[Federal Register Volume 84, Number 170 (Tuesday, September 3, 2019)]
[Notices]
[Pages 46014-46021]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-18932]
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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
[[Page 46015]]
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 nine bulk drug
substances that FDA has considered and is proposing not to include on
the list: Dipyridamole, ephedrine sulfate, famotidine, hydralazine
hydrochloride, methacholine chloride, sodium bicarbonate, sodium
tetradecyl sulfate, trypan blue, and vecuronium bromide. Additional
bulk drug substances nominated by the public for inclusion on this list
are currently under consideration and will be the subject of future
notices.
DATES: Submit either electronic or written comments on the notice by
November 4, 2019 to ensure that the Agency considers your comment on
this notice before it begins work on a notice reflecting the Agency's
final decision about whether to include these substances on the 503B
Bulks List.
ADDRESSES: You may submit comments at any time as follows:
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 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.
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.gpo.gov/fdsys/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.
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, 301-796-
3110.
SUPPLEMENTARY INFORMATION:
I. Background
A. Statutory and Regulatory 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 under 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 (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
[[Page 46016]]
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 (FDA's
drug shortage list) (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). 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 nine nominated substances that
FDA has evaluated and proposes not to include on the 503B Bulks List.
For purposes of section 503B, 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
United States 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 37750), 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 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 the bulk drug substances nominated for the
503B Bulks List on a rolling basis. FDA will 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.\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'' (81 FR 37502);
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469122.pdf.
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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 beginning
its evaluation of some of the 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.\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
[[Page 46017]]
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'' (503B Bulks Evaluation Guidance) (84 FR 7390);
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf.
This guidance describes FDA policies for developing the 503B Bulks
List, including 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.
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The bulk drug substances that we are addressing in this notice are
components of FDA-approved drug products, and we therefore began our
evaluation by asking the following questions:
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 analyze the question further.\14\ 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 starting with an approved drug product.
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\14\ FDA's 503B Bulks Evaluation Guidance sets forth four
additional factors that the Agency generally intends to consider in
such an analysis. Because we did not answer ``yes'' to both of the
threshold questions for dipyridamole, ephedrine sulfate, famotidine,
hydralazine hydrochloride, methacholine chloride, sodium
bicarbonate, sodium tetradecyl sulfate, trypan blue, or vecuronium
bromide, we did not consider these four additional factors in this
proposal.
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III. Substances Proposed for the 503B Bulks List
Because the substances in this notice 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 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) whether the drug product proposed to
be compounded must be compounded using a bulk drug substance.
The nine bulk drug substances that have been evaluated and that FDA
is proposing not to place on the list are as follows: dipyridamole,
ephedrine sulfate, famotidine, hydralazine hydrochloride, methacholine
chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue,
and vecuronium bromide. The reasons for FDA's proposals are included
below.
A. Dipyridamole
Dipyridamole has been nominated for inclusion on the 503B Bulks
List to compound drug products that are used for thallium myocardial
perfusion imaging for the evaluation of coronary artery disease in
patients who cannot exercise adequately.\15\ The proposed route of
administration is intravenous, the proposed dosage form is an
injection, and the proposed strength is 1 milligram per milliliter (mg/
mL) in a 50 mL and 60 mL syringe. The nominated bulk drug substance is
a component of FDA-approved drug products (e.g., ANDAs 074521 and
074939). FDA-approved dipyridamole is available as a 5 mg/mL injection
for intravenous administration.16 17 Per its labeling, it
should be diluted to a final concentration of less than or equal to 2.5
mg/mL.\18\
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\15\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0031.
\16\ See, e.g., ANDA 074521 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175.xml.
\17\ Dipyridamole is also approved as an oral tablet and in
combination with aspirin as an extended release capsule.
\18\ According to the label for ANDA 074521, dipyridamole
injection should be diluted in at least a 1:2 ratio with with sodium
chloride injection 0.45%, sodium chloride injection 0.9% or dextrose
injection 5% for a total volume of approximately 20 to 50 mL.
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1. Suitability of FDA-Approved Drug Product
The nomination does not identify an attribute of the FDA-approved
drug 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 5 mg/mL
injection (for dilution) is medically unsuitable for certain patients.
Accordingly, with respect to the dipyridamole drug products proposed to
be compounded, 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.
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 dipyridamole must be
compounded from bulk drug substances rather than by diluting the
approved drug product. FDA finds no basis to conclude that the
dipyridamole drug products proposed in the nominations must be
compounded using a bulk drug substance rather than the approved drug
product.
