bulk drug substances that were not 
previously nominated and included for evaluation in this notice. The 
docket is available on https://www.regulations.gov.
    To assess whether there is a clinical need for outsourcing 
facilities to use a bulk drug substance in compounding, FDA must 
evaluate the drug products that have been proposed to be made from the 
nominated bulk drug substances. Therefore, FDA's evaluation of a bulk 
drug substance includes detailed consideration of the drug products 
that are proposed to be compounded, including the conditions justifying 
clinical need under the applicable statutory standard. Comments on 
FDA's preliminary evaluation of a bulk drug substance should include 
adequate support for the commenter's position. For example, a commenter 
writing to support inclusion of a nominated bulk drug substance on the 
503B Bulks List should include sufficient information to permit a 
meaningful clinical need evaluation by FDA of the proposed product. 
Commenters writing in favor of or in opposition to a proposal to 
include or not to include an entry on the 503B Bulks List should 
address, for each proposed compounded drug product, the factors FDA 
evaluated in making its proposal.\15\ After FDA publishes a Federal 
Register notice making a final determination regarding whether a bulk 
drug substance will be placed on the 503B Bulks List, FDA will no 
longer consider comments submitted to the docket regarding that bulk 
drug substance, but interested parties may submit a citizen petition to 
FDA requesting specific action or relief (see 21 CFR 10.30).
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    \15\ See also FDA's 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), and our 
Federal Register notice of October 27, 2015.
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C. Inclusion of Bulk Drug Substances on the 503B Bulks List

    In preparing its proposal to include two bulk drug substances on 
the 503B Bulks List, FDA considered whether the clinical need for the 
bulk drug substance in the proposed compounded drug product is limited 
by, for example, route of administration or dosage form. As 
appropriate, and as explained further below, the Agency has tailored 
its proposed entries on the 503B Bulks List to reflect its findings 
related to clinical need for the bulk substances proposed for inclusion 
on the list. FDA requested comments on the proposal to limit listings 
in this manner in our Federal Register notice of July 31, 2020 (85 FR 
46126). The comment period for the July 2020 notice was reopened for 30 
days on January 8, 2021 (86 FR 1515), to provide interested parties an 
additional opportunity to comment before FDA began to develop its final 
determinations. After considering the comments submitted regarding the 
proposal, in the Federal Register notice of January 27, 2022 (87 FR 
4240), FDA listed three bulk drug substances to compound drug products 
for topical use only.
    Consistent with the approach described in the 2020 notice, and as 
reflected in the entries that appear on the 503B Bulks List to date, 
the entries proposed in this notice would authorize use of two bulk 
drug substances. Arginine HCl would be authorized for use to compound 
single-ingredient drug products for oral use only; lysine HCl would be 
authorized for use to compound single-ingredient drug products for oral 
use; and lysine HCl would also be authorized for use in combination 
with FDA-approved, single-ingredient arginine HCl injection, U.S. 
Pharmacoepia (USP) to compound drug products for intravenous (IV) use 
only.\16\ As discussed further in this notice, FDA's proposals with 
respect to inclusion of lysine HCl and arginine HCl on the 503B Bulks 
List pertain to the L- forms of lysine HCl and arginine HCl 
exclusively.\17\
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    \16\ In this notice, ``single-ingredient'' refers to a drug 
product containing one active ingredient. The drug product may also 
contain excipients.
    \17\ See footnote 18 below.
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III. Substances Considered and Proposed for Inclusion on the 503B Bulks 
List

    Because the substances in this section are components of FDA-
approved drug products, we considered whether: (1)

[[Page 71646]]

there is a basis to conclude that an attribute of each FDA-approved 
drug product that includes the nominated bulk drug substance makes each 
one medically unsuitable to treat certain patients for a condition that 
FDA has identified for evaluation, and the drug products proposed to be 
compounded are intended to address that attribute in each FDA-approved 
drug product and (2) whether the drug products proposed to be 
compounded must be compounded using a bulk drug substance. In addition, 
because we answered these two questions in the affirmative for certain 
drug products proposed to be compounded from the nominated bulk drug 
substances, we applied the four-factor balancing test described above. 
The bulk drug substances that were evaluated and that FDA is proposing 
to place on the 503B Bulks List are arginine HCl for oral use only, 
lysine HCl for oral use only, and lysine HCl for use in combination 
with FDA-approved, arginine HCl injection for intravenous use only. The 
reasons for FDA's proposals are included below.

