Notice2024-30456
Hazardous Drugs: NIOSH List of Hazardous Drugs in Healthcare Settings, 2024 and Final Reevaluation Determinations for Liraglutide and Pertuzumab
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
December 20, 2024
Issuing agencies
Health and Human Services DepartmentCenters for Disease Control and Prevention
Abstract
The National Institute for Occupational Safety and Health (NIOSH) of the Centers for Disease Control and Prevention (CDC), in the Department of Health and Human Services (HHS), announces the publication of the NIOSH List of Hazardous Drugs in Healthcare Settings, 2024, as well as final reevaluation determinations removing the drugs liraglutide and pertuzumab from the NIOSH List of Hazardous Drugs in Healthcare Settings.
Full Text
<html>
<head>
<title>Federal Register, Volume 89 Issue 245 (Friday, December 20, 2024)</title>
</head>
<body><pre>
[Federal Register Volume 89, Number 245 (Friday, December 20, 2024)]
[Notices]
[Pages 104163-104182]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-30456]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Centers for Disease Control and Prevention
[Docket No. CDC-2020-0046; NIOSH-233-C]
Hazardous Drugs: NIOSH List of Hazardous Drugs in Healthcare
Settings, 2024 and Final Reevaluation Determinations for Liraglutide
and Pertuzumab
AGENCY: Centers for Disease Control and Prevention (CDC), Department of
Health and Human Services (HHS).
ACTION: General notice.
-----------------------------------------------------------------------
SUMMARY: The National Institute for Occupational Safety and Health
(NIOSH) of the Centers for Disease Control and Prevention (CDC), in the
Department of Health and Human Services (HHS), announces the
publication of the NIOSH List of Hazardous Drugs in Healthcare
Settings, 2024, as well as final reevaluation determinations removing
the drugs liraglutide and pertuzumab from the NIOSH List of Hazardous
Drugs in Healthcare Settings.
DATES: The documents announced in this notice are available on December
20, 2024.
ADDRESSES: The documents announced in this notice are available in the
docket at <a href="http://www.regulations.gov">www.regulations.gov</a> and through the NIOSH Hazardous Drug
Exposures in Healthcare website at <a href="https://www.cdc.gov/niosh/healthcare/hazardous-drugs/index.html">https://www.cdc.gov/niosh/healthcare/hazardous-drugs/index.html</a>.
FOR FURTHER INFORMATION CONTACT: Jerald Ovesen, NIOSH, Robert A. Taft
Laboratories, 1090 Tusculum Avenue, MS-C15, Cincinnati, OH 45226,
telephone: (513)533-8472 (not a toll-free number), email:
<a href="/cdn-cgi/l/email-protection#b5dfdac3d0c6d0dbf5d6d1d69bd2dac3"><span class="__cf_email__" data-cfemail="402a2f362533252e002324236e272f36">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION: This notice is organized as follows:
I. Public Participation
II. Background
III. NIOSH Response to Public Comment in the May 2020 Federal
Register Notice and Request for Comment
A. General Characteristics of the List
1. Timing of the List
2. Drugs That Did Not Meet the NIOSH Hazardous Drug Criteria
B. General Drug Descriptors
1. Unique Identifiers
2. Use of AHFS Classifications
3. Use of AHFS Code for Hormone Drug Classification
4. Monoclonal Antibodies as a Class of Drugs
5. Progestins
6. Additional Information Requested
C. General Reorganization of the List
1. Content of Tables
2. DailyMed and DrugBank Links
D. Drugs Not on the Draft 2020 List
1. Drugs Proposed in February 2018 and Not Added to the Draft
2020 List
2. Bacillus Calmette-Guerin (BCG)
3. Botulinum Toxins
E. Requests for Specific Drugs To Be Removed From the List
1. Blinatumomab
2. Carfilzomib
3. Eslicarbazepine, Lomitapide, Mifepristone
4. Hazardous Drugs Listed for Reproductive and Developmental
Effects: Cabergoline, Clonazepam, Fluconazole, Plerixafor,
Riociguat, and Ziprasidone
5. Icatibant
6. Leuprolide
7. Olaparib and Teriflunomide
8. Oxytocin and Other Oxytocic Drugs
9. Paroxetine
10. Spironolactone
11. Topiramate
12. Ulipristal
13. Vigabatrin
F. Placement of Specific Drugs Within the List
1. Carfilzomib
2. Dasatinib and Imatinib
3. Eribulin
4. Exenatide
5. Ganciclovir and Valganciclovir
6. Hormonal Agents: Goserelin, Degarelix, Leuprolide, Estrogens,
and Progesterone
7. Mycophenolate Mofetil and Mycophenolic Acid
8. Sirolimus and Other Related mTOR Targeting Drugs
9. Thalidomide, Lenalidomide, and Pomalidomide
10. Vandetanib
G. Specific Drugs Classification/Identification
1. Triptorelin
2. Ziv-Aflibercept, Ado-Trastuzumab Emtansine, Fam-Trastuzumab
Deruxtecan
H. Suggested Copyedits
IV. NIOSH Response to Public Comment and Peer Review in the January
2024 Federal Register Notice and Request for Comment on Proposed
Removal of Liraglutide and Pertuzumab From the List
A. Public Comment
1. General Comments
2. Liraglutide
3. Pertuzumab
a. Is this an appropriate method for evaluating the potential
for exposure to pertuzumab?
b. Is oligohydramnios the best health effect to evaluate? If
not, what other health effect(s) should be evaluated and why?
c. Is a needlestick injury the only reasonable route of exposure
for healthcare workers?
d. Are the assumptions about the amount of exposure to
pertuzumab in a healthcare setting reasonable?
i. Inhalation
ii. Percutaneous Exposure
iii. Oral exposure
e. What alternatives could be considered to this approach for
monoclonal antibodies to characterize the potential hazard to
workers?
[[Page 104164]]
f. Additional Pertuzumab Comments
B. Peer Review
1. Liraglutide Peer Review
a. Are the evaluated health effects the appropriate health
effects to consider? If not, what other health effect(s) should be
evaluated and why?
b. Are the assumptions about the potential occupational
exposures to liraglutide in a healthcare setting reasonable?
c. Is the determination that the amount of exposure to
liraglutide in a healthcare setting does not constitute a hazard for
healthcare workers reasonably supported by the available scientific
information?
d. What alternative approaches could be considered to
characterize the potential hazard to workers from peptide-based
drugs?
e. Is there any additional information that NIOSH should
consider in its reevaluation of liraglutide?
2. Pertuzumab Peer Review
a. Reviewer 1
b. Reviewer 2
c. Reviewer 3
V. Summary of Updates and Changes to the NIOSH List of Hazardous
Drugs in Healthcare Settings
I. Public Participation
In a Federal Register notice (notice) published on May 1, 2020 (85
FR 25439), NIOSH invited the public to participate in the development
and reorganization of the NIOSH List of Hazardous Drugs in Healthcare
Settings. The NIOSH List of Hazardous Drugs in Healthcare Settings
(List) assists employers in providing safe and healthy workplaces by
identifying drugs approved by the Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER) that meet the NIOSH
definition of a hazardous drug and that may pose hazards to healthcare
workers who handle, prepare, dispense, administer, or dispose of these
drugs.
The public was invited to submit written comments regarding the
draft List, as well as views, opinions, recommendations, and/or data on
any topic related to the drugs reviewed by NIOSH for possible placement
on the List. The public comment period for the May 2020 notice was
initially open until June 30, 2020 (85 FR 25439), and later extended
until July 30, 2020 (85 FR 37101), to ensure commenters had adequate
time to comment.
One hundred thirty-two submissions were received from commenters in
Docket CDC-2020-0046 (NIOSH-233-C). Commenters consisted of nurses;
pharmacists; safety personnel; a veterinarian; healthcare, business,
and government administrators and committees; and anonymous and
unaffiliated individuals. The commenters represented a wide range of
institutions, including academic and general medical centers and
healthcare systems; hospital, commercial drug store, and compounding
pharmacies; manufacturers of pharmaceuticals and medical devices;
professional, healthcare, and veterinary organizations and
associations; home infusion organizations; suppliers of cleanroom
products; boards of pharmacy; and consultant companies for healthcare
improvement and the performance of healthcare facilities, risk
assessment, and waste management. Public comments on the List and two
other documents discussed in the May 2020 notice are available in the
docket for this activity.
NIOSH carefully considered all public comments and peer reviews
concerning the draft List resulting from the 2020 notice and determined
that some clarifications and changes should be made to the draft List.
Public comments on the draft List and specific drugs are summarized and
answered in section III. These changes are summarized in section V. of
this notice and are reflected in the final document described in this
notice.
In a January 16, 2024, Federal Register notice (89 FR 2614), NIOSH
sought public comment and peer review on the reevaluation of two drugs
requested to be removed from the List by their respective
manufacturers: liraglutide and pertuzumab. Responses to public and peer
review comments on the reevaluations of the placements of liraglutide
and pertuzumab on the List are in section IV. These changes to the List
are summarized in section V.
The NIOSH List of Hazardous Drugs in Healthcare Settings, 2024
(2024 List) \1\ is published on the NIOSH website and is also available
in the docket for this activity.
---------------------------------------------------------------------------
\1\ NIOSH [2024]. NIOSH List of Hazardous Drugs in Healthcare
Settings, 2024. By Ovesen JL, Sammons D, Connor TH, MacKenzie BA,
DeBord DG, Trout DB, O'Callaghan JP, Whittaker C. Cincinnati, OH:
U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention, National Institute for Occupational Safety
and Health, DHHS (NIOSH) Publication Number 2025-103 (Supersedes
2016-161), <a href="https://www.cdc.gov/niosh/docs/2025-103">https://www.cdc.gov/niosh/docs/2025-103</a>. NB: NIOSH has
periodically updated the List from 2010 through 2016; prior to the
2024 update to the List, it was named the NIOSH List of
Antineoplastic and Other Hazardous Drugs in Healthcare Settings.
---------------------------------------------------------------------------
II. Background
In 2004, NIOSH published the NIOSH Alert: Preventing Occupational
Exposures to Antineoplastic and Other Hazardous Drugs in Health Care
Settings (Alert), which contained a compilation of lists of drugs
considered to be hazardous to workers' health. NIOSH periodically
updates this list, now named the NIOSH List of Hazardous Drugs in
Healthcare Settings (List), to assist employers in providing safe and
healthful workplaces by identifying drugs that meet the NIOSH
definition of a hazardous drug. The List is informational in nature and
confers no requirements or legal obligations on users.
In 2017, NIOSH began developing a document to make the process used
to guide the addition of hazardous drugs to the List more transparent,
entitled the Policy and Procedures for Developing the NIOSH List of
Antineoplastic and Other Hazardous Drug in Healthcare Settings (Policy
and Procedures). The Policy and Procedures document was created to
formalize NIOSH's methodology and establish a process for requesting
the addition of a drug to, the removal of a drug from, or relocation of
a drug within the List. This document was reviewed by four peer
reviewers and eight interested parties before NIOSH made the document
available for public comment in a February 14, 2018, notice (83 FR
6563). The peer reviewers and interested parties also provided input on
the drugs considered for placement on the List.
Consistent with the draft Policy and Procedures, NIOSH proposed the
addition of 20 drugs and one class of drugs to the List in the
framework for the draft List in the February 2018 notice. Public
comments were invited regarding any topic related to drugs identified
in the notice, the draft Policy and Procedures, and the framework for
the February 2018 update to the List, as well as the following
questions related to this activity:
1. Has NIOSH appropriately identified and categorized the drugs
considered for placement on the NIOSH List of Antineoplastic and Other
Hazardous Drugs in Healthcare Settings, 2018?
2. Is information available from FDA or other Federal agencies or
in the published, peer-reviewed scientific literature about a specific
drug or drugs identified in this notice that would justify the
reconsideration of NIOSH's categorization decision?
3. Does the draft Policy and Procedures for Developing the NIOSH
List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings
include a methodology for reviewing toxicity information that is
appropriate for this activity?
Fifty-five public comments were submitted in response to the
February 2018 notice and summarized with NIOSH responses in a May 2020
notice (85 FR 25439). Those comments are available in Docket CDC-2018-
0004. The substantive input provided by peer
[[Page 104165]]
reviewers, interested parties, and public commenters on the February
2018 notice caused NIOSH to reconsider certain aspects of the draft
Policy and Procedures and the draft framework for the List. As a
result, NIOSH revised and updated the draft Policy and Procedures,
renamed ``Procedures,'' as well as the draft list of drugs proposed for
placement on the List. This collective input also contributed to the
development of the draft document Managing Hazardous Drug Exposures:
Information for Healthcare Settings (Managing Exposures), also
announced in the May 2020 notice. Comments resulting from the May 2020
notice are available at <a href="http://www.regulations.gov">www.regulations.gov</a> in Docket CDC-2020-0046.
In April 2023, NIOSH published a notice in the Federal Register (88
FR 25642) that announced the publication of the final versions of the
``Procedures'' and ``Managing Exposures'' documents. The April 2023
notice summarized and responded to public input on the ``Procedures''
and ``Managing Exposures'' documents. Those changes were reflected in
the finalized documents, Procedures for Developing the NIOSH List of
Hazardous Drugs in Healthcare Settings [NIOSH 2023a] and Managing
Hazardous Drugs Exposures: Information for Healthcare Settings [NIOSH
2023b], which are available on the NIOSH website at <a href="https://www.cdc.gov/niosh/healthcare/hazardous-drugs/publications.html">https://www.cdc.gov/niosh/healthcare/hazardous-drugs/publications.html</a>.
In January 2024, pursuant to the Procedures, NIOSH conducted peer
reviews and sought public comment on initial recommendations to change
the status of the drugs liraglutide and pertuzumab, added to the NIOSH
List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings
in 2014 and 2016, respectively. NIOSH published its charge to peer
reviewers and public commenters in a Federal Register notice on January
16, 2024 (89 FR 2614), requesting feedback on NIOSH's initial
recommendations to remove the drugs liraglutide and pertuzumab from the
NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare
Settings. The two initial recommendations and summaries of evidence,
NIOSH Reevaluation of Liraglutide on the NIOSH List of Antineoplastic
and Other Hazardous Drugs in Healthcare Settings and NIOSH Reevaluation
of Pertuzumab on the NIOSH List of Antineoplastic and Other Hazardous
Drugs in Healthcare Settings, were made available to peer reviewers and
public commenters in the docket for this activity.
III. NIOSH Response to Public Comment in the May 2020 Federal Register
Notice and Request for Comment
The public comments received in response to the draft NIOSH List of
Hazardous Drugs in Healthcare Settings, proposed in the May 2020 notice
and available in the docket, are summarized below, followed by NIOSH
responses.
A. General Characteristics of the List
1. Timing of the List
Public comment: Several commenters mentioned that the NIOSH review
has created a long gap between List updates and would like for NIOSH to
have more frequent updates.