B. Ephedrine Sulfate
Ephedrine sulfate has been nominated for inclusion on the 503B
Bulks List to compound drug products that treat acute bronchospasm,
drug induced hypotension due to anesthesia, and nasal congestion.\19\
The proposed route of administration is intravenous, the proposed
dosage form is a preservative-
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free solution, and the proposed strengths are 5 mg/mL and 10 mg/mL.\20\
The nominated bulk drug substance is a component of FDA-approved drug
products (e.g., NDAs 208943 and 208289). FDA-approved ephedrine sulfate
is available as a single-dose, preservative-free 50 mg/mL solution for
intravenous administration.21 22 Per its labeling, ephedrine
sulfate must be diluted before administration to achieve the desired
concentration as an intravenous bolus or intravenous infusion. The
labeling includes preparation instructions for making a solution
containing a final concentration of 5 mg/mL of ephedrine sulfate
injection for bolus intravenous administration.
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\19\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\20\ Nominator(s) proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is a
preservative-free formulation of ephedrine sulfate that is marketed
or explain why that formulation would be medically unsuitable for
certain patients.
\21\ See, e.g., NDA 208943 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/6df5e5f1-6375-45ff-9905-f19927e92ee2/6df5e5f1-6375-45ff-9905-f19927e92ee2.xml.
\22\ Per the label for NDA 208943, each mL contains ephedrine
sulfate 50 mg in water for injection as a single-dose product.
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1. Suitability of FDA-Approved Drug Product
The nominations do not identify an attribute of the FDA-approved
drug products that make them medically unsuitable to treat certain
patients and that the proposed compounded drug products are intended to
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 50 mg/mL solution (for dilution) is medically
unsuitable for certain patients. Accordingly, with respect to the
ephedrine sulfate drug products proposed to be compounded, 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.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not take the position or provide support for the
position that drug products containing ephedrine sulfate must be
compounded from bulk drug substances rather than by diluting the
approved drug product. FDA finds no basis to conclude that the
ephedrine sulfate drug products proposed in the nominations must be
compounded using a bulk drug substance rather than the approved drug
product.
C. Famotidine
Famotidine has been nominated for inclusion on the 503B Bulks List
to compound drug products that treat duodenal ulcer disease,
esophagitis, gastrointestinal reflux disease, and gastric ulcer
disease, among other conditions.\23\ The proposed route of
administration is intravenous, the proposed dosage form is a
preservative-free solution and a diluted injection solution, and the
proposed strengths range from 2 mg/mL to 10 mg/mL.\24\ The nominated
bulk drug substance is a component of FDA-approved drug products (e.g.,
ANDAs 078641 and 078642). FDA-approved famotidine is available as a
single-dose, preservative-free 10 mg/mL solution for intravenous
administration.25 26 27 Per its labeling, famotidine may be
diluted to a final concentration of 4 mg/mL or 2 mg/mL for bolus
administration.\28\
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\23\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\24\ Nominator(s) proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is a
preservative-free formulation of famotidine that is marketed or
explain why that formulation would be medically unsuitable for
certain patients.
\25\ See, e.g., ANDAs 079641 and 079641 labeling available as of
the date of this notice at https://www.accessdata.fda.gov/spl/data/99bd2efa-ef75-4daf-ae24-ab574adf1a1e/99bd2efa-ef75-4daf-ae24-ab574adf1a1e.xml.
\26\ Per the label for ANDA 079641, famotine injection is
available in a non-preserved single-dose vial.
\27\ Famotidine is also approved as an oral tablet and a powder
for suspension for oral administration.
\28\ According to the label for ANDA 078642, to prepare
famotidine intravenous solutions, aseptically dilute 2 mL of
famotidine injection, USP (solution containing 10 mg/mL) with 0.9%
Sodium Chloride Injection or other compatible intravenous solution
(see Stability, Famotidine Injection, USP) to a total volume of
either 5 mL or 10 mL and inject over a period of not less than 2
minutes. In addition, to prepare famotidine intravenous infusion
solutions, aseptically dilute 2 mL of famotidine injection, USP with
100 mL of 5% dextrose or other compatible solution (see Stability,
Famotidine Injection, USP), and infuse over a 15- to 30-minute
period.
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1. Suitability of FDA-Approved Drug Product
The nominations do not identify an attribute of the FDA-approved
drug products that make them medically unsuitable to treat certain
patients and that the proposed compounded drug products are intended to
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 10 mg/mL solution (for dilution) is medically
unsuitable for certain patients. Accordingly, with respect to the
famotidine drug products proposed to be compounded, 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.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not take the position or provide support for the
position that drug products containing famotidine must be compounded
from bulk drug substances rather than by diluting the approved drug
product. FDA finds no basis to conclude that the famotidine drug
products proposed in the nominations must be compounded using a bulk
drug substance rather than the approved drug product.