A. Arginine HCl

    Arginine HCl was nominated as a bulk drug substance for the 503B 
Bulks List to compound drug products that are used for acute 
hyperammonemia in urea cycle disorders (UCDs) and refractory metabolic 
alkalosis, among other conditions.18 19 The proposed routes 
of administration are oral and intravenous, among others,\20\ and the 
proposed dosage forms are an oral solution or suspension, capsule, 
powder for dispersion, and injectable, among others.\21\ The nominators 
proposed a range of concentrations (12.5 to 40 percent) and 200 and 500 
milligrams/milliliters (mg/mL). They also proposed strengths of 250 mg-
500 mg unspecified oral dosage forms and 700 mg-750 mg oral capsules. 
This nominated bulk drug substance is a component of an FDA-approved 
drug product (NDA 016931). FDA has approved arginine HCl (R-Gene 10) as 
a 10 gram (GM)/100 mL (100 mg/mL; 10 percent) injection for intravenous 
administration \22\ (Ref. 3).
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    \18\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0244, FDA-2015-N-3469-0169, FDA-2015-N-3469-0156-attachment 10, 
FDA-2015-N-3469-0202, and FDA-2015-N-3469-0320. The nomination in 
Docket No. FDA-2015-N-3469-0156-attachment 10 was for ``Arginine 
HCL'' and stated that the common name of the substance is ``L-
arginine hydrochloride; D-arginine hydrochloride.'' However, the 
nominator also stated that the chemical grade of the bulk drug 
substance is USP. The USP monograph for arginine HCl does not 
include D-arginine HCl. Therefore, this review focuses on L-arginine 
HCl, not the mixture of D- and L-arginine HCl. Arginine HCl USP 
grade consists of L-arginine monohydrochloride. The nomination 
discussed in this Federal Register notice nominated L-arginine HCl 
USP grade. ``Arginine HCl'' and ``L-arginine HCl'' are used 
interchangeably throughout this Federal Register notice. L-arginine 
HCl and L-lysine HCl were also nominated (Docket No. FDA-2015-N-
3469-0073-attachment 10) to be used in combination for intravenous 
administration with LUTATHERA (lutetium Lu 177 dotatate injection) 
treatment. That nomination is the subject of another evaluation.
    \19\ The following uses will not be considered in this 
evaluation because the nominations did not provide sufficient 
information, including citations to relevant literature, supporting 
a clinical need for the proposed uses: thyroid cysts; arginine 
deficiency/supplementation; orgasmic dysfunction in women; 
prevention or treatment of heart and circulatory disease; combat 
fatigue; stimulation of wound healing; boosting production of nitric 
oxide, relaxing blood vessels, and treating circulatory and other 
cardiovascular problems; and reducing waist circumference, visceral 
fat, weight, and body mass index. In addition, the following labeled 
uses will not be considered in this evaluation because the 
nominations did not provide sufficient information, including 
citations to relevant literature, supporting a clinical need for a 
more concentrated IV product or for a product to be administered via 
the oral or topical route of administration: diagnostic aid in 
conditions such as panhypopituitarism, pituitary dwarfism, 
chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, 
pituitary trauma, acromegaly, gigantism, and problems of growth and 
stature.
    \20\ The topical and IV routes of administration for use of 
arginine HCl to treat hyperammonemia associated with urea cycle 
disorder will not be considered further because the nominations did 
not provide sufficient evidence to support a clinical need for drug 
products with these routes of administration. Although some of the 
nominations included articles that describe the use of intravenous 
arginine HCl for treating patients with hyperammonemia in urea cycle 
disorder, the articles do not provide support for the nominator's 
proposal to make a more concentrated product than the approved IV 
drug product containing the same active ingredient. Therefore, the 
IV route of administration will not be considered further for 
treating hyperammonemia in urea cycle disorder because the 
nominations did not provide information supporting a clinical need 
for a more concentrated product. Similarly, the oral route of 
administration will not be considered further for the use of 
arginine HCl to treat refractory metabolic alkalosis because the 
nomination did not provide any evidence to support a clinical need 
for drug products with this route of administration. As explained in 
section II.B of this notice, if a member of the public would like 
FDA to evaluate arginine HCl based on a clinical need for a drug 
product to be compounded containing arginine HCl for administration 
by a route that was not evaluated in this notice, then that person 
should submit a nomination to Docket No. FDA-2015-N-3469, which is 
available on https://www.regulations.gov.
    \21\ The proposed dosage forms (cream, ointment, and gel) are 
associated with uses or routes of administration that will not be 
considered in this evaluation.
    \22\ See, e.g., NDA 016931 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/016931s031lbl.pdf. Arginine (not HCl salt) is available as a 
component of several approved drug products that contain multiple 
amino acids (e.g., for parenteral nutrition) (e.g., AMINOSYN II; NDA 
020015). NDA 020015 labeling is available as of the date of this 
notice at https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5b426208-f090-4650-86c3-89040ba45c2d&type=display. The arginine in these approved drug 
products is not the same bulk drug substance as arginine HCl, which 
is the subject of this evaluation.
---------------------------------------------------------------------------

    Because arginine HCl is a component of an FDA-approved drug 
product, we considered whether: (1) there is a basis to conclude that 
an attribute of the FDA-approved drug product that contains arginine 
HCl makes it medically unsuitable to treat certain patients for a 
condition that FDA has identified for evaluation, and the arginine HCl 
drug product proposed to be compounded is intended to address that 
attribute in the FDA-approved drug product and (2) whether the drug 
product proposed to be compounded must be compounded using a bulk drug 
substance. In addition, because we answered these two questions in the 
affirmative for an oral arginine HCl compounded drug product, we also 
conducted a balancing test to further evaluate this bulk drug substance 
by considering and applying the four factors described above.
1. Suitability of FDA-Approved Drug Products
    A nominator proposes that there is a clinical need for an oral, 
single-ingredient arginine HCl compounded drug product to treat 
patients with certain UCDs. The references submitted with the 
nomination describe the use of arginine HCl orally for long-term 
maintenance therapy in patients with UCDs. There is a basis to conclude 
that the FDA-approved drug product that contains only arginine HCl (R-
Gene 10) is medically unsuitable to treat patients who require long-
term oral maintenance therapy because the approved drug product is only 
available for intravenous administration and would not be suitable for 
the use proposed in the nomination, which would involve daily oral 
administration.\23\ The drug product proposed to be compounded is 
intended to address the attribute of the approved drug product that 
makes it medically unsuitable for some patients because the nominator 
proposes to compound oral formulations (capsules, powder for 
dispersion, and oral solution/suspension) of arginine HCl. Accordingly, 
FDA finds that the drug product proposed to be compounded is intended 
to address the attribute of the approved drug product that makes it 
medically unsuitable for some patients.
---------------------------------------------------------------------------