NIOSH response: NIOSH received a substantial response to its
proposed revisions of the organization of the List in 2018 and has
worked diligently to provide thorough and transparent responses to
those comments. This notice is the finalization of that process. Moving
forward, NIOSH intends to publish periodic updates to the List while
maintaining the rigor of review by multiple scientists, outside
experts, and public comment. Because the delay between the final date
of drugs being approved to market and the publication of updates to the
List is unavoidable, it is important for employers to review all
relevant potential hazard information on the drugs being used in their
facility, especially newly FDA-approved drugs that are new to the
facility's formulary and which have not yet been publicly evaluated by
NIOSH.
2. Drugs That Did Not Meet the NIOSH Hazardous Drug Criteria
Public comment: Two commenters requested that NIOSH publish a list
of which drugs did not meet the NIOSH criteria of a hazardous drug, so
that employers can avoid unnecessary reviews of drugs that do not
appear on the NIOSH List.
NIOSH response: NIOSH does not identify the drugs that have been
reviewed and have failed to meet the NIOSH criteria because doing so
might be interpreted as indicating those drugs are free of potential
hazards. In fact, even drugs that are not on the List may have some
hazards associated with exposure. In addition, NIOSH repeatedly reviews
drugs as new information and warnings are added to their package
inserts, so publishing the names of reviewed drugs would be potentially
confusing, as information changes. Moreover, some drugs do not meet the
criteria due to a lack of data. Therefore, to be clear that NIOSH is
not making an affirmative statement that drugs reviewed and not added
to the List have no associated hazards, NIOSH does not publish such a
list. No change to the 2024 List has been made in response to this
comment.
B. General Drug Descriptors
1. Unique Identifiers
Public comment: In the May 2020 notice, NIOSH asked ``Which unique
ingredient identifier is the most useful for users of the
List[hairsp]?'' Among the six responses NIOSH received, there was broad
agreement that the most useful identifier is the generic name of the
drug. One reviewer suggested also including the brand name(s) of the
drug, citing recognizability by staff unaccustomed to drug names.
NIOSH response: NIOSH agrees with the majority of commenters that
generic drug names are preferred because of the potential volatility of
brand names and the entry of generics once patents expire. No changes
were made in response to these comments.
2. Use of AHFS Classifications
Public comment: Some commenters stated that the use of AHFS
(formerly called the American Hospital Formulary Service)
classifications on the List leads to imprecise or incorrect
classification of drugs and should be discontinued.
NIOSH response: NIOSH does not use the AHFS classification to
determine hazard, nor does the AHFS classification influence placement
of a drug on a particular table. The AHFS classifications are provided
only as information for users to aid in identifying the drugs and their
potential therapeutic uses.
3. Use of AHFS Code for Hormone Drug Classification
Public comment: One commenter on the List noted that the use of
AHFS classification for hormones led to some nomenclature concerns.
NIOSH response: The AHFS identifier is provided to give users some
information on how the listed drugs are classified and utilized. Some
drugs may be classified in more than one category, and AHFS may have
used the same classification codes for drugs that have different
mechanisms of actions or uses. Further information on the drugs may be
found in their respective AHFS monograph.\2\
---------------------------------------------------------------------------
\2\ See <a href="http://www.ahfsdruginformation.com">www.ahfsdruginformation.com</a>.
---------------------------------------------------------------------------
4. Monoclonal Antibodies as a Class of Drugs
Public comment: Several commenters suggested NIOSH reconsider
listing the monoclonal antibodies as a class of
[[Page 104166]]
drugs largely based on the high molecular weight of these compounds as
an exclusionary factor or based on data from in vitro systems.
NIOSH response: NIOSH considers each drug based on the potential
hazard each active pharmaceutical ingredient poses. Each is reviewed
individually, and classes of drugs are not excluded a priori.
Monoclonal antibodies may generally have lower systemic availability
via inhalation, ingestion, and dermal absorption through intact skin,
but that availability is not zero and not all workers have intact skin.
NIOSH intends to continue reviewing each drug individually and
considering the intrinsic hazard that each drug poses, including
molecular properties, such as molecular weight, which may change the
likelihood of occupational exposure.
NIOSH encourages employers to examine the potential hazards posed
by all the therapies handled in their facility and evaluate the risk
associated with occupational exposures. NIOSH encourages workplaces to
take the appropriate risk management strategies for the risk related
for their specific workplace handling of the hazardous drugs in their
facility. The List is informational in nature and confers no legal
obligations. How facilities implement risk management strategies should
be reflective of the risk they identify in their handling scenarios. No
change to the 2024 List was made in response to this comment.
5. Progestins
Public comment: One commenter suggested that the term
``progestins'' does not provide sufficient information about what
exactly constitutes a progestin.
NIOSH response: Progestins are synthetic hormones that target the
progesterone receptor. The AHFS identifier--AHFS classification code
``68:32: Progestins''--is provided in the 2024 List to give users some
information on how the listed drugs are classified and utilized.
6. Additional Information Requested
Public comment: Some commenters requested that NIOSH include more
specific information about the relevant hazards posed to healthcare
workers in the List to provide healthcare workers access to more
information and improve safety.
NIOSH response: The List identifies drugs that meet the criteria
specified in the Procedures. It is not intended to be a comprehensive
review of every hazard potentially posed by a drug. Drugs are
repeatedly reviewed as new information and warnings are added to their
package inserts, and some drugs do not meet the criteria due to a
current lack of data. NIOSH suggests that workplaces review the
potentially hazardous drugs handled in their facilities to identify
specific details on the hazard of those drugs.
C. General Reorganization of the List
1. Content of Tables
Public comment: More than a dozen commenters voiced opinions on the
reorganization of Table 1. Table 1 was formerly focused on
antineoplastic drugs. NIOSH has dropped this nomenclature and
reorganized Table 1 in the 2024 List to include only ``[d]rugs with
MSHI [manufacturer's special handling information] in the package
insert and/or those that meet the NIOSH definition of a hazardous drug
and one or more of the following criteria: are classified by NTP
(National Toxicology Program) as known to be a human carcinogen or are
classified by IARC (International Agency for Research on Cancer) as
Group 1 carcinogenic to humans or Group 2A probably carcinogenic to
humans.'' Eight commenters suggested that the reorganization of Table 1
was appropriate, but some commenters were concerned that the change
would confuse some users and that some drugs with shared mechanism of
action ended up on different tables. In summary, commenters expressed
agreement with the proposal to remove the AHFS therapeutic descriptor
``antineoplastic'' as a criterion for placement in Table 1 and base
drug placement in Table 1 on drugs with manufacturer's special handling
information (MSHI) and/or those that are carcinogenic to humans or
probably carcinogenic to humans. Other commenters were less supportive
of the changes, citing potential end-user confusion, and perceived
conflict with United States Pharmacopeia (USP) <800> requirements.
NIOSH response: NIOSH has reorganized the tables with an
understanding that all antineoplastic drugs do not carry the same
hazard. As discussed above, the new organization creates a Table 1 in
the 2024 List that includes ``[d]rugs that have MSHI in the package
insert and/or meet the NIOSH definition of a hazardous drug and one or
more of the following criteria: are classified by NTP as known to be a
human carcinogen or are classified by IARC as Group 1 carcinogenic to
humans or Group 2A probably carcinogenic to humans.'' Table 1 does not
contain all drugs that are used in the treatment of cancer, which may
carry different types of potential occupational hazards because of
their mechanism of action. This aligns more with the NIOSH goal of
providing a list that helps identify potential workplace hazards. To
alleviate some confusion, NIOSH has maintained the AHFS classification
of drugs so that antineoplastic drugs on both tables can be identified.
In June 2020, USP revised Chapter <800> to clarify that the chapter's
requirements for antineoplastic drugs apply only to those
antineoplastic drugs found in Table 1 of the List.\3\ Questions
concerning the language of USP Chapter <800> should be directed to USP.
---------------------------------------------------------------------------
\3\ U.S. Pharmacopeia [June 2020], Revision Bulletin, <a href="https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-800-rb-notice-20200626.pdf">https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-800-rb-notice-20200626.pdf</a>.
---------------------------------------------------------------------------
Public comment: Several commenters noted concerns about combining
Tables 2 and 3 into one table. Table 3, included in previous iterations
of the List but removed in the 2020 draft, addressed only those non-
antineoplastic drugs that have adverse reproductive effects. Concerned
commenters thought that not enough was done to identify drugs that were
only reproductive or developmental hazards, citing challenges for
healthcare workers in adequately identifying drugs with reproductive
and/or developmental risks. In addition, a commenter expressed concern
that the information on reproductive and developmental hazards was not
clearly identified in Table 2.
NIOSH response: NIOSH has reorganized Table 2 in the 2024 List to
include ``[d]rugs that meet the NIOSH definition of a hazardous drug
and do not have MSHI, are not classified by NTP as known to be a human
carcinogen, and are not classified by IARC as Group 1, carcinogenic to
humans, or Group 2A, probably carcinogenic to humans. (Some may also
have adverse developmental and/or reproductive effects.)''
NIOSH recognizes that there is an important interest in identifying
drugs that pose a developmental and reproductive hazard so that risk
management strategies can be tailored to the situation and has revised
Table 2 in the 2024 List to include a new column to allow readers to
find those drugs more easily on the List. In addition, NIOSH worked
with its visual information specialists to ensure that the information
is clear and easy to find.
With regard to the concern that some Table 2 drugs are more toxic
than Table 1 drugs, it is important to note that placement of a drug on
Table 1 or Table 2 does not indicate relative potency or relative
hazard of the drugs. All drugs
[[Page 104167]]
on the List have been determined by NIOSH to meet the definition of a
hazardous drug. The List is intended to identify potential hazards in
the healthcare workplace so that workplaces can further consider what
risk management strategies are appropriate for their specific needs.
The drugs are separated into two tables based on type of hazard. The
word ``only'' in the notation regarding reproductive and developmental
toxicity allows for identification of drugs that met just one or both
of these NIOSH toxicity criteria for inclusion on the List. Pointing
out that a drug met just one or both of these criterion helps
management tailor strategies to the hazard. However, this designation
does not indicate the severity of the hazard.
2. DailyMed and DrugBank Links
Public comment: Two commenters requested that NIOSH keep the links
to DailyMed and DrugBank on the NIOSH List.
NIOSH response: Because internet links change frequently and links
in the PDF of the List cannot be updated once published, NIOSH has
removed the DailyMed and DrugBank links. However, users are encouraged
to access these databases to find more information about drugs of
interest.
D. Drugs Not on the Draft 2020 List
1. Drugs Proposed in February 2018 and Not Added to the Draft 2020 List
Public comment: One commenter noted some drugs proposed for
placement on the List in February 2018 were no longer proposed for
placement in the May 2020 draft List.
NIOSH response: In response to public and interested party comments
to the proposals published in the February 2018 notice, NIOSH clarified
the Procedures for developing the List and reevaluated specific drugs
in drafts published for public comment in the May 2020 notice. After
consideration of the revised draft Procedures and the public comments,
NIOSH ultimately determined that several drugs proposed to be placed on
the List in the February 2018 notice either did not meet the NIOSH
criteria or were identified as needing additional review to be
considered for future List updates. Accordingly, the following drugs
proposed in 2018 were not included on the draft 2020 List: bevacizumab,
botulinum toxins, darbepoetin alfa, interferon beta-1b, osimertinib,
trastuzumab, and triazolam.
2. Bacillus Calmette-Guerin (BCG)
Public comment: Several commenters requested that NIOSH relist BCG
and suggested NIOSH broaden its definition of a hazardous drug to
include drugs approved by FDA Center for Biologics Evaluation and
Research (CBER). The major issue was that by excluding drugs approved
by CBER, healthcare workers would not be apprised of occupational
hazards that may occur from exposure to those drugs.
NIOSH response: BCG is an infectious agent approved for use by the
FDA CBER. It was included in the 2004 Alert as part of the compiled
list of drugs sourced from other external hazardous drug lists. It was
maintained on the List from that time. While BCG is an infectious agent
and should be handled appropriately, it does not fall under the NIOSH
definition of a hazardous drug for evaluation for placement on the List
and has thus been removed. Healthcare workplaces should review the
potential hazards of all treatments utilized in their facilities,
including potentially infectious agents, gene therapy treatments,
radiological treatments, and experimental treatments that may not be
evaluated by NIOSH and identify the proper strategies to reduce the
risk of worker exposure to those hazards.
3. Botulinum Toxins
Public comment: NIOSH received four comments in response to its
request for information on botulinum toxins. Comments included requests
for clarification of the criteria to place drugs on the List and a
request for additional information about how NIOSH considers balancing
the hazard with other considerations.
NIOSH response: In response to comments, NIOSH determined that
additional review of the issues raised by commenters on the toxicity
data on botulinum toxins would be beneficial. Therefore, as stated in
the May 2020 notice, NIOSH is not adding botulinum toxins to the 2024
List at this time. One of the issues with botulinum toxins is whether
the molecular weight of the molecule precludes consideration of the
drugs as an occupational hazard. NIOSH intends to apply those concepts
as described in the Procedures to the botulinum toxins in a future
reevaluation of the drugs.
As to the issue of whether NIOSH considers balancing the hazard
with other considerations, NIOSH reminds readers that the List is a
hazard identification tool. It should be used to identify drugs that
may pose an occupational hazard in healthcare settings. However, NIOSH
does not conduct risk assessment for these drugs. NIOSH recommends that
employers familiarize themselves with the toxicity of the drugs in
their formularies, considering factors such as use, dosage form,
engineering controls, work practices, and personal protective equipment
(PPE) in developing risk mitigation strategies for their workplace.
E. Requests for Specific Drugs To Be Removed From the List
1. Blinatumomab
Public comment: Some commenters suggested that NIOSH remove the
recombinant therapeutic protein-based drug blinatumomab from the List.
This was primarily based on molecular size and related bioavailability.
With regard to the observed neurological effects of blinatumomab, one
commenter suggested that these effects may be caused by a response of
lymphoma cells present in the brain and may not be relevant in healthy
people exposed to blinatumomab.
Alternatively, one commenter noted that the manufacturer of
blinatumomab has provided the statements ``[e]nsure that personnel are
appropriately trained in aseptic manipulations and admixing of oncology
drugs'' and ``[e]nsure that personnel wear appropriate protective
clothing and gloves.'' The commenter indicated that such warnings are
similar to MSHI and therefore the drug warrants inclusion in Table 1.
NIOSH response: Blinatumomab has been found to have neurological
effects at low doses. NIOSH intends to review the information available
on the role of lymphoma cells present in the brain and is considering
reevaluating blinatumomab in a future update of the List. For now, no
change to the 2024 List was made in response to these comments.