D. Hydralazine Hydrochloride (HCl)
Hydralazine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat essential hypertension.\29\
The proposed routes of administration are intravenous and
intramuscular, the proposed dosage form is a preservative-free
solution, and the proposed strengths are 0.2 mg/mL and 20 mg/mL.\30\
The nominated bulk drug substance is a component of FDA-approved drug
products (e.g., ANDAs 204680 and 040730). FDA-approved hydralazine HCl
is available as a preservative-free 20 mg/mL solution for intravenous
and intramuscular administration.31 32 33
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\29\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\30\ Nominator(s) proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is a
preservative-free formulation of hydralazine HCl that is marketed or
explain why that formulation would be medically unsuitable for
certain patients.
\31\ See, e.g., ANDA 204680 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/92e234dc-d44e-4e81-b305-4a47b1cfe2c3/92e234dc-d44e-4e81-b305-4a47b1cfe2c3.xml.
\32\ Per the label for ANDA 204680, hydralazine HCl is available
in a preservative-free, single-dose vial.
\33\ Hydralazine HCl is also approved as an oral tablet, as an
oral capsule in combination with hydrochlorothiazide, and as an oral
tablet in combination with isosorbide dinitrate.
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1. Suitability of FDA-Approved Drug Product
The nominations do not identify an attribute of the FDA-approved
drug products that make them medically unsuitable to treat certain
patients and that the proposed compounded drug products are intended to
address. Specifically, the nominations do not explain why the
preservative-free 20 mg/mL solution is medically unsuitable for certain
patients. Accordingly, with respect to the hydralazine HCl drug
[[Page 46019]]
products proposed to be compounded, 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.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not take the position or provide support for the
position that drug products containing hydralazine HCl must be
compounded from bulk drug substances rather than by diluting the
approved drug product. FDA finds no basis to conclude that hydralazine
HCl drug products proposed in the nominations must be compounded using
a bulk drug substance rather than the approved drug product.
E. Methacholine Chloride
Methacholine chloride has been nominated for inclusion on the 503B
Bulks List to compound drug products that aid in the diagnosis of
bronchial airway hyperactivity.\34\ The proposed route of
administration is inhalation tapering dose kits, the proposed dosage
form is an inhalant, and the proposed strengths are as follows: 8
dilutions (0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/
mL, 8 mg/mL, 16 mg/mL) and 10 dilutions (0.031 mg/mL, 0.0625 mg/mL,
0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL,
16 mg/mL). The nominated bulk drug substance is a component of an FDA-
approved drug product (NDA 019193). FDA-approved methacholine chloride
is available as a 100 mg/vial powder for solution to be administered
only by inhalation.\35\ Per its labeling, methacholine chloride is
reconstituted and diluted to the following concentrations with 0.9%
sodium chloride injection or 0.9% sodium chloride injection containing
0.4% phenol (pH 7.0): 0.025 mg/mL, 0.25 mg/mL, 2.5 mg/mL, 10 mg/mL, and
25 mg/mL.
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\34\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
\35\ See, e.g., NDA 208943 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/7f538d73-80e2-4c00-911a-df2637e5a4d1/7f538d73-80e2-4c00-911a-df2637e5a4d1.xml.
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1. Suitability of FDA-Approved Drug Product
The nomination does not identify an attribute of the FDA-approved
drug product that makes it 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 100 mg/
vial powder for solution (for reconstitution) is medically unsuitable
for certain patients. Accordingly, with respect to the methacholine
chloride drug products proposed to be compounded, 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.
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 methacholine chloride must
be compounded from bulk drug substances rather than by diluting the
approved drug product. FDA finds no basis to conclude that the
methacholine chloride drug products proposed in the nominations must be
compounded using a bulk drug substance rather than the approved drug
product.
F. Sodium Bicarbonate
Sodium bicarbonate has been nominated for inclusion on the 503B
Bulks List to compound drug products that treat various conditions,
including metabolic acidosis, certain drug intoxications, severe
diarrhea, and indigestion.\36\ The proposed route of administration is
intravenous, the proposed dosage forms are an injectable, preservative-
free solution, and injection solutions, and the proposed strengths
range from 4.2% to 8.4%, as well as unspecified higher
concentrations.\37\ The nominated bulk drug substance is a component of
FDA-approved drug products (e.g., ANDAs 203449 and 202494). FDA-
approved sodium bicarbonate is available as a single-dose,
preservative-free 1 milliequivalent (mEq/mL) (8.4%) solution for
intravenous administration.38 39 40
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\36\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298. Also, see Docket No. FDA-2015-N-
3469, document no. FDA-2015-N-3469-0095.