    \23\ Empower Pharmacy proposed to make several different dosage 
forms, including ``oral capsules, powder for dispersion, oral 
solutions/suspensions.'' We are not commenting on the potential 
suitability of these various proposed dosage forms due to the lack 
of data available on the various dosage forms. Furthermore, none of 
the scientific literature reviewed by FDA referred to off-label use 
of the approved intravenous arginine HCL drug product in patients 
with urea cycle disorder.
---------------------------------------------------------------------------

    A nominator also proposes that there is a clinical need for an 
intravenous single-ingredient arginine HCl

[[Page 71647]]

compounded drug product to treat patients with refractory metabolic 
alkalosis. The nomination does not identify an attribute of the FDA-
approved arginine HCl (R-Gene 10) 10 GM/100 mL (100 mg/mL; 10 percent) 
injection for intravenous administration that makes it medically 
unsuitable for certain patients or indicate that the compounded drug 
product is intended to address any such attribute. 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
    FDA finds that there is a basis to conclude that the oral drug 
products proposed to be compounded must be made from a bulk drug 
substance rather than from FDA-approved R-Gene 10 because of the 
difficulties and complexities associated with starting with the 
approved solution for intravenous administration and converting it 
either to capsules or to a powder for dispersion that would be 
administered orally. The nominator also proposed to compound an oral 
solution of arginine HCl that is at a higher concentration than the 
approved intravenous product (100 mg/mL). There is a basis to conclude 
that the proposed oral liquid drug product must also be compounded 
starting from the bulk drug substance because of the difficulties and 
complexities associated with compounding a more concentrated solution 
beginning with the approved product.
    With regard to an intravenous, single-ingredient arginine HCl 
compounded drug product proposed to treat patients with refractory 
metabolic alkalosis, the nominator has not identified patients for whom 
the approved products are medically unsuitable or identified an 
attribute of the approved drug product that the proposed compounded 
drug product is intended to address. Because the nominations do not 
identify specific differences between drug products that would be 
compounded using arginine HCl and the approved drug product containing 
arginine HCl, there is nothing for FDA to evaluate under question 2 for 
intravenous single-ingredient arginine HCl.
3. Balancing Test
    Because FDA answered ``yes'' to both of the threshold questions for 
arginine HCl for oral administration, we next conducted the following 
balancing testing to determine whether the statutory ``clinical need'' 
standard has been met. We considered data and information regarding the 
physical and chemical characterization of arginine HCl, 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.
    Arginine HCl is a well-characterized amino acid and is stable under 
ordinary storage conditions. Provided the quality of arginine HCl meets 
the standards in its USP drug substance monograph, arginine HCl is well 
characterized physically and chemically.\24\
---------------------------------------------------------------------------

    \24\ See section 503B(a)(2)(B) of the FD&C Act.
---------------------------------------------------------------------------

    Oral administration of arginine HCl does not raise serious safety 
issues. The available literature and general clinical practice 
guidelines for the treatment of UCDs indicate that the oral formulation 
of arginine HCl may be effective in treating UCDs. There is evidence of 
the historical and current use of arginine HCl in compounding as an 
oral formulation for the treatment of UCDs (except those with arginase 
deficiency) in the United States, Belgium, and the United Kingdom. 
There are no FDA-approved oral arginine HCl drug products in the United 
States.
    Arginine HCl is a well-characterized amino acid, does not raise 
serious safety concerns, may be effective in treating UCDs, and there 
is evidence of historical and current use of arginine HCl in 
compounding. Therefore, on balance, the physical and chemical 
characterization, safety, effectiveness, and historical and current use 
of arginine HCl for oral use weigh in favor of including this substance 
on the 503B Bulks List. Accordingly, we propose adding arginine HCl to 
the 503B Bulks List for oral use only.

B. Lysine HCl

    Lysine HCl was nominated as a bulk drug substance for the 503B 
Bulks List to compound drug products that are used to correct lysine 
deficiency with lysinuric protein intolerance (LPI) and for prophylaxis 
and acute treatment of herpes simplex outbreak, among other 
conditions.25 26 The proposed route of administration is 
oral, among others; the proposed dosage forms are capsules and 
solutions, among others.\27\ The nominations proposed a strength range 
of 100 to 500 mg. This nominated bulk drug substance is a component of 
many approved drug products as part of a combination with multiple 
other amino acids for intravenous administration (e.g., NDA 
018931).\28\ Lysine HCl is not approved as a single-ingredient drug 
product in any dosage form (Ref. 4).
---------------------------------------------------------------------------