Regarding the issue of large molecules, NIOSH considers each drug
based on the potential hazard posed intrinsically. Each is reviewed
individually. NIOSH recognizes that large molecules may have lower
systemic availability via inhalation, ingestion, and dermal absorption
through intact skin, and takes that into account in its assessment.
However, the systemic availability of these drugs, though low, is not
zero, and not all workers have intact skin. In response to comments,
NIOSH has added a column to both tables in the 2024 List that allows
for identification of drugs that have been approved by CDER under a
biologics license application (BLA). These drugs are often large
protein/peptide-based drugs. Identifying drugs that are approved by
CDER under BLAs will make it easier for users to identify drugs that
are large peptides and make the appropriate risk management strategies.
[[Page 104168]]
With regard to the statements from the manufacturer that appear
similar to MSHI, NIOSH has thus far used manufacturers' identification
of cytotoxic/genotoxic hazards and suggestions that special care be
taken with these drugs as MSHI. NIOSH continues to review how it
considers MSHI with each List update to ensure these criteria are
applied consistently and appropriately. In any case, NIOSH recommends
that employers familiarize themselves with the potential hazards posed
by the drugs in their formularies and prepare the appropriate
strategies to reduce the risks of occupational exposure.
2. Carfilzomib
Public comment: One commenter suggested that carfilzomib should be
removed from the List based on recent studies that suggest less than 1
percent bioavailability of the drug via oral and inhalation
bioavailability.
NIOSH response: This comment appears to be based on proprietary
data that is not currently available to NIOSH, but NIOSH will consider
evaluating carfilzomib again in a future update of the List.
3. Eslicarbazepine, Lomitapide, Mifepristone
Public comment: A commenter suggested NIOSH remove eslicarbazepine
from the List because of insufficient human data on the reproductive
and developmental effects and no data about occupational exposure and
risk. Two commenters suggested that lomitapide be removed from the List
due to a lack of data on risk associated with occupational exposure.
One commenter suggested NIOSH remove mifepristone due to a lack of data
identifying a risk associated with occupational exposure.
NIOSH response: Developmental effects were observed in experimental
animals exposed to eslicarbazepine at concentrations lower than the
maximum recommended human dose (MRHD). Results in humans are
inconclusive to rule out the potential for occupational hazard.
Therefore, NIOSH is maintaining eslicarbazepine on the 2024 List.
Lomitapide was observed to be teratogenic in several animal species.
Mifepristone has been shown to cause termination of pregnancy and is
listed due to potential reproductive and developmental effects. Some
reproductive effects are seen in humans and teratogenicity has been
observed in rabbits.
NIOSH also notes that sufficient data on health effects related to
occupational exposure to individual drugs are very rarely available.
The List is intended to identify potential hazards to aid employers in
assessing risks to workers, therefore, no change to the 2024 List was
made in response to these comments.
4. Hazardous Drugs Listed for Reproductive and Developmental Effects:
Cabergoline, Clonazepam, Fluconazole, Plerixafor, Riociguat, and
Ziprasidone
Public comment: One commenter suggested that NIOSH remove
cabergoline from the List. They cited data suggesting in humans it does
not cause reproductive or developmental harm. They suggested that
effects in some tested species are secondary to maternal toxicity and
that the effects seen in a rat study on embryo survival were species
specific.
Another commenter suggested that clonazepam should be removed from
the List. The commenter noted that the manufacturer's safety data sheet
states that it is neither teratogenic nor embryotoxic. They noted,
however, that exposure during late stages of pregnancy can lead to
post-natal dependence and withdrawal, while exposures immediately prior
to childbirth may lead to adverse outcomes. They also noted some,
though inconsistent, evidence of adverse developmental effects in
animals and stated that there are no studies of occupational exposures
to clonazepam.
Two commenters suggested that fluconazole should be removed from
the NIOSH List. One commenter noted that teratogenic risk had only been
associated with exposures in excess of 400 mg/day. The commenter also
noted that data suggested that lower doses were not associated with
potential hazard to reproduction or the developing offspring in
pregnancy or through breastfeeding. Finally, the commenter noted that
no data were available on the health effects of occupational exposures.
One commenter suggested NIOSH remove the drug plerixafor from the
NIOSH List because no data were identified on occupational exposures
leading to reproductive hazards. They also noted that reproductive
effects in animals occurred mainly at a dose 10 times the MRHD.
One commenter suggested NIOSH remove riociguat. The commenter noted
that the observed developmental and reproductive effects seen in rats
and rabbits only occurred at doses that correlated with doses greater
than twice the MRHD.
One commenter suggested that NIOSH remove ziprasidone from the List
because occupational exposures via dermal or inhalation routes have not
been shown to cause teratogenicity. However, animal studies have
demonstrated potential embryofetal toxicities without a no-observed-
adverse-effect level (NOAEL) as low as 0.2 times the MRHD. The
commenter also described two case studies of in utero exposure, one
with no adverse outcome and one with cleft palate attributed to
ziprasidone exposure.
NIOSH response: In reviewing the totality of the evidence, NIOSH
believes the evidence supports listing cabergoline, clonazepam,
fluconazole, plerixafor, riociguat, and ziprasidone. In the case of
fluconazole, the teratogenic effects observed are consistent with
effects seen in animals at similar species at equivalent doses, and in
rats at lower doses. In the case of ziprasidone, embryofetal toxicity
was observed with a NOAEL as low as 0.2 times the MRHD and at least one
case study resulted in a cleft palate in the offspring of an individual
exposed to ziprasidone. NIOSH notes that it is not unusual that there
are no studies of occupational exposure to these drugs, as there are
few occupational studies of hazardous drugs exposure. However, NIOSH
intends to reevaluate the evidence on reproductive and developmental
hazards for these drugs, along with other potential reproductive and
developmental hazards, in a future update of the List to assure
consistency of application of the criteria. No changes to the 2024 List
were made in response to these comments.
5. Icatibant
Public comment: One commenter suggested that NIOSH remove icatibant
from the NIOSH List because the limited case studies and reports have
not shown signs of adverse effects in humans.
NIOSH response: The data indicate that in rats, at doses lower than
human doses, there is fetal death, preimplantation loss, and delayed
parturition. In addition, in rabbits, increased abortion rate,
increased fetal death, increased preimplantation loss, and increased
preterm births were observed at doses lower than MRHD. Reproductive
effects were also seen in dog studies that affected both males and
females, though these effects were reversible 4 weeks after exposure
ceased. In an occupational setting, where a drug is being used on a
regular basis, repeated exposure to the drug or to contaminated
surfaces are not unexpected. Therefore, NIOSH has retained icatibant on
the 2024 List. No change to the 2024 List was made in response to this
comment.
[[Page 104169]]
6. Leuprolide
Public comment: One commenter noted that leuprolide requires
continuous systemic exposure for 2-3 weeks to cause the decrease in sex
hormones that would lead to either fetal toxicity or reproductive harm.
They suggested that occupational exposures would not lead to continuous
systemic exposure, and relevant levels of exposure can only occur
following injection of the extended-release formulation. They
acknowledged that initial exposure may cause a spike in gonadotropin
release and sex hormones levels rather than a decrease.
Another commenter suggested that leuprolide should be removed from
the List because it can be obtained in a kit that decreases the risk of
exposure to healthcare workers.
NIOSH response: With regard to occupational exposures not being
equivalent to a sustained systemic exposure, NIOSH notes that working
in areas with contaminated surfaces or working regularly with hazardous
materials may lead to chronic or repeated exposures. However, as with
some of the other drugs identified as reproductive or developmental
hazards, NIOSH intends to consider reevaluating leuprolide during a
future update to the List to ensure consistent application of the NIOSH
criteria.
Regarding the distribution of leuprolide in a kit that may lower
occupational exposure, NIOSH notes that the List contains active
pharmaceutical ingredients based on the hazards they pose. The List
does not differentiate based on dosage form. Many things may affect the
risk associated with handling hazardous drugs, including drug
formulation, proper handling technique, and PPE utilization. In
addition, formulations may change, and packaging and delivery
mechanisms can be damaged. Therefore, NIOSH identifies the intrinsic
hazards of drugs and not the scenario-based risks associated with
handling each drug in a specific way. Healthcare workplaces should
further consider what risk management strategies are appropriate for
their specific needs, given their specific exposure scenarios.
7. Olaparib and Teriflunomide
Public comment: One commenter suggested that NIOSH remove olaparib
because the risk of direct occupational exposure is likely low when
handling intact olaparib capsules. One commenter noted that while the
hazards posed by teriflunomide exposure exist, the risk of exposure due
to formulation and packaging means it should not be on the NIOSH List.
NIOSH response: The List is intended as a hazard identification
tool. The List does not differentiate based on dosage form. Many things
may affect the risk associated with handling hazardous drugs, including
drug formulation, proper handling technique, and PPE utilization. In
addition, formulations may change, and packaging and delivery
mechanisms can be damaged. Therefore, NIOSH identifies the hazards of
drugs and not the scenario-based risks associated with handling each
drug in a specific way. Healthcare workplaces should further consider
what risk management strategies are appropriate for their specific
needs, given their specific exposure scenarios. No change to the 2024
List was made in response to these comments.
8. Oxytocin and Other Oxytocic Drugs
Public comment: Many commenters asked NIOSH to remove oxytocin and
the other oxytocic drugs ergonovine and methylergonovine from the List.
Most commenters stated that there are no documented cases where routine
handling has resulted in occupational hazard. In addition, some noted
that because the mechanism of action of ergonovine, methylergonovine,
and oxytocin differs, they should not be treated similarly.
NIOSH response: NIOSH has recognized that the oxytocic drugs were
added to the List as part of the initial compilation in 2004. They have
been maintained as a class on the List since that time. In response to
comments on the mechanism of action, NIOSH agrees that ergonovine,
methylergonovine, and oxytocin do not appear to have the same mechanism
of action. Oxytocin and methylergonovine have been observed to pose a
hazard to fetuses in the third trimester of pregnancy. Therefore, they
are retained on the 2024 List. However, NIOSH intends to evaluate
oxytocin and methylergonovine in a future List update. Ergonovine has
never been approved for use in humans by the FDA and therefore does not
meet NIOSH's definition as a drug. Therefore, ergonovine has been
removed from the 2024 List.
9. Paroxetine
Public comment: One commenter suggested NIOSH remove paroxetine
from the List, stating that the studies are currently inconclusive. The
commenter also noted that there are no data on occupational exposures.
NIOSH response: Studies indicate that therapeutic doses are
suspected of damaging fertility in males and increasing congenital
malformations in developing fetuses. These effects suggest a potential
hazard to workers who are pregnant, trying to conceive, or males who
are trying to have children. There are also data suggesting that there
are negative adverse effects on neonates exposed during the third
trimester of pregnancy. These data clearly support maintaining
paroxetine on the 2024 List. With regard to the lack of data from
occupational exposures, NIOSH notes that this is not uncommon, as there
are few studies of occupational exposure to hazardous drugs. However,
the totality of the evidence supports maintaining paroxetine on the
2024 List. No change to the 2024 List was made in response to this
comment.
10. Spironolactone
Public comment: Two commenters suggested spironolactone be removed
from the NIOSH List because the health effects were only observed after
long-term relatively high exposures.
NIOSH response: Studies have shown that long-term (18-month)
exposures in rats led to significant increases in hepatocellular
adenomas. There were also increases in adenoma of the testes in males
and proliferative changes in the liver in that study. Doses ranged from
50 to 200 mg/kg/day. In another study, significant increases in
hepatocellular adenomas and testicular interstitial cell tumors were
observed in rats exposed to 10 mg/kg/day to 100 mg/kg/day; 100 mg/kg/
day represents a dose five times the human dose of 200 mg/day.
NIOSH also notes that evidence of changes in estrous cycles,
retardation of follicular development, decreased numbers of implanted
embryos, and increases in stillborn pups were also observed in some
studies. NIOSH has determined that the totality of the evidence
supports maintaining spironolactone on the 2024 List. However, as with
some of the other drugs identified as reproductive and/or developmental
hazards, NIOSH intends to consider evaluating spironolactone again in a
future List update to ensure consistent application of the NIOSH
criteria. No change to the 2024 List was made in response to these
comments.
11. Topiramate
Public comment: One commenter recommended that topiramate be
removed from the List and noted that no data were identified describing
reproductive risk of associated with occupational exposure to
topiramate.
NIOSH response: The lack of occupational exposure studies is not
unusual. In evaluating the totality of the
[[Page 104170]]
available evidence, NIOSH notes that studies have shown limb
malformations and reduced fetal body weights in rats exposed to doses
half the recommended human dose. In addition, the NOAEL for rats in
that study was less than the MRHD. In rabbits, embryofetal effects were
seen only at doses greater than human recommended doses.
In a different rat developmental study with administration through
the later part of gestation and throughout lactation, it was observed
that doses as low as 2 mg/kg/day led to decreased pre- and/or post-
weaning body weights. The NOAEL for these studies, 0.2 mg/kg/day, was
also below the MRHD. In mice, when topiramate was administered during
organogenesis fetal malformations, primarily craniofacial were seen at
all tested doses (0, 20, 100, or 500 mg/kg/day) with no NOAEL. The
lowest dose tested in this study was lower than the MRHD. Human data
from the pregnancy registries suggest that infants exposed in utero are
at increased risk for cleft palate and being small at gestational age,
the latter seen at all tested doses and appearing to be dose dependent.
From this evidence, NIOSH determined that topiramate poses a potential
hazard to the development of offspring of workers exposed while
pregnant and has maintained it on the 2024 List. No change to the 2024
List was made in response to these comments.
12. Ulipristal
Public comment: One commenter suggested NIOSH remove ulipristal
from the List. The commenter noted that the effects after pregnancy are
established are insufficient to determine if ulipristal poses a
teratogenic/developmental hazard at that time.
NIOSH response: Ulipristal is a progesterone agonist/antagonist
indicated for pregnancy prevention within 5 days of unprotected
intercourse or contraception failure. Workers may be trying to become
pregnant or be pregnant potentially at any time, and the data indicate
that there may be a hazard that affects reproductive ability within the
first 5 days of attempted conception. Therefore, NIOSH has maintained
ulipristal on the 2024 List.
13. Vigabatrin
Public comment: One commenter suggested that vigabatrin should be
removed from the NIOSH List because no adverse effects on fertility
have been reported in rats up to a dose of \1/2\ the MRHD. They also
stated that the manufacturer notes that changes in post-natal
development and male fertility in rats may be related to the drug-
related effects on food intake and weight. When exposed to vigabatrin
during development, there was an increase in cleft palate and
embryofetal deaths for rabbits but not for rats. In rabbits, the no
effect level for development was approximately \1/2\ of the MRHD, and
the effects in rabbits were repeated in two studies.