\37\ Nominator(s) proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is a
preservative-free formulation of sodium bicarbonate that is marketed
or explain why that formulation would be medically unsuitable for
certain patients.
\38\ See, e.g., ANDA 203449 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/0e955d36-928c-4f09-9b34-0cc954e5b1f4/0e955d36-928c-4f09-9b34-0cc954e5b1f4.xml.
\39\ Per the label for ANDA 203449, the solutions contain no
bacteriostat, antimicrobial agent, or added buffer and are intended
only for use as a single-dose injection.
\40\ Sodium bicarbonate is also approved in combination with
other ingredients as an injectable, solution for irrigation, and
various oral formulations.
---------------------------------------------------------------------------
1. Suitability of FDA-Approved Drug Product
The nominations do not identify an attribute of the FDA-approved
drug products that make them medically unsuitable to treat certain
patients and that the proposed compounded drug products are intended to
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 1 mEq/mL (8.4%) solution is medically
unsuitable for certain patients. A nomination submitted by the
Outsourcing Facilities Association states that it may be necessary to
compound a product with 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.
Accordingly, with respect to the sodium bicarbonate drug products
proposed to be compounded, 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.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not take the position or provide support for the
position that the proposed sodium bicarbonate products with
concentrations at or below 8.4% (1 mEQ/mL) must be compounded from bulk
drug substances rather than by diluting the approved drug product. In
light of the analysis in section III.6.a. above, we do not consider
whether a bulk drug substance must be used to compound a sodium
bicarbonate drug product at concentrations higher than 8.4%. FDA finds
no basis to conclude that the sodium bicarbonate drug products proposed
in the nominations must be compounded using a bulk drug substance
rather than the approved drug product.
G. Sodium Tetradecyl Sulfate
Sodium tetradecyl sulfate has been nominated for inclusion on the
503B Bulks List to compound drug products that treat varicose
veins.\41\ The proposed route of administration is intravenous, the
proposed dosage form is an injection solution, and the proposed
strengths range from 0.1% to 3%. The nominated
[[Page 46020]]
bulk drug substance is a component of an FDA-approved drug product
(ANDA 040541). FDA-approved sodium tetradecyl sulfate is available as a
20 mg/2 mL (10 mg/mL; 1%) and 60 mg/2 mL (30 mg/mL; 3%) solution for
intravenous administration.\42\
---------------------------------------------------------------------------
\41\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
\42\ See, e.g., ANDA 040541 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/5450f902-fb17-44b8-8c4b-4fefeed1908e/5450f902-fb17-44b8-8c4b-4fefeed1908e.xml.
---------------------------------------------------------------------------
1. Suitability of FDA-Approved Drug Product
The nomination does not identify an attribute of the FDA-approved
drug product that makes it 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 20 mg/2
mL (10 mg/mL; 1%) and 60 mg/2 mL (30 mg/mL; 3%) solutions are medically
unsuitable for certain patients. Accordingly, with respect to the
sodium tetradecyl sulfate drug products proposed to be compounded, 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.
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 tetradecyl sulfate
must be compounded from bulk drug substances rather than by diluting
the approved drug product. FDA finds no basis to conclude that the
sodium tetradecyl sulfate drug products proposed in the nominations
must be compounded using a bulk drug substance rather than the approved
drug product.
H. Trypan Blue
Trypan blue has been nominated for inclusion on the 503B Bulks List
to compound drug products that aid in staining the eye for cataract
surgery and vitrectomy.\43\ The proposed route of administration is
intraocular,\44\ the proposed dosage form is a preservative-free
solution, and the proposed strengths are 0.05%, 0.06%, and 0.15%.\45\
The nominated bulk drug substance is a component of FDA-approved drug
products (e.g., NDAs 021670 and 022278). FDA-approved trypan blue is
available as a single-dose, preservative-free 0.06% and 0.15% solution
for intraocular administration.46 47
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\43\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\44\ One nominator proposed the following route of
administration and dosage form: Ophthalmic solution; injection.
Thus, FDA determined that the proposed route of administration is
intraocular.
\45\ Nominator(s) proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is a
preservative-free formulation of trypan blue that is marketed or
explain why that formulation would be medically unsuitable for
certain patients.