    \25\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0200 and FDA-2015-N-3469-0245. All of the nominations included 
in this evaluation nominated lysine HCl USP grade. Lysine HCl USP 
grade consists of L-lysine hydrochloride. A nominator submitted 
duplicate nominations for L-lysine HCl to the docket: FDA-2015-N-
3469-0199 (submitted on August 31, 2018) and FDA-2015-N-3469-0200 
(submitted on September 4, 2018). For the purposes of this 
evaluation, FDA referred to the information in the most recent 
nomination submitted to the docket (FDA-2015-N-3469-0200). On 
February 26, 2021, this nominator provided additional information 
regarding their nomination for lysine HCl to the University of 
Maryland Center of Excellence in Regulatory Science and Innovation 
(M-CERSI). The updated information is also considered in this 
evaluation. Another nominator nominated ``L-lysine;'' M-CERSI 
clarified with this nominator that they intended to nominate L-
lysine HCl. L-arginine HCl and L-lysine HCl were also nominated by a 
different nominator (FDA-2015-N-3469-0074) to be used in combination 
for intravenous administration with LUTATHERA (lutetium Lu 177 
dotatate injection) treatment, which is the subject of another 
evaluation.
    \26\ The following uses will not be considered in this 
evaluation because the nominations did not provide any information, 
including citations to relevant literature, supporting a clinical 
need for the proposed use: correcting lysine deficiency without LPI, 
rehydration and immune support, osteoporosis, muscle recovery, 
prevention of mucositis. The use of lysine HCl during peptide 
receptor radionuclide therapy to reduce the radiation dose to the 
kidneys is discussed in a separate evaluation. In the updated 
nomination information provided to M-CERSI, a nominator proposed an 
additional use of ``rehydration and immune support'' as an 
intramuscular injection.
    \27\ The proposed topical, intravenous, and intramuscular routes 
of administration will not be considered in this evaluation because 
the nominations do not provide any evidence to support a clinical 
need for drug products with these routes of administration for use 
of lysine HCL to correct lysine deficiency with LPI or for the use 
of lysine HCL for prophylaxis and acute treatment of herpes simplex 
outbreak. Accordingly, the proposed dosage forms associated with 
these routes of administration (cream, ointment, and solutions for 
injection) will not be considered in this evaluation. A nominator 
cited one article that studied the use of the topical product 
``SuperLysinePlus+'' every 2 hours during waking hours in patients 
with symptoms of a cold sore consistent with a herpes simplex virus 
infection of <=24 hours duration (Ref. 5). ``[L]ysine'' is included 
in ``SuperLysinePlus+'' as an inactive ingredient. Thus, this study 
does not provide evidence that there is a need for topical lysine 
HCl in patients with herpes simplex virus.
    \28\ See, e.g., NDA 018931 labeling is available as of the date 
of this notice at https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8543b5be-0f43-4891-9e56-d7c39fe839b5&type=display.
---------------------------------------------------------------------------

    Because lysine HCl is a component of FDA-approved drug products, we 
considered whether: (1) there is a basis to conclude that an attribute 
of each FDA-approved drug product that contains lysine HCl makes each 
one medically unsuitable to treat certain patients for a condition that 
FDA has identified for evaluation, and the lysine HCl drug product 
proposed to be

[[Page 71648]]

compounded is intended to address that attribute in each FDA-approved 
drug product and (2) whether the drug product proposed to be compounded 
must be compounded using a bulk drug substance. In addition, because we 
answered these two questions in the affirmative for an oral lysine HCl 
compounded drug product, we also conducted a balancing test to further 
evaluate this bulk drug substance by considering and applying the four 
factors described above.
1. Suitability of FDA-Approved Drug Products
    A nominator proposes that there is a clinical need for an oral, 
single-ingredient lysine HCl compounded drug product to treat patients 
with lysine deficiency with LPI and for prophylaxis and treatment of 
acute herpes simplex outbreak. We find there is a basis to conclude 
that the FDA-approved drug products that contain lysine HCl are 
medically unsuitable for the proposed uses. The approved drug products 
all contain lysine HCl in combination with multiple other amino acids 
and are for intravenous administration. The nominators did not provide, 
and FDA did not otherwise identify, evidence that these additional 
active ingredients are needed to treat the conditions proposed by the 
nominators. In addition, the approved products are only available for 
intravenous administration and would not be suitable for the uses 
proposed in the nominations, which would involve daily oral 
administration. Accordingly, FDA finds that the drug products proposed 
to be compounded, oral formulations of single-ingredient lysine HCl, 
are intended to address the attribute of the approved drugs that makes 
them medically unsuitable for some patients.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    FDA finds that there is a basis to conclude that the oral drug 
products containing lysine as the single ingredient proposed to treat 
patients with lysine deficiency with LPI and for prophylaxis and 
treatment of acute herpes simplex outbreak must be produced from a bulk 
drug substance because of the difficulties and complexities associated 
with removing lysine HCl from the approved products, which are all 
multiple amino acid solutions.
3. Balancing Test
    Because FDA answered ``yes'' to both of the threshold questions for 
lysine HCl, we next conducted the following balancing testing to 
determine whether the statutory ``clinical need'' standard has been 
met. We considered data and information regarding the physical and 
chemical characterization of lysine HCl, 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.
    Lysine HCl is well-characterized chemically and physically and is 
expected to be stable under ordinary storage conditions. Provided the 
quality of lysine HCl meets the standards in its USP drug substance 
monograph, lysine HCl is well characterized physically and 
chemically.\29\
---------------------------------------------------------------------------

    \29\ See section 503B(a)(2)(B) of the FD&C Act.
---------------------------------------------------------------------------