NIOSH response: The manufacturer's package insert notes that
exposure throughout organogenesis in rats led to decreased fetal
weights and increased fetal anatomical variations with an embryo-fetal
NOAEL approximately equivalent to \1/5\ of the MRHD. Additionally, when
rats were exposed through the later part of pregnancy throughout
lactation, long-term neuro-histopathological changes and
neurobehavioral effects were observed. These effects had no NOAEL and a
lowest-observed effect level of \1/5\ of the MRHD. Exposure during
early post-natal period in rats, a period that is generally thought to
correspond with late pregnancy in humans, also resulted in
neurobehavioral and neuro-histopathological with a NOAEL that was \1/
30\ of the measured plasma exposures in pediatric patients receiving a
50 mg/kg dose. Therefore, NIOSH determined that vigabatrin may pose a
potential hazard to the development of unborn offspring when the mother
is exposed during pregnancy and has maintained it on the 2024 List.
F. Placement of Specific Drugs Within the List
1. Carfilzomib
Public comment: Some commenters noted that carfilzomib is on Table
2 while a similar proteosome inhibitor bortezomib appears on Table 1.
One noted that while the manufacturers of bortezomib provide ample
identification of bortezomib as a cytotoxic agent and suggest
appropriate handling for the protection of healthcare workers, the
manufacturers of carfilzomib do not.
NIOSH response: Table 1 of the 2024 List includes ``[d]rugs that
have MSHI in the package insert and/or meet the NIOSH definition of a
hazardous drug and one or more of the following criteria: are
classified by NTP as known to be a human carcinogen or are classified
by IARC as Group 1 carcinogenic to humans or Group 2A probably
carcinogenic to humans.'' The manufacturers of carfilzomib did not
provide MSHI. Nor was carfilzomib evaluated by NTP or IARC. Therefore,
it was not included on Table 1.
Table 2 of the 2024 List includes ``[d]rugs that meet the NIOSH
definition of a hazardous drug and do not have MSHI, are not classified
by NTP as known to be a human carcinogen, and are not classified by
IARC as Group 1 carcinogenic to humans or Group 2A probably
carcinogenic to humans. (Some may also have adverse developmental and/
or reproductive effects.)'' However, NIOSH notes that the tables in the
List are not hierarchical; Table 1 does not contain inherently more
hazardous drugs than Table 2. It is expected that in some cases, drugs
in the same class with similar activity could be on different tables
because of the information available.
2. Dasatinib and Imatinib
Public comment: One commenter suggested dasatinib and imatinib
should be moved to Table 2. They noted similar kinase inhibitors,
bosutinib, nilotinib, and ponatinib, are on Table 2.
NIOSH response: In reviewing the package insert, some data suggest
that dasatinib and imatinib may be carcinogenic, clastogenic, or
genotoxic. The manufacturers of dasatinib and imatinib include MSHI,
which provides guidance on appropriately handling these clastogenic
and/or genotoxic compounds to protect healthcare workers. At this time,
all evaluated drugs with this information are included on Table 1 of
the 2024 List. However, NIOSH notes that the tables in the List are not
hierarchical; Table 1 does not contain inherently more hazardous drugs
than Table 2. It is expected that in some cases, drugs in the same
class with similar activity could be on different tables because of the
information available. No change to the 2024 List was made in response
to this comment.
3. Eribulin
Public comment: One commenter suggested that NIOSH include eribulin
on Table 1 because the mechanism of action, mitotic inhibition by
suppression of microtubule growth, is similar to those of several other
cytotoxic drugs such as vinblastine and paclitaxel, which are located
on Table 1.
NIOSH response: Table 1 of the 2024 List includes ``[d]rugs that
have MSHI in the package insert and/or meet the NIOSH definition of a
hazardous drug and one or more of the following criteria: are
classified by NTP as known to be a human carcinogen or by IARC as Group
1 carcinogenic to humans or Group 2A probably carcinogenic to humans.''
NIOSH agrees that manufacturers of other genotoxic/cytotoxic drugs that
inhibit mitosis via microtubule inhibition have included
[[Page 104171]]
MSHI for healthcare workers to handle them appropriately. In 2021 the
manufacturers of eribulin updated the eribulin prescribing information
noting that it is a cytotoxic drug with the instructions that special
handling and disposal procedures should be followed. Because the
manufacturer of eribulin suggests special handling it has been placed
on Table 1 in the NIOSH List of Hazardous Drugs, 2024.
4. Exenatide
Public comment: One commenter suggested that exenatide should be
listed on Table 1 because it meets NIOSH criteria as carcinogenic.
NIOSH response: Table 1 of the 2024 List includes ``[d]rugs that
have MSHI in the package insert and/or meet the NIOSH definition of a
hazardous drug and one or more of the following criteria: are
classified by NTP as known to be a human carcinogen or are classified
by IARC as Group 1 carcinogenic to humans or Group 2A probably
carcinogenic to humans.'' However, NIOSH notes that the tables in the
List are not hierarchical; Table 1 does not contain inherently more
hazardous drugs than Table 2. It is expected that in some cases, drugs
in the same class with similar activity could be on different tables
because of the information available. In the 2024 List, Table 2
includes ``[d]rugs that meet the NIOSH definition of a hazardous drug
and do not have MSHI, are not classified by NTP as known to be a human
carcinogen and are not classified by IARC as Group 1 carcinogenic to
humans or Group 2A probably carcinogenic to humans. (Some may also have
adverse developmental and/or reproductive effects.)''
5. Ganciclovir and Valganciclovir
Public comment: One commenter suggested NIOSH move these antiviral
drugs to Table 2 from Table 1 because of confusion regarding the
application of USP <800>.
NIOSH response: Ganciclovir and valganciclovir are listed on Table
1 because these nucleoside drugs have been identified by the
manufacturers to pose a hazard to workers handling them and they both
have MSHI. According to NIOSH criteria, this warrants placement on
Table 1. Table 1 of the 2024 List includes ``[d]rugs that have MSHI in
the package insert and/or meet the NIOSH definition of a hazardous drug
and one or more of the following criteria: are classified by NTP as
known to be a human carcinogen or are classified by IARC as Group 1
carcinogenic to humans or Group 2A probably carcinogenic to humans.''
This means some drugs listed on Table 1 may not be antineoplastic
drugs. The tables comprising the List are not intended to stratify
levels of hazard, and neither are the inclusion of AHFS classification.
The AHFS classifications are included as helpful information for users.
NIOSH suggests that concerns with USP <800> standard be addressed with
USP. No change to the 2024 List was made in response to this comment.
6. Hormonal Agents: Goserelin, Degarelix, Leuprolide, Estrogens, and
Progesterone
Public comment: One commenter suggested NIOSH moving the hormonal
agents goserelin, degarelix, and leuprolide to Table 3 as they were
previously listed under Table 1--Antineoplastic Drugs. Two commenters
asked NIOSH to move the estrogens and progesterone drugs from Table 1
to Table 2.
NIOSH response: In the current List, leuprolide, goserelin, and
degarelix are listed on Table 2. There is no longer a Table 3, and all
of these drugs on Table 2 are now described as only having met NIOSH
criteria as a developmental or reproductive hazard.
For the estrogens and progesterone, Table 1 of the 2024 List
includes ``[d]rugs that have MSHI in the package insert and/or meet the
NIOSH definition of a hazardous drug and one or more of the following
criteria: are classified by NTP as known to be a human carcinogen or
are classified by IARC as Group 1 carcinogenic to humans or Group 2A
probably carcinogenic to humans.'' This means some drugs that are
potential carcinogens via different mechanisms may be listed on Table 1
because they met one of the criteria for placement on Table 1. The
tables comprising the List are not intended to stratify risk and NIOSH
recommends that facilities evaluate the potential hazards of the drugs
in their formulary so they can make the appropriate exposure control
management strategies. Specifically, for the estrogens and
progesterone, IARC classifies the estrogen/progesterone combination
drugs as carcinogenic to humans (Group 1) with sufficient evidence that
they cause cancer of the breast and endometrium. . While as one
commenter noted, the increased risk for estrogen-related endometrial
cancer is decreased depending on the number of days that progesterone
is included in the treatment, the drugs are still classified as IARC
Group 1 and are therefore the appropriate placement according to the
NIOSH criteria is on Table 1. No change to the 2024 List was made in
response to these comments.
7. Mycophenolate Mofetil and Mycophenolic Acid
Public comment: Two commenters requested NIOSH move mycophenolate
mofetil and mycophenolic acid to Table 1 because of the potential
carcinogenic hazard and because most facilities currently treat them as
hazardous antineoplastic drugs.
NIOSH response: Table 1 in the 2024 List includes ``[d]rugs that
have MSHI in the package insert and/or meet the NIOSH definition of a
hazardous drug and one or more of the following criteria: are
classified by NTP as known to be a human carcinogen or are classified
by IARC as Group 1 carcinogenic to humans or Group 2A probably
carcinogenic to humans.'' This means some drugs that are potential
carcinogens and are potential genotoxic/cytotoxic compounds may be on
Table 2 because they had not yet been evaluated by IARC or NTP or
because the manufacturer has not identified the need for safe handling
to protect healthcare workers who may handle the drug. The tables
comprising the List are not intended to stratify hazard. Some drugs on
Table 2 may be more hazardous than those on Table 1. In general, NIOSH
recommends that facilities evaluate the potential hazards of the drugs
in their formulary so they can make the appropriate exposure control
management strategies. Mycophenolate mofetil, while not an
antineoplastic, had MSHI added to the prescribing information in 2019
and has been moved to Table 1 in response to this comment.
8. Sirolimus and Other Related mTOR Targeting Drugs
Public comment: One commenter requested NIOSH move sirolimus to
Table 1 because of the potential carcinogenic hazard and because the
similar drug, tacrolimus, is on Table 1. Another reviewer asked that
everolimus and temsirolimus be moved to Table 2 because they are a
similar class as sirolimus, which is on Table 2.
NIOSH response: Table 1 in the 2024 List includes ``[d]rugs that
have MSHI in the package insert and/or meet the NIOSH definition of a
hazardous drug and one or more of the following criteria: are
classified by NTP as known to be a human carcinogen or are classified
by IARC as Group 1 carcinogenic to humans or Group 2A probably
carcinogenic to humans.'' This means some drugs that are in the same
class and may carry similar hazards may be listed on different tables
because of differences in MSHI and evaluation of the drugs by IARC or
NTP. The tables
[[Page 104172]]
comprising the List are not intended to stratify hazard and NIOSH
recommends that facilities evaluate the potential hazards of the drugs
in their formulary so they can make the appropriate exposure control
management strategies. No change to the 2024 List was made in response
to these comments.
9. Thalidomide, Lenalidomide, and Pomalidomide
Public comment: One commenter suggested thalidomide and the related
analogs lenalidomide and pomalidomide should not be listed on Table 1
because they have only reproductive and developmental effects and have
not demonstrated genotoxicity or carcinogenicity.
NIOSH response: Table 1 in the 2024 List includes ``[d]rugs that
have MSHI in the package insert and/or meet the NIOSH definition of a
hazardous drug and one or more of the following criteria: are
classified by the NTP as known to be a human carcinogen or are
classified by IARC as Group 1 carcinogenic to humans or Group 2A
probably carcinogenic to humans.'' Thalidomide, lenalidomide, and
pomalidomide include MSHI with guidance on handling these drugs in a
way that protects workers. In the 2024 List, not all drugs on Table 1
are genotoxic or carcinogenic. Additionally, drugs that are
carcinogenic on Table 1 may not be genotoxic but act through a
different mechanism of carcinogenicity. It is important that workplaces
identify what the specific hazards are related to the drugs in their
facility's formulary and use the appropriate exposure management
strategies for those hazards. No change to the 2024 List was made in
response to these comments.
10. Vandetanib
Public comment: One commenter suggested that vandetanib should be
placed in Table 2 similar to other EGFR tyrosine kinase inhibitors.
NIOSH response: The vandetanib package insert includes MSHI
indicating that it be handled and disposed of in a way that protects
the healthcare workers. All evaluated drugs with this information are
included on Table 1 of 2024 List. However, NIOSH notes that the tables
in the List are not hierarchical; Table 1 does not contain inherently
more hazardous drugs than Table 2. It is expected that in some cases,
drugs in the same class with similar activity could be on different
tables because of the information available. No change to the 2024 List
was made in response to this comment.
G. Specific Drug Classification/Identification
1. Triptorelin
Public comment: One commenter suggested that noting the
antineoplastic designation for the drug triptorelin will confuse some
healthcare professionals and lead them to deny patients needed therapy
due to special handling of neoplastic agents.
NIOSH response: Triptorelin is identified on the List in Table 2 as
having both AHFS classifications ``68:18:08 Gonadotropin Agonist/
Antagonist'' and ``10:00 Antineoplastic.'' These are offered as
information to aid the user. NIOSH suggests that facilities evaluate
all the hazards that may be present in their formulary. A designation
of antineoplastic by AHFS does not identify some special hazard. Cancer
treatments have changed over time and not all drugs utilized in the
treatment of cancer have the same hazards. Because of this, NIOSH no
longer groups all antineoplastic drugs together on a single table. The
tables comprising the List are not intended to rank levels of hazard,
and neither are the identification of AHFS classifications. These are
only intended as potentially useful information for users. No change to
the 2024 List was made in response to this comment.
2. Ziv-Aflibercept, Ado-Trastuzumab Emtansine, Fam-Trastuzumab
Deruxtecan
Public comment: In the draft List published in the docket for the
May 2020 notice, NIOSH removed the prefixes that are part of several
generic drug names in an attempt to focus on identifying the active
pharmaceutical ingredient. NIOSH was alerted by several commenters that
in doing so NIOSH had listed names that were not actual products or
were different products than originally intended.
NIOSH response: NIOSH appreciates the commenters who brought up
this issue and regrets the confusion that this caused. NIOSH has
revised the 2024 List to include the FDA assigned prefixes (i.e., ziv-,
ado-, and fam-) in the appropriate generic drugs names (ziv-
aflibercept, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan) to
correct the issue and refer to the appropriate pharmaceutical products.
H. Suggested Copyedits
Public comment: Several commenters noted spelling mistakes, errors
in tables, and other editorial improvements.
NIOSH response: NIOSH accepted all editorial, spelling, and
correction comments in the 2024 List, as appropriate.
IV. NIOSH Response to Public Comment and Peer Review in the January
2024 Federal Register Notice and Request for Comment on Proposed
Removal of Liraglutide and Pertuzumab From the List
As described above, on January 16, 2024, NIOSH published a request
for public comment in the Federal Register, charging peer reviewers and
public commenters with considering five questions about the liraglutide
initial recommendation and summary of evidence:
1. Are the evaluated health effects the appropriate health effects
to evaluate? If not, what other health effect(s) should be evaluated
and why?
2. Are the assumptions about the potential exposures to liraglutide
in a healthcare setting reasonable? Please explain.
3. Is the determination that the amount of exposure to liraglutide
in a healthcare setting does not constitute a hazard for healthcare
workers reasonably supported by the available scientific information?