\46\ See, e.g., NDA 021670 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/7c57aaf4-e1a1-d191-e053-2a91aa0a757a/7c57aaf4-e1a1-d191-e053-2a91aa0a757a.xml
and NDA 022278 labeling available as of the date of this notice at
https://www.accessdata.fda.gov/spl/data/7c57f83d-da8f-2499-e053-2a91aa0afe8e/7c57f83d-da8f-2499-e053-2a91aa0afe8e.xml.
\47\ Per the label for NDA 021670, each mL contains: 0.6 mg
trypan blue, 1.9 mg sodium mono-hydrogen orthophosphate, 0.3 mg
sodium di-hydrogen orthophosphate, 8.2 mg sodium chloride, and water
for injection. Per the label for NDA 022278, each mL contains: 1.5
mg trypan blue, 1.9 mg sodium mono-hydrogen orthophosphate, 0.3 mg
sodium di-hydrogen orthophosphate, 8.2 mg sodium chloride, and water
for injection.
---------------------------------------------------------------------------
1. Suitability of FDA-Approved Drug Product
The nominations do not identify an attribute of the FDA-approved
drug products that make them medically unsuitable to treat certain
patients and that the proposed compounded drug products are intended to
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 0.06% and 0.15% solutions are medically
unsuitable for certain patients. Accordingly, with respect to trypan
blue drug products proposed to be compounded, 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.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not take the position or provide support for the
position that drug product containing trypan blue must be compounded
from bulk drug substances rather than by diluting the approved drug
product. FDA finds no basis to conclude that the trypan blue drug
products proposed in the nominations must be compounded using a bulk
drug substance rather than the approved drug product.
I. Vecuronium Bromide
Vecuronium bromide has been nominated for inclusion on the 503B
Bulks List to compound drug products that facilitate endotracheal
intubation.\48\ The proposed route of administration is rapid
intravenous injection or by intravenous infusion using an infusion
control device, the proposed dosage form is an injection, and the
propose strengths are 10 mg/10 mL (1 mg/mL) in sterile water for
injection and 100 mg/100 mL (1 mg/mL) in 0.9% sodium chloride solution.
The nominated bulk drug substance is a component of FDA-approved drug
products (e.g., ANDAs 079001 and 206670). FDA-approved vecuronium
bromide is available as a 10 mg/vial and 20 mg/vial lyophilized powder
for solution for intravenous administration (bolus dosing or continuous
infusion).\49\ Per its labeling, vecuronium bromide is 1 mg/mL after
reconstitution with either 10 mL (10 mg/vial) or 20 mL (20 mg/vial) of
diluent.\50\
---------------------------------------------------------------------------
\48\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0011.
\49\ See, e.g., ANDA 079001 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/82d6bc45-04a5-409a-9223-da1884b2468f/82d6bc45-04a5-409a-9223-da1884b2468f.xml.
\50\ In addition, the labeling contains infusion rate
information for two separate strength solutions: 0.1 mg/mL (10 mg of
vecuronium bromide in 100 mL solution) and 0.2 mg/mL (20 mg of
vecuronium bromide in 100 mL solution).
---------------------------------------------------------------------------
1. Suitability of FDA-Approved Drug Product
The nomination does not identify an attribute of the FDA-approved
drug products that make 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 10 mg/
vial and 20 mg/vial lyophilized powders for solution (for
reconstitution) are medically unsuitable for certain patients.
Accordingly, with respect to the vecuronium bromide drug products
proposed to be compounded, 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.
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 vecuronium bromide must be
compounded from bulk drug substances rather than by diluting the
approved drug product. FDA finds no basis to conclude that the
vecuronium bromide drug products proposed in the
[[Page 46021]]
nominations must be compounded using a bulk drug substance rather than
the approved drug product.
IV. 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 providing drug products
containing each of these bulk drug substances that do not require
dilution or reconstitution prior to administration. More broadly, as
explained above, when a bulk drug substance is a component of an
approved drug, FDA asks 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 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.\51\
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\51\ 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'' (503B Bulks Evaluation
Guidance) (84 FR 7390); available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf 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.
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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.\52\
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\52\ 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.
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V. Conclusion
For the reasons stated above, we find no basis to conclude that
there is a clinical need for outsourcing facilities to compound drug
products using the bulk drug substances dipyridamole, ephedrine
sulfate, famotidine, hydralazine hydrochloride, methacholine chloride,
sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, and
vecuronium bromide. We therefore propose to not include dipyridamole,
ephedrine sulfate, famotidine, hydralazine hydrochloride, methacholine
chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue,
and vecuronium bromide on the 503B Bulks List.
Dated: August 27, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-18932 Filed 8-30-19; 8:45 am]
BILLING CODE 4164-01-P