    The available data do not provide evidence to support the 
effectiveness of oral lysine in the prophylaxis or treatment of herpes 
simplex, and a number of FDA-approved therapies are available for acute 
treatment and prophylaxis of herpes simplex. Oral lysine is also 
nominated for use in LPI, an extremely rare disease, the exact 
prevalence of which in the United States is unknown. Oral lysine is 
used in the treatment of LPI patients in small doses established and 
prescribed on a per patient basis to avoid gastrointestinal 
intolerance. Published data show that oral lysine normalizes plasma 
concentration of lysine in patients with LPI. While the long-term 
results are inconclusive as to whether chronic supplementation or 
intermittent supplementation is consistently helpful (or needed), they 
do suggest a positive impact on growth in some patients. In addition, 
there are no FDA-approved products indicated for the treatment of LPI 
and no FDA-approved, single-ingredient lysine drug products for lysine 
supplementation. Oral use of lysine HCl does not raise serious safety 
issues. The most commonly reported adverse events of abdominal pain and 
diarrhea are associated with high doses of lysine HCl and are usually 
prevented by titrating the dose to a lower acceptable level. There is 
evidence regarding the current and historical use of lysine HCl in 
pharmacy compounding, commonly in an injectable dosage form, within the 
United States. We found no evidence of current or historical use of a 
compounded lysine HCl product for oral administration.
    Lysine HCl is well-characterized chemically; does not raise serious 
safety issues; and although the data do not support the effectiveness 
of lysine HCl in the prophylaxis or treatment of herpes simplex, 
published data show that oral lysine normalizes plasma concentration of 
lysine in patients with LPI. There is evidence of historical and 
current use of lysine HCl in compounding. Therefore, on balance, the 
physical and chemical characterization, safety, effectiveness, and 
historical and current use of lysine HCl weigh in favor of including 
this substance for oral use on the 503B Bulks List. Accordingly, we 
propose adding lysine HCl to the 503B Bulks List for oral use only.

C. Lysine HCl as a Single Ingredient and in Combination With Single-
Ingredient Arginine HCl

    Lysine HCl was also nominated for the 503B Bulks List both as a 
single-ingredient and in combination with arginine HCl.30 31 
Lysine HCl was nominated to compound single-ingredient drug products 
that are used for reduction of radiolabeled peptides during peptide 
receptor radionuclide therapy (PRRT).\32\ Lysine HCl in combination 
with arginine HCl was nominated for post-LUTATHERA \33\ treatment. 
LUTATHERA is indicated to treat somatostatin receptor-positive 
gastroenteropancreatic neuroendocrine tumors, including foregut, 
midgut, and hindgut neuroendocrine tumors in adults. The proposed route 
of administration for lysine HCl used in a compounded drug product in 
combination with arginine HCl, is intravenous and the proposed dosage 
form is injection. For lysine HCl as a

[[Page 71649]]

single-ingredient drug product, the proposed route of administration is 
intravenous, among others, and the proposed dosage form is 
injection.\34\ The nominations proposed a strength range of 25 to 100 
mg/mL. The nominated bulk drug substances arginine HCl \35\ and lysine 
HCl \36\ are components of FDA-approved drug products labeled for 
intravenous administration. Lysine HCl is not a component of any 
single-ingredient, approved drug product in any dosage form, but 
arginine HCl is a component of one single-ingredient, approved drug 
product for intravenous administration (Ref. 6).
---------------------------------------------------------------------------

    \30\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0073 attachment 10, FDA-2015-N-3469-0074 attachment 4, and FDA-
2015-N-3469-0245. A nominator nominated ``L-lysine.'' M-CERSI 
clarified with the nominator that they intended to nominate L-lysine 
HCl. L-arginine HCl as a single ingredient product was nominated by 
other parties for different uses and in different formulations. 
Those nominations are the subject of another evaluation. In 
addition, L-lysine HCl was nominated as a single ingredient product 
for the following uses: to correct lysine deficiency with or without 
lysinuric protein intolerance, prophylaxis and treatment of herpes 
simplex outbreak, osteoporosis, muscle recovery, and prevention of 
mucositis. These nominated uses are the subject of another 
evaluation.
    \31\ Lysine HCl USP grade consists of L-lysine hydrochloride. 
All the nominations discussed in this Federal Register notice 
nominated lysine HCl USP grade. ``lysine HCl'' and ``L-lysine HCl'' 
are used interchangeably throughout this Federal Register notice. 
Arginine HCl USP grade consists of L-arginine monohydrochloride. The 
nomination discussed in this Federal Register notice nominated L-
arginine HCl USP grade. ``Arginine HCl'' and ``L-arginine HCl'' are 
used interchangeably throughout this Federal Register notice.
    \32\ FDA interprets the nominator's proposed use to be to reduce 
the radiation dose to the kidneys during PRRT.
    \33\ Lutetium Lu-177 dotatate (LUTATHERA) was approved by FDA on 
January 26, 2018. It is a PRRT used to treat patients with 
neuroendocrine tumors.
    \34\ The oral and topical routes of administration will not be 
considered in this evaluation because the nomination does not 
provide any evidence to support FDA's evaluation of these routes of 
administration for use of lysine HCl to reduce the radiation dose to 
the kidneys during PRRT.
    \35\ See NDA 016931 labeling is available as of the date of this 
notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/016931s031lbl.pdf.
    \36\ See, e.g., NDA 018931 labeling is available as of the date 
of this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/018931s055,020849s025lbl.pdf. TRAVASOL contains essential 
(including lysine as the HCl salt) and nonessential amino acids 
(including arginine base, not HCl salt).
---------------------------------------------------------------------------