Please explain.
4. What alternative approaches could be considered to characterize
the potential hazard to workers from peptide-based drugs?
5. Is there any additional information that NIOSH should consider
in its reevaluation of liraglutide?
Peer reviewers and public commenters were also charged with
considering six questions about the pertuzumab initial recommendation
and summary of evidence:
1. Is this an appropriate method for evaluating the potential for
exposure to pertuzumab?
2. Is oligohydramnios the best health effect to evaluate? If not,
what other health effect(s) should be evaluated and why?
3. Is a needlestick injury the only reasonable route of exposure
for healthcare workers? Please explain.
4. Are the assumptions about the amount of exposure to pertuzumab
in a healthcare setting reasonable? Please explain.
5. Is the determination that the amount of exposure to pertuzumab
in a healthcare setting does not constitute a hazard for healthcare
workers reasonably supported by the available scientific information?
Please explain.
6. What alternatives could be considered to this approach for
monoclonal antibodies to characterize the potential hazard to workers?
NIOSH received comments from three public commenters on the January
2024
[[Page 104173]]
notice, including a trade association, a pharmaceutical manufacturer,
and a private individual. One commenter addressed liraglutide and
pertuzumab, as well as the process NIOSH used to reevaluate placing
liraglutide and pertuzumab on the List. Two commenters addressed just
pertuzumab. NIOSH received two peer reviews of the proposal to remove
liraglutide from the List and three peer reviews of the proposal to
remove pertuzumab from the List.
Following review and consideration of the peer reviews and public
comments, and as discussed below, NIOSH has agreed to clarify some
points in the initial recommendations and summaries of evidence, NIOSH
Reevaluation of Liraglutide on the NIOSH List of Antineoplastic and
Other Hazardous Drugs in Healthcare Settings and NIOSH Reevaluation of
Pertuzumab on the NIOSH List of Antineoplastic and Other Hazardous
Drugs in Healthcare Settings. Those changes are reflected in the NIOSH
Final Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings and NIOSH Final Reevaluation
Determination of Pertuzumab on the NIOSH List of Hazardous Drugs in
Healthcare Settings, available in the docket for this activity. Based
on the evaluations described in the initial recommendations and on peer
reviews and public comments discussed below, NIOSH has made final
determinations to remove both liraglutide and pertuzumab from the List.
A. Public Comment
1. General Comments
Public comment: The commenter ``expresses concern that the methods
used to reevaluate liraglutide and pertuzumab for inclusion in the List
represent risk assessment, not hazard identification. The physical
properties of a drug molecule are not among the six characteristics
considered for hazard determination. The purpose of the NIOSH List
should be to identify hazards so that healthcare settings can assess
and mitigate risk. If NIOSH removes these drugs based on risk
assessment, healthcare settings may incorrectly think that a hazard
does not exist.
While [we] agree[ ] that a drug's physical properties may reduce
the risk of absorption through common methods of occupational exposure,
NIOSH should not assume that all healthcare staff and healthcare
environments are the same. Exposure through mucous membranes or other
routes may be rare, but they are still important considerations that
healthcare settings should evaluate when performing a risk assessment
specific to their environment and to their employees.''
NIOSH response: NIOSH evaluates the hazard to healthcare workers
posed by exposure to FDA Center for Drug Evaluation and Research (CDER)
approved drugs. NIOSH considers hazards at maximum human recommended
dose via all relevant routes of exposure. NIOSH considers the molecular
properties as they relate to the specific adverse effects posed by the
drug via all relevant routes of exposure. The NIOSH hazardous drugs
definition \4\ clarifies that NIOSH considers molecular properties when
characterizing the hazard a drug actually poses to healthcare worker
after exposure. It recognizes that although a drug may meet the
definition of a hazardous drug, the drug may be excluded from the List
if NIOSH determines that occupational hazards are limited due to the
molecular properties of the drug. The purpose of this exclusion is to
focus the List on drugs that have a potential for toxicity due to
occupational exposure, so that workers' attention is focused on drugs
that are likely to be hazardous in occupational settings. This is a way
for NIOSH to more specifically characterize the hazard posed by the
pharmaceutical ingredients; it is important to note that this is not an
automatic exclusion. NIOSH has not established specific molecular
properties for which drugs are automatically excluded from the List.
Instead, NIOSH reviewers look at the totality of the evidence and
evaluate whether there is a hazard to healthcare workers. NIOSH
considers molecular properties as they relate to the specific adverse
effects to characterize those hazards posed by the drug being
evaluated.
---------------------------------------------------------------------------
\4\ The NIOSH definition of a hazardous drug is established in
sec. IV of the Procedures for Developing the NIOSH List of Hazardous
Drugs in Healthcare Settings [2023].
---------------------------------------------------------------------------
Public comment: The commenter ``also urges caution when making
assumptions about occupational exposure based on commercially available
dosage forms of a drug. NIOSH should not base hazard identification on
a specific route of exposure, such as needlestick injuries. Splashes,
leaks, and spills all occur in healthcare settings. While a currently
available dosage form (e.g., prefilled syringe or pen) may limit the
risk of a splash, leak, or spill, dosage forms available at some time
in the future may not offer the same protection.
Pharmacy employees may handle bulk active pharmaceutical
ingredients when compounding various preparations. In the case of 503B
registered outsourcing facilities [FDA 2022], workers may handle a
hazardous drug in bulk powder form in higher quantities and with more
frequency than a typical healthcare worker might handle a commercial
preparation. Duration and intensity of exposure are important factors
to consider when assessing and mitigating exposure risk. Individual
healthcare settings can evaluate exposure duration and intensity when
assessing risk, but that evaluation is unlikely to occur if the hazard
has not been recognized.''
NIOSH response: NIOSH agrees that evaluating the hazards of
potentially hazardous drugs should not be limited to currently
commercially available formulations. NIOSH evaluates how the molecular
properties influence hazard potential at occupational exposures to
doses equivalent to therapeutic human recommended doses via
occupationally relevant routes of exposure. This is true even if a
route of exposure is unlikely given currently available formulations.
NIOSH understands that formulations may change, and handling needs may
be different across facilities. For liraglutide and pertuzumab, NIOSH
evaluated how the molecular properties influence bioavailability after
exposures via needlesticks, dermal exposure, ingestion, and inhalation.
A large peptide molecule, currently only available in liquid
formulations, may not lead to exposure equal to a human recommended
dose via inhalation of dust or droplets, but NIOSH still considered
that potential exposure route in its reevaluations. NIOSH noted in both
reevaluations that inhalation of a full therapeutic dose is unlikely to
result in systemic exposures that would cause the relevant adverse
effects. This is not based on any formulation, but rather on intrinsic
molecular properties of the reevaluated pharmaceutical ingredients. The
formulations and marketed products that include the pharmaceutical
ingredients may decrease the risk of exposure, but they were not part
of NIOSH's characterization of the hazard posed by the active
pharmaceutical ingredients, pertuzumab and liraglutide.
NIOSH uses a recommended human dose as a benchmark to indicate the
high end of doses of concern. NIOSH would be typically concerned with
toxic effects that occurred below this level. NIOSH considers exposures
at the human recommended doses to be greater than the expected dose for
healthcare workers. In situations where
[[Page 104174]]
healthcare workers may be exposed to therapeutic agents at levels
greater than what patients are exposed to, then pharmacological effects
may occur. Based on this comment, NIOSH made changes in the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings and NIOSH Final Reevaluation
Determination of Pertuzumab on the NIOSH List of Hazardous Drugs in
Healthcare Settings.
2. Liraglutide
Public comment: The commenter ``agrees that repeated exposure and
absorption to peptide-based drugs is not likely in many clinical
settings. However, we again stress concern about using physical
properties for hazard identification for reasons already mentioned.
Since carcinogenic effects and fetal abnormalities cannot be ruled out
in humans, liraglutide meets the existing criteria for hazard
identification. The duration, intensity, and routes of exposure should
be part of a healthcare setting's risk assessment. [We] disagree[ ]
with removal of liraglutide from the NIOSH List.''
NIOSH response: Consideration of intrinsic molecular properties of
potentially hazardous drugs is important to characterizing if they pose
a hazard to healthcare workers in the workplace. The NIOSH hazardous
drugs definition [NIOSH 2023] considers the molecular properties of
hazardous drugs because although a drug may meet some criteria as a
hazardous drug, those occupational hazards may not be significant due
to intrinsic molecular properties of the drug and therefore that drug
may be excluded from the List. The purpose of this exclusion is to
focus the List on drugs that have a potential for toxicity due to
occupational exposure, so that workers' attention is focused on drugs
that are likely to be hazardous in occupational settings. This is a way
for NIOSH to more specifically characterize the hazard posed by the
pharmaceutical ingredients; it is important to note that this is not an
automatic exclusion. Occupational exposure to liraglutide is unlikely
to reach systemic exposure levels that pose a hazard to workers. No
changes were made to the NIOSH Final Reevaluation Determination of
Liraglutide on the NIOSH List of Hazardous Drugs in Healthcare Settings
and NIOSH Final Reevaluation Determination of Pertuzumab on the NIOSH
List of Hazardous Drugs in Healthcare Settings as a result of this
comment.
3. Pertuzumab
Public comment: While the commenter ``agrees that repeated exposure
and absorption of a monoclonal antibody is not likely in many clinical
scenarios, we again express concern about assumptions made about
healthcare workers and environments when defining a hazard. [We] also
[have] concerns with consideration about whether a condition is
reversible or not when performing hazard identification. While
oligohydramnios may be reversible, the condition can lead to fetal
complications [Keilman and Shanks 2022]. [We] question[ ] whether NIOSH
will begin considering whether an adverse effect is reversible when
determining other hazard assessments. [We] disagree[ ] with removal of
pertuzumab from the NIOSH list.''
Public comment: ``I think the biggest issue is whatever is the most
fatal or can cause the most damage or permanent damage. While this
sounds reversible, I still would not want to risk my fetus through the
possibility of exposure.''
NIOSH response: NIOSH agrees that whether a hazard is reversible
alone is not enough to determine if a drug is hazardous to healthcare
workers. In the case of pertuzumab, data for the related drug
trastuzumab show that continuous exposures at therapeutic levels causes
delayed-genitourinary development-related oligohydramnios.\5\ If
systemic exposure is continuous, that will lead to further fetal
complications. However, if treatment is ceased, and oligohydramnios is
resolved in the first trimester, further fetal complications are
avoided. Oligohydramnios requires continuous systemic exposure to
pertuzumab, and continued HER2 inhibition, to occur. As noted in the
reevaluation, for the related HER2 inhibitor monoclonal antibody
trastuzumab, use during pregnancy showed that patients who had exposure
during just the first trimester had babies born with no complications,
deaths, or oligohydramnios. There was a trend of increased incidence in
oligohydramnios with increased exposure to trastuzumab. In the
available studies, it appears that trastuzumab-related oligohydramnios
was reversible following cessation of treatment with generally good
outcomes for the fetus, as seen in the Watson [2005] case.
---------------------------------------------------------------------------
\5\ HER2 inhibition refers to the inhibition of the activation
of the Human Epidermal growth factor Receptor 2. Oligohydramnios is
the disorder during pregnancy of having a low level of amniotic
fluid for gestational age. HER2 inhibitory monoclonal antibodies
cause oligohydramnios by causing a delayed development of the
urinary tract development of the embryo, leading to decreased
amniotic fluid production.
---------------------------------------------------------------------------
Healthcare workers are unlikely to experience prolonged and
consistent exposure to pertuzumab in the workplace that would lead to
high levels of systemic exposure. This is due to various factors, such
as limited availability of systemic exposure and the rarity of
incidental needlestick injuries with significant volumes, which are
necessary for sustained high systemic exposures. As a result, the
development of oligohydramnios that goes unresolved beyond the first
trimester is not expected in healthcare workers. No changes were made
in the document based on these comments.
a. Is this an appropriate method for evaluating the potential for
exposure to pertuzumab?
Public comment: This commenter ``agrees it is appropriate to
consider the physicochemical properties of pertuzumab that minimize the
potential for adverse health effects from inhalation, dermal, or oral
exposure. With regard to potential exposures via inhalation, [We]
agree[ ] there is no scenario in which substantial air concentrations
of pertuzumab could be generated while preparing or administering
Perjeta[supreg] in a healthcare setting. In addition, [We] agree[ ] it
is appropriate to consider the minimal volume that could be delivered
to a healthcare worker when evaluating the potential exposure to
pertuzumab in a needlestick scenario.
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Pertuzumab on the NIOSH List of Hazardous
Drugs in Healthcare Settings based on these comments.
b. Is oligohydramnios the best health effect to evaluate? If not, what
other health effect(s) should be evaluated and why?
Public comment: ``The notable potential health effects in patients
treated with Perjeta[supreg] (i.e., those described in the Warnings and
Precautions section of the prescribing information) include embryo-
fetal toxicity, left ventricular dysfunction, infusion-related
reactions, and hypersensitivity reactions/anaphylaxis.
Embryo-fetal toxicity and left ventricular dysfunction are
recognized as pharmacologically mediated class effects of therapies
that target HER-2. In addition to being over-expressed in some tumors,
HER2 is expressed in normal renal epithelium and cardiomyocytes. The
embryo-fetal effects of HER2 inhibitors are secondary
[[Page 104175]]
to delayed fetal kidney development that can result in oligohydramnios
and related effects (oligohydramnios sequence). In cardiomyocytes, HER2
activation results in a protective effect that may be inhibited in
patients treated with HER2 antagonists [Perez et al. 2008]. In contrast
to anthracycline-induced cardiac toxicity, HER2-related cardiac
dysfunction does not appear to increase with cumulative dose or to be
associated with ultrastructural changes in the myocardium; it is also
generally reversible. Both oligohydramnios and left ventricular
dysfunction are non-acute effects that would require sustained,
biologically significant inhibition of HER2 to manifest. Such exposures
can only be reasonably expected to occur via intentional intravenous
administration of pertuzumab in a therapeutic context. Consequently,
Genentech does not consider oligohydramnios or left ventricular
dysfunction to be relevant health effects for the purpose of evaluating
potential risks to healthcare workers.
Other notable adverse reactions observed in patients receiving
pertuzumab include infusion-related reactions and hypersensitivity
reactions/anaphylaxis. Both are common risks of intravenous monoclonal
antibody therapies and are not specific to pertuzumab. In addition, the
risk of infusion-related reactions is only relevant to patients being
treated with pertuzumab via intravenous infusion. Neither of these
endpoints would therefore be appropriate to evaluate for the purposes
of the List.
Because none of the notable adverse reactions associated with
therapeutic uses of pertuzumab are considered relevant to healthcare
exposure scenarios, it would not be meaningful to consider any of these
hazards to be better suited for evaluation for the purpose of the
List.''
