Hazardous Drugs: NIOSH List of Hazardous Drugs in Healthcare Settings, 2024 and Final Reevaluation Determinations for Liraglutide and Pertuzumab, 104163-104182 [2024-30456]

Agencies

• Centers for Disease Control and Prevention
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 89, Number 245 (Friday, December 20, 2024)]
[Notices]
[Pages 104163-104182]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-30456]


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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.

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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 www.regulations.gov and through the NIOSH Hazardous Drug 
Exposures in Healthcare website at https://www.cdc.gov/niosh/healthcare/hazardous-drugs/.

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: 
[email protected].

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.
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    \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), https://www.cdc.gov/niosh/docs/2025-103. 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.
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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 www.regulations.gov 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 https://www.cdc.gov/niosh/healthcare/hazardous-drugs/publications.html.
    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\
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    \2\ See www.ahfsdruginformation.com.
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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.
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    \3\ U.S. Pharmacopeia [June 2020], Revision Bulletin, https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-800-rb-notice-20200626.pdf.
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    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 https://www.cdc.gov/niosh/healthcare/hazardous-drugs/) 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:
     Contain MSHI in the package insert, and/or
     Meet the NIOSH definition of a hazardous drug, and
     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:
     Meet one or more of the NIOSH definitions of a hazardous 
drug, and
     Are not drugs with MSHI, and
     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\ https://www.cdc.gov/niosh/healthcare/hazardous-drugs/?CDC_AAref_Val=https://www.cdc.gov/niosh/topics/hazdrug/default.html.
---------------------------------------------------------------------------

    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.

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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