    Because lysine HCl and arginine HCl are components of FDA-approved 
drug products, we considered whether: (1) there is a basis to conclude 
that an attribute of each FDA-approved drug product that contains 
lysine HCl or arginine HCl makes each one medically unsuitable to treat 
certain patients for a condition that FDA has identified for 
evaluation, and the lysine HCl and arginine HCl drug products proposed 
to be compounded are intended to address that attribute in each FDA-
approved drug product and (2) whether the drug product proposed to be 
compounded must be compounded using a bulk drug substance. In addition, 
because we answered these two questions in the affirmative for lysine 
HCl for the intravenous route of administration, we also conducted a 
balancing test to further evaluate both the proposed lysine HCl single-
ingredient product and the use of lysine HCl to compound a drug product 
containing both lysine HCl and FDA-approved arginine HCl by considering 
and applying the four factors described above.
1. Suitability of FDA-Approved Drug Products
    A nominator proposes that there is a clinical need for an 
intravenous product containing a unique combination of lysine HCl and 
arginine HCl to be used in patients receiving LUTATHERA treatment.\37\ 
According to the LUTATHERA labeling, a dual combination of arginine HCl 
and lysine HCl is recommended for renal protection during LUTATHERA 
treatment.\38\ FDA-approved drug products that contain lysine HCl are 
medically unsuitable for the proposed use for patients. Although 
approved drug products that contain lysine HCl in combination with 
multiple other amino acids are used off-label for this indication, the 
nominators did not provide, and FDA did not otherwise identify, 
evidence that these additional active ingredients are needed for 
radiation protection. Furthermore, there is evidence that suggests that 
combination L-lysine HCl/L-arginine HCl compounded intravenous 
infusions produce less nausea in patients receiving them for this 
indication than the FDA-approved amino acid solutions, and therefore 
would lead to fewer episodes of vomiting. The FDA-approved product 
containing arginine HCl, R-Gene 10 10 GM/100 mL injection for 
intravenous administration, is medically unsuitable for patients 
receiving LUTATHERA treatment because LUTATHERA's labeling recommends 
administering an amino acid solution containing L-lysine and L-arginine 
before administering LUTATHERA, rather than administering arginine HCl 
as a single-ingredient.
---------------------------------------------------------------------------

    \37\ In addition, a letter from the Society of Nuclear Medicine 
and Molecular Imaging (SNMMI) provided support for the proposed 
compounded drug product, stating that ``patients receiving lysine 
and arginine solution suffered from much less vomiting incidents in 
comparison with patients infused with commercial solutions'' and 
``lysine and arginine solution is also more effective in inhibiting 
renal uptake of radioactivity during peptide receptor radionuclide 
therapy.'' (Ref. 7).
    \38\ See NDA 208700 labeling is available as of the date of this 
notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf.
---------------------------------------------------------------------------

    The drug product proposed to be compounded is intended to address 
the attributes of the approved drugs that make them medically 
unsuitable for some patients because the nominator proposes to compound 
an intravenous formulation containing both lysine HCl and arginine HCl 
without additional active ingredients.
    A nominator also proposes that there is a clinical need for an 
intravenous product containing lysine HCl as a single ingredient (i.e., 
not in combination with arginine-HCl) to reduce radiolabeled peptides 
during PRRT. The FDA-approved drug products that contain lysine HCl all 
contain lysine HCl in combination with multiple other amino acids. The 
FDA-approved drug products that contain lysine HCl are medically 
unsuitable for the proposed use for some patients. Although FDA-
approved drug products that contain lysine HCl in combination with 
multiple other amino acids are used off-label for this indication, the 
nominators did not provide, and FDA did not otherwise identify, 
evidence that these additional active ingredients are needed for 
radiation protection.
    The drug product proposed to be compounded is intended to address 
the attribute of the approved drug that makes it medically unsuitable 
for some patients because the nominator proposes to compound an 
intravenous product containing lysine HCl as the single ingredient, 
without the other amino acids that are present in the approved drug 
product.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    In order to compound the proposed drug product containing a 
combination of lysine HCl and arginine HCl, FDA has a basis to conclude 
that lysine HCl must be compounded from bulk drug substance rather than 
from the FDA-approved drug products. The bulk drug substance lysine HCl 
must be used because of the difficulties and complexities associated 
with removing lysine HCl from the approved drug products that contain 
multiple other amino acids (e.g., TRAVASOL).\39\
---------------------------------------------------------------------------

    \39\ See, e.g., NDA 018931 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/018931s055,020849s025lbl.pdf.
---------------------------------------------------------------------------

    FDA does not have a basis to conclude that, in order to compound 
the proposed drug product, arginine HCl must be compounded from a bulk 
drug substance rather than from the FDA-approved drug product. There is 
one FDA-approved drug product containing arginine HCl as the single 
ingredient (R-Gene 10). R-Gene 10 is a solution of 10 g/100 mL of 
arginine HCl, USP in water for injection, USP. We do not anticipate 
compatibility or stability issues if this approved drug product is used 
as the starting material to be combined with the bulk drug substance 
lysine HCl to produce a combined solution of lysine HCl and arginine 
HCl at the concentration proposed in the nomination. The pH of the 
compounded drug product must be adjusted to the target pH irrespective 
of the source of arginine HCl (R-Gene 10 or bulk drug substance). In 
addition, the desired osmolarity of <1050 mOsmol is attainable 
irrespective of the source of arginine (R-Gene 10 or bulk drug 
substance) used for compounding the

[[Page 71650]]