NIOSH response: NIOSH agrees that none of these effects posed a
hazard to healthcare workers. No changes were made to the NIOSH Final
Reevaluation Determination of Pertuzumab on the NIOSH List of Hazardous
Drugs in Healthcare Settings based on these comments.
Public comment: ``We might however, want to think about allergic
reactions from exposure? Utilizing less measures than chemo with
tubing, gear, and gloving exposes nursing and pharmacy teams to the
drugs more because of less need for precautions.''
NIOSH response: Sensitization and allergic reaction are not
criteria under the Procedures for Developing the NIOSH List of
Hazardous Drugs in Healthcare Settings. No changes were made to the
NIOSH Final Reevaluation Determination of Pertuzumab on the NIOSH List
of Hazardous Drugs in Healthcare Settings based on this comment.
c. Is a needlestick injury the only reasonable route of exposure for
healthcare workers? Please explain.
Public comment: ``There is no scenario in which inhalation, dermal,
or oral exposure could be expected to result in a pharmacologically
active dose of pertuzumab. [We] therefore agree[ ] that a needlestick
injury is the only relevant route of exposure for Perjeta[supreg] for
healthcare providers.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Pertuzumab on the NIOSH List of Hazardous
Drugs in Healthcare Settings based on this comment.
d. Are the assumptions about the amount of exposure to pertuzumab in a
healthcare setting reasonable? Please explain.
One commenter stated their agreement with the general approach and
conclusions described for each route.
i. Inhalation
Public comment: ``The peer-reviewed publications support the
statement that the inhalation bioavailability of monoclonal antibodies
such as pertuzumab is minimal. The 5% value utilized in the review is
considered to be a conservative, upper-limit estimate for the
inhalation bioavailability of an IgG antibody, and the systemically
available fraction is more likely <1% [Gould et al. 2018; Pfister et
al. 2014]; Perjeta[supreg] is supplied as a liquid in vial, is prepared
using aseptic techniques, and is not administered as a powder or
aerosol. [We] agree[ ] there is no mechanism by which volumes of
pertuzumab dusts or aerosols sufficient to achieve systemic exposures
associated with adverse effects could be generated in a healthcare
setting.''
NIOSH response: When evaluating the potential hazard to healthcare
workers, NIOSH does not limit evaluation to just the currently produced
commercially available formulations and therefore also considers
powders or aerosol exposures. NIOSH based the evaluation on assumptions
for exposures that are unlikely in commercially available formulations
and on intrinsic properties of the active pharmaceutical ingredients,
not on any particular formulation or treatment product. No changes were
made to the NIOSH Final Reevaluation Determination of Pertuzumab on the
NIOSH List of Hazardous Drugs in Healthcare Settings based on this
comment.
Public comment: ``[P]harmacy compounds the medication and moving
drugs to the nonhazardous list means we use more needles than safety
features. Hazardous medications we use items such as chemolock to
protect us from needle sticks, we do not with the nonhazardous
medications. My concern with medications like this is we can compound
these for prolonged times and over days, months, and years. We could
expose technicians to the amount listed and harm them and if they were
to not know they were pregnant yet or whatever the case this could be
an issue.''
NIOSH response: NIOSH evaluated how the molecular properties
affected bioavailability after exposures via needlesticks, dermal
exposure, ingestion, and inhalation. A large molecule currently only
available in liquid formulations may not lead to exposure equal to a
human recommended dose via inhalation of dust or droplets, but that
potential route of exposure was considered.
NIOSH has used the recommended human dose as a benchmark to
indicate the high end of doses of concern. NIOSH is typically only
concerned with toxic effects that occurred below this level. NIOSH
considers exposures at the human recommended doses to be greater than
the expected dose for healthcare workers. In situations where
healthcare workers may be exposed to therapeutic agents at levels
greater than the levels that patients are exposed to, then the
pharmacological effects may occur. Some changes were made to the NIOSH
Final Reevaluation Determination of Pertuzumab on the NIOSH List of
Hazardous Drugs in Healthcare Settings to clarify.
ii. Percutaneous Exposure
Public comment: ``The published literature on needlestick injuries
supports the statement that the volume of Perjeta[supreg] delivered
from an inadvertent percutaneous exposure is expected to be minimal
(e.g., <1 microliter) and would be insufficient to deliver a
toxicologically relevant dose. However, the 670 microliter `human
dose,' because needlestick exposures are expected to occur
infrequently, it would be more appropriate to compare the <1 microliter
needlestick volume to the volume of Perjeta[supreg] that would be
required to deliver a therapeutic dose (30 mL).''
NIOSH response: NIOSH agrees that the use of a relevant human dose
is
[[Page 104176]]
highly protective, and an incidental percutaneous exposure is unlikely
to result in such a high exposure; however, NIOSH evaluated what was
certainly a worst-case scenario. No changes were made to the NIOSH
Final Reevaluation Determination of Pertuzumab on the NIOSH List of
Hazardous Drugs in Healthcare Settings in response to this comment.
iii. Oral Exposure
Public comment: ``The peer-reviewed publications support the
statement that the oral bioavailability of monoclonal antibodies such
as pertuzumab is negligible. In addition, the sterile preparation and
administration procedures used to administer pertuzumab further reduce
any potential for oral exposure.''
NIOSH response: When evaluating the potential hazard to healthcare
workers, NIOSH does not limit its evaluation to just the currently
produced commercially available formulations, therefore it also
considers powders or aerosol exposures. NIOSH based the evaluation on
assuming unlikely exposures in commercially available formulations and
considering intrinsic properties of the active pharmaceutical
ingredients, rather than focusing on any particular formulation or
treatment product. No changes were made to the NIOSH Final Reevaluation
Determination of Pertuzumab on the NIOSH List of Hazardous Drugs in
Healthcare Settings in response to this comment.
e. What alternatives could be considered to this approach for
monoclonal antibodies to characterize the potential hazard to workers?
Public comment: ``Monoclonal antibodies have been approved for use
to treat humans for more than 25 years and have been safely prepared
and administered using routine aseptic procedures. Although they were
still relatively novel when the List was first developed, monoclonal
antibody-based products are now mainstream therapies for cancer and
other conditions in humans, and their molecular and physiological
properties are well characterized. The properties of monoclonal
antibodies and other high molecular weight molecules result in
occupational risk profiles that are clearly distinct from that of
traditional, small molecule `chemotherapies' that drove the original
2004 NIOSH Alert [2004] and subsequent publication of the List.
The current process for evaluating monoclonal antibodies for
potential inclusion on the List is initially based on hazard (i.e., any
potential effect associated with a molecule). The various exposure-
related factors that determine that the potential risk to a healthcare
worker are secondary considerations.
An alternative approach to characterizing the potential hazard that
a monoclonal antibody-based product poses to healthcare workers would
be a risk-based paradigm that initially considers exposure potential.
Based on the properties of monoclonal antibodies that minimize the
potential for systemic exposure, nearly all monoclonal antibody-based
pharmaceuticals could be excluded from consideration without the need
for a comprehensive review of all hazards that are considered to be
relevant to patients in a therapeutic context. Eliminating products
with little potential to cause health effects in workers would greatly
streamline the nomination and review process for the List.
Potential exceptions to this approach may include immunoglobulin-
based products with usually high potency (e.g., a monoclonal antibody
with a therapeutic maintenance dose <1 mg) or immunoglobulin-based
products that are conjugated to a low-molecular weight component that
may meet the criteria for the List (e.g., a product consisting of a
monoclonal antibody conjugated to a small molecule anti-mitotic agent).
However, such examples are relatively rare and can be readily
identified based on the description in the prescribing information
(Section 11).''
NIOSH response: NIOSH considers each drug based on the potential
hazard posed intrinsically. Each is reviewed individually, and classes
of drugs are not excluded. Monoclonal antibodies may generally have
lower systemic availability via inhalation, ingestion, and dermal
absorption through intact skin, but that availability is not zero and
not all workers have intact skin. NIOSH intends to continue reviewing
each drug individually and will consider the intrinsic hazard that each
drug poses, including molecular properties, such as molecular weight,
which may change the likelihood of occupational exposure. The process
of excluding a whole class of drugs proposed by the commenter may miss
some hazards for some healthcare workplaces. The NIOSH List of
Hazardous Drugs in Healthcare Settings is a hazard identification tool,
and using a risk-based paradigm that considers exposure potential first
may not be sufficient to identify hazards that many drugs may
potentially pose in a wide variety of healthcare settings.
Public comment: ``For compounding, could there possibly be the
consideration of an adapter that goes with it? This would prevent a
needle from technically being used at all as we often use a bag spike
to inject the medications in the bags on either side.''
NIOSH response: The List does not take into consideration the
specific practices used when handling different formulations of the
potentially hazardous drugs used by each facility. No changes were made
to the NIOSH Final Reevaluation Determination of Pertuzumab on the
NIOSH List of Hazardous Drugs in Healthcare Settings based on this
comment.
f. Additional Pertuzumab Comments
Public comment: The commenter ``requests clarification of the
statement that `No oral, inhalation, or dermal exposure studies of
therapeutic monoclonal antibodies have been conducted' (on Page 4 of
the reevaluation). This statement suggests that there is a large degree
of uncertainty related to these key presumptions related to the
evaluation of the risk posed by pertuzumab to healthcare workers.''
NIOSH response: NIOSH agrees and has clarified NIOSH Final
Reevaluation Determination of Pertuzumab on the NIOSH List of Hazardous
Drugs in Healthcare Settings that these studies were not performed
because those therapies are not typically delivered via these routes.
Public comment: The commenter ``requests clarification of the
statement that `The toxicity profile of pertuzumab shows it is a potent
developmental hazard.' There is no regulatory or other consensus
definition for a `potent' hazard in a pharmaceutical context. The use
of this term in policy or regulatory documents is therefore likely to
cause confusion and/or an unwarranted degree of concern among the
intended audiences. The doses of pertuzumab that have been associated
with adverse developmental outcomes in a therapeutic context are
relatively high when compared with many other pharmaceuticals or
chemicals, so its characterization as a potent developmental hazard is
potentially misleading. In addition, the available data from
nonclinical studies and human experience provide evidence of a dose-
responsive effect that is unlikely to occur at far sub-therapeutic
exposures. The description of pertuzumab as a potent developmental
hazard therefore overstates the risk of Perjeta[supreg] to healthcare
workers.''
NIOSH response: NIOSH agrees and has rephrased this sentence in
NIOSH
[[Page 104177]]
Final Reevaluation Determination of Pertuzumab on the NIOSH List of
Hazardous Drugs in Healthcare Settings to note that pertuzumab caused
oligohydramnios which is a clear developmental hazard. The word
``potent'' has been removed.
Public comment: In relation to the results of a study included in
the reevaluation, in the table form on Page 7, the commenter states,
``[t]he findings from the embryo-fetal development toxicity study
support the expectation that the adverse developmental effects of
pertuzumab are dose-related and are not expected to occur at the far
sub-therapeutic exposure scenarios relevant to healthcare workers. The
evidence of a dose-responsive relationship between maternal pertuzumab
doses and adverse outcomes can be leveraged to support many of the
presumptions in the external review.''
NIOSH response: The evidence in this study does not provide a dose
at which developmental effects are not seen. The commenter is correct
that it does support a dose-response relationship between pertuzumab
and developmental effects, supporting the conclusion that lower
systemic doses resulting from occupational exposures are less likely to
cause developmental effects. No changes were made to the NIOSH Final
Reevaluation Determination of Pertuzumab on the NIOSH List of Hazardous
Drugs in Healthcare Settings based on this comment.
B. Peer Review
1. Liraglutide Peer Review
Two external peer reviewers submitted responses to NIOSH, which are
marked as ``Reviewer comment'' below. In general, both peer reviewers
agreed with the approach NIOSH used to determine if liraglutide posed a
hazard to workers in healthcare settings. Both peer reviewers also
agreed with NIOSH that thyroid tumors and adverse developmental effects
were appropriate health outcomes to consider. Lastly, both peer
reviewers agreed that the systemic and occupational exposure
assumptions NIOSH used in the evaluation were appropriate, and the
resulting determination that liraglutide does not constitute a hazard
for healthcare workers is correct.
a. Are the evaluated health effects the appropriate health effects
to consider? If not, what other health effect(s) should be evaluated
and why?
Reviewer 1 comment: ``Yes, the evaluated health effects are the
appropriate health effects to consider.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
Reviewer 2 comment: ``Yes. Thyroid tumors as indicated in the black
box warning and developmental effects, as indicated by the Pregnancy
Category C determination, and are the most relevant adverse health
effects to be considered. The assertions made concerning a causal
association between incretin-based drugs like liraglutide and
pancreatitis or pancreatic tumors, as expressed currently in the
scientific literature and in the media, are inconsistent with the
current data. In the NIOSH review, concerns about the potential
effects, including thyroid cancer and developmental effects, should be
reduced in light of more recent data. There are no other potential
health effects to be considered that are supported by current data.
Other nonspecific effects noted in the package insert, such as nausea,
injection site pain, and low blood sugar, are manageable and not
serious.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
b. Are the assumptions about the potential occupational exposures
to liraglutide in a healthcare setting reasonable? Please explain.
Reviewer 1 comment: ``The assumptions about the potential
occupational exposures to liraglutide in a healthcare setting are
reasonable. Given the formulation and packaging of liraglutide, it
would be expected that occupational exposure may occur if a vial leaks
or breaks, which would lead to inhalation or dermal exposure, neither
of which produce significant systemic bioavailability; or if a
needlestick injury occurs, in which the quantity of drug actually
injected would also be insignificant in the majority of cases.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
Reviewer 2 comment: ``Yes. This is a peptide with approximately
3750 molecular weight. Substances with molecular weights greater than
1000 Daltons show nil to poor absorption (less than 0.1%). Thus, dermal
absorption in a healthcare workplace exposure would be nil, as the skin
is a barrier for substances of this molecular weight. Normally (in
clinical use) this substance is injected. The substance would also be
expected to be degraded in oral exposure scenarios. Inhalation exposure
scenarios can also be ruled out as this substance is in aqueous form in
prefilled syringes and thus aerosolization is not expected. Absorption
through this route would also be expected to be nil to poor.
Needlestick exposures do occur in healthcare situations, but the
mechanism of action for a chronic carcinogenic mechanism of action
would not be triggered by needlestick exposures because of the
toxicokinetics of peptides. A sufficient peak concentration would not
be sustained for a sufficient duration to produce chronic effects. In
short, exposures to this drug in the occupational exposure scenarios
are exceedingly low . . . de minimis, in my opinion.''
NIOSH response: While inhalation of liraglutide in current
formulations can be ruled out, NIOSH still evaluated inhalation routes
of exposure. NIOSH does not limit the evaluation to current
formulations. NIOSH determined that liraglutide would not pose a hazard
to workers even via the inhalation route. No changes were made to the
NIOSH Final Reevaluation Determination of Liraglutide on the NIOSH List
of Hazardous Drugs in Healthcare Settings based on this comment.
c. Is the determination that the amount of exposure to liraglutide
in a healthcare setting does not constitute a hazard for healthcare
workers reasonably supported by the available scientific information?