lysine HCl and arginine HCl drug product for injection. The nomination 
does not provide any support for the proposition that the proposed 
product must be compounded from a bulk drug substance rather than by 
starting with the FDA-approved drug product R-Gene 10. Because the 
nomination does not provide support for the proposition that the 
arginine HCl component of the drug product must be compounded from a 
bulk drug substance rather than by starting with the FDA-approved drug 
product R-Gene 10, as explained further below, FDA is proposing not to 
add arginine HCl to the 503B Bulks List for use in combination with 
lysine HCl (bulk drug substance).
    For the same reason that there is a basis to conclude that lysine 
HCl for combination with arginine HCl must be compounded from a bulk 
drug substance, there is also a basis to conclude that lysine HCl as a 
single-ingredient compounded drug product for the intravenous route of 
administration must be produced from a bulk drug substance. As with the 
preceding analysis, this is because of the difficulties and 
complexities associated with removing lysine HCl from the approved 
multiple amino acid solutions.
3. Balancing Test
    Because FDA answered ``yes'' to both of the threshold questions for 
lysine HCl as a single ingredient for reducing the radiation dose to 
the kidneys during PRRT and for use in combination with FDA-approved 
arginine HCl, we next conducted the following balancing test to 
determine whether the statutory ``clinical need'' standard has been 
met. We considered data and information regarding the physical and 
chemical characterization of lysine HCl as a single ingredient and in 
combination with arginine HCl, safety issues raised by use of these 
substances in compounding, available evidence of effectiveness or lack 
of effectiveness, and historical and current use in compounding.
    Arginine HCl and lysine HCl are well characterized physically and 
chemically. Each of these amino acids has a USP drug substance 
monograph. In addition, lysine HCl and arginine HCl are stable under 
ordinary storage conditions. The FDA-approved arginine HCl drug 
product, R-Gene 10, is stable at room temperature. Therefore, provided 
the quality of lysine HCl meets the standards in its USP drug substance 
monograph and L-arginine HCl is used starting from the FDA-approved 
drug product, R-Gene 10, both these components are physically and 
chemically well characterized.
    Safety risks associated with the combination of lysine HCl and 
arginine HCl for intravenous infusion are not such that they outweigh 
the benefits, and can be managed. The most common adverse events 
associated with its use are nausea and vomiting. Although there are 
hyperkalemia concerns associated with lysine HCl/arginine HCl infusion, 
this risk could be monitored and managed, if necessary. There is 
evidence of effectiveness of lysine HCl as a single ingredient during 
PRRT; however, lysine HCl as a single ingredient for intravenous 
administration is associated with a higher risk of and more severe 
hyperkalemia and a higher incidence of vomiting than the lysine HCl/
arginine HCl combination for intravenous administration. There is 
evidence of effectiveness of combination lysine HCl and arginine HCl 
infusions for reducing the radiation dose to the kidneys during PRRT in 
the published literature and as described in the approved labeling of 
LUTATHERA. There is also evidence in the published literature that 
suggests that combination lysine HCl/arginine HCl compounded 
intravenous infusions produce less nausea than FDA-approved amino acid 
solutions when used to reduce the radiation dose to the kidneys during 
PRRT, and therefore would lead to fewer episodes of vomiting. There is 
current and historical evidence that lysine HCl and arginine HCl are 
used in combination to compound injectable drug products within the 
United States for nephroprotection during PRRT. There also appears to 
be current and historical evidence that lysine HCl and arginine HCl are 
used in combination to compound injectable drug products outside the 
United States.
    On balance, consideration of the physical and chemical 
characterization, safety, effectiveness, and historical and current use 
weighs against lysine HCl as a single ingredient (bulk drug substance) 
for intravenous use, but weighs in favor of placement on the 503B Bulks 
List of lysine HCl (bulk drug substance) in combination with FDA-
approved, single ingredient arginine HCl injection for intravenous use 
only. Accordingly, we propose adding lysine HCl for use in combination 
with FDA-approved, single-ingredient arginine HCl injection to the 503B 
Bulks List for intravenous use only. FDA encourages public comment on 
any particular considerations related to compounding a drug product 
using FDA-approved, single-ingredient arginine HCl injection in 
combination with lysine HCl (bulk drug substance).
4. Additional Comments
    Due to the safety risks referred to above, if the lysine HCl in 
combination with FDA-approved, single-ingredient arginine HCl injection 
is placed on the 503B Bulks List, FDA intends to make safety 
information about the use of lysine HCl/arginine HCl available to 
prescribers, pharmacists, outsourcing facilities, and the public 
through information on FDA's website, in a safety guide, or through 
other mechanisms, as appropriate.

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

    The three bulk drug substances that have been evaluated and that 
FDA is proposing not to place on the list are as follows: etomidate, 
furosemide, and rocuronium bromide. The reasons for FDA's proposals are 
included below.\40\
---------------------------------------------------------------------------

    \40\ We note that furosemide injection currently appears on 
FDA's drug shortage list. Under section 503B(a)(2)(A)(ii of the FD&C 
Act), outsourcing facilities may compound using a bulk drug 
substance if the drug compounded from such bulk drug substance 
appears on FDA's drug shortage list at the time of compounding, 
distribution, and dispensing, provided all of the conditions in 
section 503B are met. See also FDA's Guidance for Industry, 
``Interim Policy on Compounding Using Bulk Drug Substances Under 
Section 503B of the Federal Food, Drug, and Cosmetic Act,'' which 
describes an enforcement policy for compounding a drug product that 
appeared on FDA's drug shortage list using a bulk drug substance 
that is not on the 503B Bulks List provided certain conditions are 
met. We further note that both furosemide and rocuronium bromide 
appear on the list maintained by FDA of drugs used for hospitalized 
patients with COVID-19. FDA's Guidance for Industry, ``Temporary 
Policy for Compounding of Certain Drugs for Hospitalized Patients by 
Outsourcing Facilities During the COVID-19 Public Health Emergency'' 
describes an enforcement policy, subject to certain conditions, for 
compounding a drug product using a bulk drug substance that is not 
on the 503B Bulks List during the COVID public health emergency.
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    Because the substances in this section are components of FDA-
approved drug products, we considered, as applicable, one or both of 
the following questions: (1) is there 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.