Please explain.
Reviewer 1 comment: ``Yes, the determination that the amount of
exposure to liraglutide in a healthcare setting does not constitute a
hazard for healthcare workers is reasonably supported by the available
scientific information. Given the mechanisms of action of liraglutide,
sustained exposure is required for significant effect, which would not
likely be encountered in the occupational setting if medication is
prepared, transported and administered as indicated (i.e., in sealed
vials).''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
Reviewer 2 comment: ``Yes. In my review of the literature, the
hazard to humans due to the ``black box'' warning about thyroid tumors
is low. In the study, at least some of the cases of thyroid tumors
occurred in subjects with existing thyroid disease, and
[[Page 104178]]
should have been excluded. Secondly, a mitogenic mode of action is
suggested, which would require continuous exposures, which are
unlikely. Evidence suggests species-specific effects due to elevated
GLP-1R receptor levels and downstream signaling. The knockout mouse
study seems compelling in suggesting that the effects observed in
rodents should not be directly extrapolated to humans. Thus, in
addition to having a de minimis exposure, the potential of adverse
effects is less than previously recognized. While the developmental
effects in rats/rabbits cannot be ruled out, the statistical
significance/magnitude of these hazards was not identified. For
example, while it was stated that doses in the same range as human
caused developmental effects, it was not clear that this was a `human
equivalent dose' . . . some sort of body weight \3/4\ calculation. That
lack of significance/magnitude of these potential hazards also raise
concerns about the potential over-interpretation of these developmental
effects. Thus, de minimis exposures coupled with lower than previously
recognized hazards combine to lower the risks to healthcare workers in
clinical settings. NIOSH has evaluated data and estimated exposures and
has come to the correct conclusion. I fully agree.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
d. What alternative approaches could be considered to characterize
the potential hazard to workers from peptide-based drugs?
Reviewer 1 comment: ``The alternative approaches that could be
considered to characterize the potential hazard to workers from
peptide-based drugs include surveillance regarding OSHA reportable
injuries or illness related to occupational exposure to liraglutide and
periodic review of the Medullary Thyroid Carcinoma (MTC) Surveillance
Study [Hale et al. 2020].''
NIOSH response: The Medullary Thyroid Carcinoma (MTC) registry
could provide data that could affect future evaluations of liraglutide.
NIOSH evaluates drugs when a safety related labeling change is posted
regarding the drugs [NIOSH 2023]. Further, if new data related to the
MTC surveillance study were brought to NIOSH's attention, NIOSH could
further evaluate the potential hazards of liraglutide exposures to
healthcare workers as indicated in the NIOSH Procedures for Developing
the NIOSH List of Hazardous Drugs in Healthcare Settings [NIOSH 2023].
Reviewer 2 comment: ``It might be possible to do a literature
search on studies for adverse effects in occupational exposures to
insulin. This is a common peptide hormone with 100 years of clinical
experience. I'd imagine that the exposures to healthcare workers to
insulin (by all routes) would be similar to liraglutide. As liraglutide
had a molecular weight about 7-fold higher than that of insulin, it
would be more poorly absorbed and less of a risk. The incidence of
adverse effects in worker exposures in health care settings for insulin
could be used as a `worst-case' analogue to estimate of the incidence
of liraglutide exposures and potential risk.''
NIOSH response: Due to the rapid acute effects of insulin, NIOSH
agrees it would likely serve as a worst-case scenario and overestimate
the effects of exposure to liraglutide. Also, as the reviewer notes,
any use of insulin as a surrogate would involve consideration of many
caveats, including absorption, effect intensity/duration, and different
specific mechanisms of action. These uncertainties would make the
resulting evaluation less useful for the purpose of NIOSH's hazard
identification for placement on the List. Therefore, NIOSH would not
use insulin as a surrogate for evaluation of the hazard of liraglutide
or other GLP-1 agonist drugs since only hazard identification is the
basis for placement on the List. No changes were made to the NIOSH
Final Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
e. Is there any additional information that NIOSH should consider
in its reevaluation of liraglutide?
Reviewer 1 comment: ``There is no additional information that NIOSH
should consider in its reevaluation of liraglutide at this time.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
Reviewer 2 comment: ``As with all things, decisions are based on
the best available data. As the availability of data will change with
time, a further reevaluation in the decades that come will be
appropriate should new data become available about any of the potential
health effects or new ones that emerge.''
NIOSH response: No changes were made to the NIOSH Final
Reevaluation Determination of Liraglutide on the NIOSH List of
Hazardous Drugs in Healthcare Settings based on this comment.
2. Pertuzumab Peer Review
Three external peer reviewers submitted responses to NIOSH.
Overall, all agreed with the general approach NIOSH used to determine
if the molecular properties, molecular size in this case, of pertuzumab
would limit the hazard it poses in healthcare settings. Two of the
reviewers agreed with the conclusion that NIOSH proposed, which was
that pertuzumab would not be able to pose a developmental hazard in
healthcare settings. They did however believe that the NIOSH inhalation
exposure scenario overestimated the potential systemic exposure and
that an incidental needlestick would pose the most relevant exposure.
Both expressed an interest in other potential hazards. One expressed an
interest in cardiac hazards and one in sensitization.
The third reviewer, while agreeing that the approach was sound and
the assumptions reasonable, disagreed with NIOSH on some points and
felt that pertuzumab should remain on the List. This reviewer stated
that there was not enough quantitative data to rule out potentially
relevant levels of exposures via the dermal and oral routes. They
stated that without quantitative data to support the assumptions made
that the lack of a NOAEL and the severity of effects in the animal
study in the FDA review supported leaving pertuzumab on the List. This
reviewer expressed a concern that while the observed effect,
oligohydramnios, was reversible that did not rule out that there are no
adverse effects to the fetus, including potential upstream and
downstream effects. They also expressed concerns that using trastuzumab
as a model for pertuzumab effects might not be appropriate. There may
be some differences in their effects, as some differences in molecular
signaling have been identified in a cell system model.
a. Reviewer 1
Reviewer 1 comment 1: ``More quantitative information is needed,
quantitative gaps need to be addressed, and justification in the face
of the gaps need to be outlined. The examination of routes of exposure
seems to be limited to the molecular properties of the drug. Workplace
exposure scenarios are not described (e.g., opportunities of splashing,
use of PPE such as gloves, potential for hand to mouth activity, etc.).
Inclusion of these exposure scenarios would be informative, but if they
are not described the rationale for
[[Page 104179]]
not providing a set of exposure scenarios, should be explained.''
NIOSH response: Evaluation of workplace exposure scenarios are
outside of the scope of the List. Because the large variety of
scenarios that may take place in healthcare workplaces and the
different properties of hazardous drugs, NIOSH does not take into
account all of the possible workplace exposure scenarios. Therefore,
for pertuzumab, NIOSH considered maximum occupational systematic
exposure via all available routes to be less than a full therapeutic
dose. In this case, NIOSH considered if the properties of the drug
might limit the systemic availability via worst-case relevant routes of
occupational exposure. Individual scenario analysis would not add
significantly to these findings, as the resultant exposures would
likely be much less than the worst-case scenarios. This is why the
examination is limited to molecular properties of the drug and an
evaluation of worst-case workplace exposures.
Reviewer 1 comment 2: ``The assumptions are reasonable, but the
evidence to support them is very limited. Research gaps should be
identified and described. An example is the lack of quantitative data
on the absorption of pertuzumab following oral exposure. The statement
that bioavailability as `low' lacks clarity. The studies cited to back
up the qualitative statement do not present quantitative data or
reference other studies to support the claims regarding oral
bioavailability.''
NIOSH response: No quantitative data on the oral bioavailability of
pertuzumab exist. The bioavailability of monoclonal antibodies and
proteins are low because they are degraded in the gastrointestinal
tract and are poorly absorbed through the gastrointestinal epithelium
[Keizer et al. 2010; Wang et al. 2008]. This severely limits the
bioavailability of intact proteins passing through the GI tract.
Because of this, systemic exposure via the oral route is likely much
lower when compared with the inhalation worst-case scenario NIOSH
considered. The same is true for dermal exposures. The worst-case
scenario NIOSH addressed in the inhalation scenario is likely the
worst-case scenario overall. Some clarifying language has been added to
the appropriate sections of the document.
Reviewer 1 comment 3: ``Oligohydramnios being reversible does not
necessarily indicate no adverse effect on the fetus. Downstream and
upstream effects should be considered.''
NIOSH response: Only one case study of exposure to pertuzumab
during pregnancy in a human was identified and that exposure included
co-exposure with trastuzumab. Information was available on exposure to
trastuzumab, the similar monoclonal antibody targeting the same HER2
mechanism. No long-term follow-up on the exposed children was
identified, but the Zagouri et al. [2013] review noted that all
children with only first trimester exposure, when treatment was ceased,
had good outcomes, and all babies born healthy were still healthy at
nine months after birth. However, this is the only follow-up
identified.
Reviewer 1 comment 4: ``Given the severity of the renal effects
seen in cynomolgus monkey offspring, removal of pertuzumab from the
List based on its molecular properties related to exposure should be
based on a strong evidence base (e.g., direct evidence in humans that a
single low exposure dose does not carry risk of renal effects in the
fetus).''
NIOSH response: Only one case study identifying human pregnancy
exposure to pertuzumab was identified and that patient was also
receiving trastuzumab. In the cynomolgus monkey study, the effects did
appear to be dose-related and treatment was continued throughout
gestation. Data in humans with in utero exposure to the monoclonal
antibody trastuzumab, which targets the same mechanism, suggest that
the effects are reversible, and when exposure is ceased, outcomes
improve with healthy babies being born. Lambertini et al. [2019] found
12 cases of potential in utero exposure to trastuzumab and/or the HER2
targeting small molecule drug lapatinib, seven had elective abortions
and five continued the pregnancy. In all cases where the child was
born, exposure was only during the first trimester. Outcomes at birth
were normal for four. In the fifth, the baby was delivered via
caesarian at 34 weeks due to growth retardation. In that case, the
mother had received radiation therapy for brain metastasis and died 17
days following delivery. The mechanism of action of pertuzumab appears
to lead to reversible effects when exposure is not continuous.
Reviewer 1 comment 5: ``The use of another drug, trastuzumab, as a
model for pertuzumab, may provide some insights, but this evidence must
be interpreted with caution because small differences between
substances with similar structures or mechanisms of action can
significantly impact their biological activity, as exemplified by (but
not limited to) the ability of pertuzumab, but not trastuzumab to
induce activation of the PI3K cell survival pathway [FDA 2012].''
NIOSH response: In cell lines, pertuzumab does block activation of
the PI3K survival pathway as indicated by decreased phosphorylation of
AKT in a cancer cell line.\6\ Physiological effects appear similar
between the two monoclonal antibodies. There are no available reports
of fetal effects of pertuzumab without concurrent trastuzumab exposure
in humans during pregnancy. Trastuzumab was used as a model of human
exposure during pregnancy because the primary target pathway for the
two molecules is the same, and the effect in humans and the cynomolgus
monkeys are the same. This indicates that the mechanism of action is
related to the similar HER2 inhibition of the two molecules.
---------------------------------------------------------------------------
\6\ Pertuzumab, but not trastuzumab, blocks the activation of a
cell survival pathway in cultured cell lines in an in vitro assay.
---------------------------------------------------------------------------
Reviewer 1 comment 6: ``The lack of a NOAEL suggests that a strong
case is needed for this drug to be exempt based on the `molecular
properties' argument.''
NIOSH response: While there is no identified NOAEL stated in the
available monkey studies, the effects do appear to increase in severity
with dose. For trastuzumab, which targets the same molecular mechanism,
it also appears that continued exposure in the later trimesters of
pregnancy is required to initiate the effects that lead to
oligohydramnios. The molecular properties of monoclonal antibodies mean
the bioavailability to a single exposure is lower. Repeated exposure to
a level that might lead to systemic exposures that could lead to
continued reversible effects are also unlikely.
Reviewer 1 comment 7: ``Would this section [the section called
Hazard Characterization] be more appropriately named something related
to exposure rather than hazard?''
NIOSH response: Under the heading Integrated Toxicity and Molecular
Property Hazard Characterization of the NIOSH Reevaluation of
Pertuzumab on the NIOSH List of Antineoplastic and Other Hazardous
Drugs in Healthcare Settings, NIOSH discussed how the relevant
molecular properties, in this case, molecular weight, affect the hazard
of the drug. In this case, consideration of relevant potential
exposures influence how the potential hazard is characterized. This
information is about hazard characterization rather than exposure. No
change was made to the NIOSH Final Reevaluation Determination of
Pertuzumab on the NIOSH List of Hazardous Drugs in Healthcare Settings
in response to this comment.
[[Page 104180]]
b. Reviewer 2
Reviewer 2 comment 1: ``An accidental needle stick is the only
reasonable route of exposure for healthcare workers. The skin serves as
an effective barrier to penetration of most environmental sources of
chemicals, including large molecules such as pertuzumab. Orally,
pertuzumab will be degraded by intestinal proteases. Since pertuzumab
is provided as a solution in a single use vial to be mixed with saline
prior to infusion, inhalation of droplets will not provide sufficient
exposure to result in risks to the fetus of a healthcare worker.''
NIOSH response: NIOSH does not limit the consideration to the
currently available formulation. Formulations may change over time, so
inhalation was considered.
Reviewer 2 comment 2: ``The estimate for inhalation exposure of 5%
was developed for workers in a manufacturing setting to derive
occupational exposure limits but is likely an overestimate of potential
exposure of pertuzumab in a healthcare setting. According to the data
and discussion in Pfister et al. [2014], the 5% value represents a
maximum bioavailability for proteins >40 kDa; 1.7% was the median.
According to the package insert, pertuzumab has an approximate
molecular weight of 148 kDa. Proteins >40 kDa were applied by
intratracheal instillation (Table 1). This is not a likely route of
exposure for pertuzumab in a healthcare setting.''
NIOSH response: While intratracheal instillation is not a likely
route of exposure for a drug in a healthcare setting, it provided the
only data to consider bioavailability through the respiratory tract
tissues. The studies reviewed by Pfister et al. [2014] did include
studies that looked at intratracheal instillation of monoclonal
antibodies like pertuzumab.
Reviewer 2 comment 3: ``Another sensitive endpoint could be
assessing respiratory sensitization in workers though workplace
monitoring, but this should be applied only if there is a hazard
identified in a clinical trial or post marketing setting. According to
Pfister et al., respiratory sensitization has not been observed in a
manufacturing setting to date.''
NIOSH response: The NIOSH List does not consider respiratory
sensitization as a criterion for identifying potential drug hazards.
c. Reviewer 3
Reviewer 3 comment 1: ``[A]nother potential health effect could be
heart problems associated with Perjeta treatment [Shrim et al. 2007;
Swain et al. 2014]. The decreased left ventricular ejection fraction
resulting in cardiac failure and congestive heart failure has been
listed as possible side effects of the treatment and should be
reversible when the treatment is stopped. To the best of my knowledge,
there were no reported heart related issues with the offsprings from
the in vivo studies. Whether the occupational exposure concentrations
would be high enough to cause the potential heart problems or not, this
should be considered as a probable hazard to healthcare workers in
occupational exposure settings.''
NIOSH response: Cardiac effects may occur at treatment levels, but
these do not meet NIOSH criteria. Even in the worst-case scenario,
systemic exposures in healthcare workplaces are unlikely to reach
levels near treatment levels. The cardiac effects are unlikely to be of
relevance in occupational exposures in healthcare settings because they
are associated with exposures only at treatment levels.
Reviewer 3 comment 2: ``Based on the highest concentration provided
(30 mg/mL), an accidental needle stick delivery based on the different
needle properties [Foster et al. 2010; Gaughwin et al. 1991; Krikorian
et al. 2007; Mast et al. 1993; Napoli and McGowan 1987] would be
negligible (<1 [mu]L) to achieve the human dose. Since pertuzumab is
not volatile, an inhalation route would pose negligible hazard. As
mentioned above, the accidental needle stick delivery would be
extremely low to achieve the human dose.''
NIOSH response: NIOSH evaluated a scenario for needlestick that
went beyond the worst case. NIOSH agrees that an incidental needlestick
would not deliver a human dose, but even if it did, multiple needle
sticks providing the relevant exposures are not considered to be
likely. The effect of concern is reversible and requires repeated
exposure to maintain the systemic exposure levels that would cause
oligohydramnios, which would not happen even in the NIOSH evaluated
worst-case scenario.
V. Summary of Updates and Changes to NIOSH List of Hazardous Drugs in
Healthcare Settings
In this update, 25 drugs have been added to the List since the
publication of the NIOSH List of Antineoplastics and Other Hazardous
Drugs, 2016. Twelve of those newly added drugs have special handling
information from the manufacturers. Seven drugs have been removed from
the List, including liraglutide and pertuzumab. These additions and
removals, as well as the reorganization discussed below, are now
reflected in the NIOSH List of Hazardous Drugs in Healthcare Settings,
2024, available on the NIOSH website (see <a href="https://www.cdc.gov/niosh/healthcare/hazardous-drugs/index.html">https://www.cdc.gov/niosh/healthcare/hazardous-drugs/index.html</a>) and in the docket for this
activity.
Drugs reviewed for this update were either new drug approvals or
those drugs that received new safety-related warnings from FDA in the
period between January 2014 and December 2015. In addition to these
updates, the tables categorizing hazardous drugs have been reorganized.
Table 1 now includes drugs that:
<bullet> Contain MSHI in the package insert, and/or
<bullet> Meet the NIOSH definition of a hazardous drug, and
<bullet> Are classified by NTP as known to be a human carcinogen
and/or by IARC as carcinogenic to humans (Group 1) or probably
carcinogenic to humans (Group 2A).
In the 2016 List, Table 1 focused on antineoplastic drugs. However,
in the 2024 List, NIOSH has removed the identifier ``antineoplastic''
because of advances in cancer treatment, the therapeutic designation
``antineoplastic'' no longer indicates drugs of high toxicity.
Therefore, Table 1 focuses on the toxicity and carcinogenicity of
drugs, regardless of their therapeutic use.
Table 2 now contains drugs that:
<bullet> Meet one or more of the NIOSH definitions of a hazardous
drug, and
<bullet> Are not drugs with MSHI, and
<bullet> Are not classified by NTP as known to be a human
carcinogen or by IARC as carcinogenic to humans (Group 1) or probably
carcinogenic to humans (Group 2A).
Some of the drugs in Table 2 have adverse reproductive effects for
populations at risk.
This table includes those drugs that only meet the NIOSH criteria
as a developmental (including teratogenicity) and/or reproductive
hazard. In the 2016 update of the List, such drugs were included in a
separate table (Table 3), which has been combined with Table 2. Drugs
that only meet the NIOSH criteria as a reproductive and/or
developmental hazard are identified in a column labeled ``Only
Developmental and/or Reproductive Hazard'' in the 2024 List.
Changes to the placement of drugs on the List, including drugs that
are no longer considered hazardous and those that have been moved from
one table to another, are described in a new section in the 2024 List
and not called out in a
[[Page 104181]]
separate table as in the 2016 update (former Table 4).
In the 2016 update, Table 5 provided information on recommended
exposure controls for hazardous drugs based on formulations. NIOSH
moved and expanded the risk management information formerly provided in
Table 5 and developed a new document, Managing Exposures. This document
includes information on engineering controls, administrative controls,
and PPE for working with hazardous drugs in healthcare settings. It is
available on the NIOSH Hazardous Drug Exposures in Healthcare
website.\7\
---------------------------------------------------------------------------
\7\ <a href="https://www.cdc.gov/niosh/healthcare/hazardous-drugs/?CDC_AAref_Val=https://www.cdc.gov/niosh/topics/hazdrug/default.html">https://www.cdc.gov/niosh/healthcare/hazardous-drugs/?CDC_AAref_Val=https://www.cdc.gov/niosh/topics/hazdrug/default.html</a>.
---------------------------------------------------------------------------
In previous updates, NIOSH included a supplemental information
column that contained additional information about individual drugs,
including pregnancy categories. However, as of 2015, FDA no longer uses
the pregnancy categories for drugs and this information was not
necessarily related to the NIOSH decision to place the drug on the
List. Therefore, NIOSH has removed the supplemental information column
from the 2024 List.
Finally, in the 2024 List, NIOSH has added a column to identify
drugs that were approved by CDER under a BLA. These drugs tend to be
large, protein-based molecules. The properties of these drugs may
affect the strategies used to address the hazards they pose.
Identifying them would aid in hazard identification for risk management
in healthcare settings. NIOSH notes that some of the drugs that were
approved under a BLA may include conjugates with their own separate
hazards, which should also be taken into account.
References
FDA [2012]. Pharmacology review of Perjeta. Application No.
125409Orig1s000. Reviewer: Ringgold K. Washington, DC: U.S.
Department of Health Food and Drug Administration, Center for Drug
Evaluation and Research, <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000PharmR.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000PharmR.pdf</a>.
FDA [2022]. Information for outsourcing facilities. Washington, DC:
U.S. Department of Health and Human Services, Food and Drug
Administration, <a href="https://www.fda.gov/drugs/human-drug-compounding/information-outsourcing-facilities">https://www.fda.gov/drugs/human-drug-compounding/information-outsourcing-facilities</a>.
Foster TM, Lee MG, McGaw CD, Frankson MA [2010]. Prevalence of
needlestick injuries and other high risk exposures among healthcare
workers in Jamaica. West Indian Med J 59(2):153-159.
Gaughwin MD, Gowans E, Ali R, Burrell C [1991]. Bloody needles: the
volumes of blood transferred in simulations of needlestick injuries
and shared use of syringes for injection of intravenous drugs. AIDS
5(8):1025-1027.
Gould JC, Carvajal I, Davidson T, Graham J, Hillegass J, Julien S,
Kozhich A, Wang B, Wei H, Yamniuk AP, Mathias N, Haggerty HG,
Graziano M [2018]. Bioavailability of protein therapeutics in rats
following inhalation exposure: relevance to occupational exposure
limit calculations. Regul Toxicol Pharmacol 100:35-44, <a href="https://doi.org//10.1016/j.yrtph.2018.10.003">https://doi.org//10.1016/j.yrtph.2018.10.003</a>.
Hale PM, Ali AK, Buse JB, McCullen MK, Ross DS, Sabol ME, Tuttle RM,
Stemhagen A [2020]. Medullary Thyroid Carcinoma Surveillance Study:
a case-series registry. Thyroid 30(10):1397-1398, <a href="https://doi.org/10.1089/thy.2019.0591">https://doi.org/10.1089/thy.2019.0591</a>.
Keilman C, Shanks AL [2022]. Oligohydramnios. In: StatPearls
[internet]. Treasure Island, FL: StatPearls Publishing, <a href="https://www.ncbi.nlm.nih.gov/books/NBK562326/">https://www.ncbi.nlm.nih.gov/books/NBK562326/</a>.
Keizer RJ, Huitema ADR, Schellens JHM, Beijnen [2010]. Clinical
pharmacokinetics of therapeutic monoclonal antibodies. Clin
Pharmacokinet 49(8):493-507, <a href="https://doi.org/10.2165/11531280-000000000-00000">https://doi.org/10.2165/11531280-000000000-00000</a>.
Krikorian R, Lozach-Perlant A, Ferrier-Rembert A, Hoerner P, Sonntag
P, Garin D, Crance J-M [2007]. Standardization of needlestick injury
and evaluation of a novel virus-inhibiting protective glove. J Hosp
Infect 66(4):339-345, <a href="https://doi.org/10.1016/j.jhin.2007.05.008">https://doi.org/10.1016/j.jhin.2007.05.008</a>.
Lambertini M, Martel S, Campbell C, Guillaume S, Hilbers FS,
Schuehly U, Korde L, Azim HA Jr, Di Cosimo S, Tenglin RC, Huober J,
Baselga J, Moreno-Aspitia A, Piccart-Gebhart M, Gelber RD, de
Azambuja E, Ignatiadis M [2019]. Pregnancies during and after
trastuzumab and/or lapatinib in patients with human epidermal growth
factor receptor 2-positive early breast cancer: analysis from the
NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials. Cancer 25(2):307-
316, <a href="https://doi.org/10.1002/cncr.31784">https://doi.org/10.1002/cncr.31784</a>.
Mast ST, Woolwine JD, Gerberding JL [1993]. Efficacy of gloves in
reducing blood volumes transferred during simulated needlestick
injury. J Infect Dis 168(6):1589-1592, <a href="https://doi.org/10.1093/infdis/168.6.1589">https://doi.org/10.1093/infdis/168.6.1589</a>.
Napoli VM, McGowan JE Jr [1987]. How much blood is in a needlestick?
J Infect Dis 15(4):828, <a href="https://doi.org/10.1093/infdis/155.4.828">https://doi.org/10.1093/infdis/155.4.828</a>.
NIOSH [2004]. NIOSH alert: preventing occupational exposures to
antineoplastic and other hazardous drugs in health care settings. By
Burroughs GE, Connor TH, McDiarmid MA, Mead KR, Power LA, Reed LD,
Coyle BJ, Hammond DR, Leone MM, Polovich M, Sharpnack DD.
Cincinnati, OH: U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention, National Institute for
Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-
165, <a href="https://www.cdc.gov/niosh/docs/2004-165/">https://www.cdc.gov/niosh/docs/2004-165/</a>.
NIOSH [2016]. NIOSH list of antineoplastic and other hazardous drugs
in healthcare settings, 2016. By Connor TH, MacKenzie BA, DeBord DG,
Trout DB, O'Callaghan JP. Cincinnati, OH: U.S. Department of Health
and Human Services, Centers for Disease Control and Prevention,
National Institute for Occupational Safety and Health, DHHS (NIOSH)
Publication Number 2016-161 (Supersedes 2014-13), <a href="https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf">https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf</a>.
NIOSH [2023]. Procedures for developing the NIOSH list of hazardous
drugs in healthcare settings. By Whittaker C, Ovesen JL, MacKenzie
BA, Hartley T, Berry KA, Piacentino J. Cincinnati, OH: U.S.
Department of Health and Human Services, Centers for Disease Control
and Prevention, National Institute for Occupational Safety and
Health, DHHS (NIOSH) Publication No. 2023-129, <a href="https://doi.org/10.26616/NIOSHPUB2023129">https://doi.org/10.26616/NIOSHPUB2023129</a>.
Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA,
Martino S, Gralow JR, Dakhil SR, Ingle JN, Winer EP, Gelmon KA,
Gersh BJ, Jaffe AS, Rodeheffer RJ [2008]. Cardiac safety analysis of
doxorubicin and cyclophosphamide followed by paclitaxel with or
without trastuzumab in the North Central Cancer Treatment Group
N9831 adjuvant breast cancer trial. J Clin Oncol 26(8):1231-1238,
<a href="https://doi.org/10.1200/JCO.2007.13.5467">https://doi.org/10.1200/JCO.2007.13.5467</a>.
Pfister T, Dolan D, Bercu J, Gould J, Wang B, Bechter R, Barle EL,
Pfannkuch F, Flueckiger A [2014]. Bioavailability of therapeutic
proteins by inhalation--worker safety aspects. Ann Occup Hyg
58(7):899-911, <a href="https://doi.org/10.1093/annhyg/meu038">https://doi.org/10.1093/annhyg/meu038</a>.
Shrim A, Garcia-Bournissen F, Maxwell C, Farine D, Koren G [2007].
Favorable pregnancy outcome following Trastuzumab
(Herceptin[supreg]) use during pregnancy: case report and updated
literature review. Reprod Toxicol 23(4):611-613, <a href="https://doi.org/10.1016/j.reprotox.2007.02.003">https://doi.org/10.1016/j.reprotox.2007.02.003</a>.
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos
E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes
MC, Cort[eacute]s J [2014]. Pertuzumab, trastuzumab, and docetaxel
in HER2-positive metastatic breast cancer. N Engl J Med 372(8):724-
734, <a href="https://doi.org/10.1056/NEJMoa1413513">https://doi.org/10.1056/NEJMoa1413513</a>.
Wang W, Wang EQ, Balthasar JP [2008]. Monoclonal antibody
pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther
84(5):548-558, <a href="https://doi.org/10.1038/clpt.2008.170">https://doi.org/10.1038/clpt.2008.170</a>.
Watson WJ [2005]. Herceptin (trastuzumab) therapy during pregnancy:
association with reversible anhydramnios. Obstet Gynecol 105(3):642-
643, <a href="https://doi.org/10.1097/01.aog.0000141570.31218.2b">https://doi.org/10.1097/01.aog.0000141570.31218.2b</a>.
Zagouri F, Sergentanis TN, Chrysikos D,
[[Page 104182]]
Papadimitriou CA, Dimopoulos M-A, Bartsch R [2013]. Trastuzumab
administration during pregnancy: a systematic review and meta-
analysis. Breast Cancer Res Treat 137(2):349-357, <a href="https://doi.org/10.1007/s10549-012-2368-y">https://doi.org/10.1007/s10549-012-2368-y</a>.
John Howard,
Director, National Institute for Occupational Safety and Health,
Centers for Disease Control and Prevention, Department of Health and
Human Services.
[FR Doc. 2024-30456 Filed 12-19-24; 8:45 am]
BILLING CODE 4163-18-P
</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>Indexed from Federal Register on December 20, 2024.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.