A. Etomidate

    Etomidate has been nominated for inclusion on the 503B Bulks List 
to compound drug products for the

[[Page 71651]]

induction of general anesthesia and as an adjunct in maintenance of 
general anesthesia.\41\ The proposed route of administration is 
intravenous, the proposed dosage form is a preservative-free solution, 
and the proposed concentration is 2 mg/mL. The nominations propose to 
compound a preservative-free solution. However, they fail to 
acknowledge that there is a preservative-free formulation of etomidate 
that is FDA-approved or explain why that formulation would be medically 
unsuitable for certain patients. The nominations state that etomidate 
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 018227). FDA-approved etomidate 
is available as a single dose, preservative-free 20 mg/10 mL (2 mg/mL) 
solution to be administered by intravenous injection.42 43
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    \41\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \42\ See, e.g., NDA 018227 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/41253af6-deac-43de-9af3-3b727ea351d8/41253af6-deac-43de-9af3-3b727ea351d8.xml.
    \43\ According to the label for NDA 018227, each mL contains 
etomidate, 2 mg, propylene glycol 35% v/v.
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1. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of each of the FDA-
approved single dose, preservative-free 2 mg/mL solution products for 
intravenous injection 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 etomidate and 
approved drug products containing etomidate, there is nothing for FDA 
to evaluate under question 2.

B. Furosemide

    Furosemide has been nominated for inclusion on the 503B Bulks List 
to compound drug products that treat congestive heart failure, edema, 
renal failure, and hypertension, among other conditions.\44\ The 
proposed routes of administration are intravenous and intramuscular, 
the proposed dosage forms are both a preservative-free and a preserved 
solution, and the proposed concentration is 10 mg/mL. The nominations 
propose to compound both preservative-free and preserved solutions. 
However, they fail to acknowledge that there is a preservative-free 
formulation of furosemide that is FDA-approved or explain why that 
formulation would be medically unsuitable for certain patients. The 
nominations state that furosemide 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 
212174). FDA-approved furosemide is available as a preservative-free 40 
mg per 4 mL (10 mg/mL) solution for intravenous or intramuscular 
administration.45 46 47
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    \44\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \45\ See, e.g., ANDA 212174 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/421aa6d5-623b-4dc2-abd5-bb9e7765bf37/421aa6d5-623b-4dc2-abd5-bb9e7765bf37.xml.
    \46\ Per the label for ANDA 212174, the solution is 
preservative-free and is intended for intravenous or intramuscular 
administration.
    \47\ Furosemide is also approved as an oral solution and as a 
tablet.
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1. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of each of the FDA-
approved preservative-free 40 mg per 4 mL (10 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 products are intended to 
address. For example, the nominations propose to compound a preserved 
solution because the available FDA-approved products are preservative-
free, but the nominations do not identify specific data or information 
supporting the need for a preserved product. 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 
furosemide must be compounded from bulk drug substances rather than 
using the approved drug product.

C. Rocuronium Bromide

    Rocuronium bromide has been nominated for inclusion on the 503B 
Bulks List to compound drug products that serve as an adjunct to 
general anesthesia to facilitate both rapid sequence and routine 
tracheal intubation and to provide skeletal muscle relaxation during 
surgery or mechanical ventilation.\48\ The proposed route of 
administration is intravenous, the proposed dosage form is a 
preservative-free solution for injection, and the proposed 
concentration is 10 mg/mL. The nominations propose to compound a 
preservative-free solution. However, they fail to acknowledge that 
there is a preservative-free formulation of rocuronium bromide that is 
FDA-approved or explain why that formulation would be medically 
unsuitable for certain patients. The nominations state that rocuronium 
bromide 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 079195). FDA-
approved rocuronium bromide is available as a preservative-free 10 mg/
mL solution for intravenous administration.49 50
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    \48\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \49\ See, e.g., ANDA 079195 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/e21db7bf-3cab-4000-94dd-15c6d2a213de/e21db7bf-3cab-4000-94dd-15c6d2a213de.xml.
    \50\ Per the label for ANDA 079195 each mL contains 10 mg 
rocuronium bromide and 2 mg sodium acetate. The aqueous solution is 
adjusted to isotonicity with sodium chloride and to a pH of 4 with 
acetic acid and/or sodium hydroxide.
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1. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of each of the FDA-
approved 10 mg/mL preservative-free solution products is medically 
unsuitable for certain patients or

[[Page 71652]]

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 rocuronium bromide 
and approved drug products containing rocuronium bromide, there is 
nothing for FDA to evaluate under question 2.

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 arginine HCl for oral use only, lysine 
HCl for oral use only, and lysine HCl in combination with FDA-approved 
single-ingredient arginine HCl for injection for intravenous use only. 
We therefore propose to include those bulk drug substances 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 etomidate, furosemide, and rocuronium bromide. 
Therefore, we 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 Arginine 
Hydrochloride in Compounding Under Section 503B of the FD&C Act,'' 
October 2022.
*4. FDA Memorandum to File, ``Clinical Need for Lysine Hydrochloride 
in Compounding Under Section 503B of the FD&C Act,'' October 2022.
5. Singh, B.B., J. Udani, S.P, Vinjamury, C, Der-Martirosian, et al, 
2005, ``Safety and Effectiveness of an L-lysine, Zinc, and Herbal-
Based Product on the Treatment of Facial and Circumoral Herpes,'' 
Alternative Medicine Review, 10: 123-7
*6. FDA Memorandum to File, ``Clinical Need for Lysine Hydrochloride 
(HCl) Alone and in Combination With Arginine HCl in Compounding 
Under Section 503B of the FD&C Act,'' October 2022.
*7. Letter from SNMMI to FDA dated May 25, 2018, requesting FDA 
place arginine and lysine on the 503B Bulks List.

    Dated: November 17, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-25549 Filed 11-22-22; 8:45 am]
BILLING CODE 4164-01-P