[Federal Register Volume 86, Number 177 (Thursday, September 16, 2021)]
[Proposed Rules]
[Pages 51640-51643]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-19953]


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CONSUMER PRODUCT SAFETY COMMISSION

16 CFR Part 1700

[Docket No. CPSC-2021-0027]


Poison Prevention Packaging Requirements; Proposed Exemption of 
Baloxavir Marboxil Tablets in Packages Containing Not More Than 80 mg 
of the Drug

AGENCY: Consumer Product Safety Commission.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Consumer Product Safety Commission (Commission or CPSC) is 
proposing to amend the child-resistant packaging requirements to exempt 
baloxavir marboxil tablets in packages containing not more than 80 mg 
of the drug, currently marketed as XOFLUZA,TM from the 
special packaging requirements. XOFLUZA is used to treat the flu, and 
is taken in one dose within 48 hours of experiencing flu symptoms. The 
proposed rule would exempt this prescription drug product on the basis 
that child-resistant packaging is not needed to protect young children 
from serious injury or illness because the product is not acutely toxic 
and lacks adverse human experience associated with ingestion.

DATES: Comments should be submitted no later than November 30, 2021.

ADDRESSES: You may submit comments, identified by Docket No. CPSC-2021-
0027, by any of the following methods:
    Electronic Submissions: Submit electronic comments to the Federal 
eRulemaking Portal at: https://www.regulations.gov. Follow the 
instructions for submitting comments. The CPSC does not accept comments 
submitted by electronic mail (email), except through https://www.regulations.gov. The CPSC encourages you to submit electronic 
comments by using the Federal eRulemaking Portal, as described above.
    Mail/Hand Delivery/Courier Written Submissions: Submit comments by 
mail/hand delivery/courier to: Division of the Secretariat, Consumer 
Product Safety Commission, 4330 East West Highway, Bethesda, MD 20814; 
telephone (301) 504-7479.
    Instructions: All submissions received must include the agency name 
and docket number for this notice. All comments received may be posted 
without change, including any personal identifiers, contact 
information, or other personal information provided, to: https://www.regulations.gov. Do not submit electronically confidential business 
information, trade secret information, or other sensitive or protected 
information that you do not want to be available to the public. If you 
wish to submit such information please submit it according to the 
instructions for written submissions.
    Docket: For access to the docket to read background documents or 
comments received, go to: https://www.regulations.gov, and insert the 
docket number, CPSC-2021-0027, into the ``Search'' box, and follow the 
prompts.

FOR FURTHER INFORMATION CONTACT: Cheryl A. Scorpio, Ph.D., Division of

[[Page 51641]]

Pharmacology and Physiology Assessment, Directorate for Health 
Sciences, Consumer Product Safety Commission, 5 Research Place, 
Rockville, MD 20850; telephone (301) 987-2572; [email protected].

SUPPLEMENTARY INFORMATION:

A. Background

1. The Poison Prevention Packaging Act of 1970 and Implementing 
Regulations

    The Poison Prevention Packaging Act of 1970 (PPPA), 15 U.S.C. 1471-
1476, gives the Commission authority to establish standards for the 
``special packaging'' of household substances, such as drugs, when 
child-resistant (CR) packaging is necessary to protect children from 
serious personal injury or illness due to the substance, and the 
special packaging is technically feasible, practicable, and appropriate 
for such substance. 15 U.S.C. 1472(a). Special packaging requirements 
under the PPPA have been codified at 16 CFR parts 1700 and 1702. 
Specifically, CPSC regulations require special packaging for oral 
prescription drugs. 16 CFR 1700.14(a)(10). CPSC regulations allow 
companies to petition the Commission for an exemption from CR 
requirements. 16 CFR part 1702. Two ``reasonable grounds'' \1\ for 
granting an exemption from the special packaging requirements are: (1) 
That the degree or nature of the hazard to children in the availability 
of the substance, by reason of its packaging, is such that special 
packaging is not required to protect children from serious personal 
injury or serious illness resulting from handling, using or ingesting 
the substance; or (2) special packing is not technically feasible, 
practicable, or appropriate for the subject substance. 16 CFR 
1702.17(a) and (b).
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    \1\ A third reasonable ground for an exemption is that special 
packaging is incompatible with the particular substance. 16 CFR 
1702.17(c). The petitioner has not requested an exemption on this 
basis so it is not relevant here.
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    If the Commission determines that reasonable grounds for an 
exemption are presented by a petition, CPSC regulations require 
publication in the Federal Register of a proposed amendment to the 
listing of substances that require special packaging, stating that the 
substance at issue is exempt. 16 CFR 1702.17.

2. The Product for Which an Exemption Is Sought

    On March 30, 2020, Genentech, Inc. (Genentech), petitioned the 
Commission to exempt two specified sized tablets of baloxavir marboxil, 
which it markets as XOFLUZA from the special packaging requirements for 
oral prescription drugs. XOFLUZA was approved by the U.S. Food and Drug 
Administration (FDA) in October 2018, with a two-tablet dose for the 
acute uncomplicated flu in patients older than 12 years old showing 
symptoms for less than 48 hours. Single tablet doses have recently been 
approved by the FDA in March 2021. XOFLUZA has been marketed in tablet 
form and is currently dispensed in CR packaging. The petitioner 
asserted that an exemption from special packaging is justified because 
of the lack of toxicity and lack of adverse human experience with the 
drug. The petitioner also claimed that special packaging is not 
technically feasible, practicable, or appropriate for XOFLUZA. Staff's 
briefing memorandum provides a detailed assessment of the petitioner's 
claims regarding a request for an exemption from the special packing 
requirements for XOFLUZA. https://cpsc-d8-media-prod.s3.amazonaws.com/s3fs-public/Petition-to-Exempt-Baloxavir-Marboxil-XOFLUZA-in-40-mg-and-80-mg-Tablet-Doses-from-Special-Packaging-Requirements-of-the-PPPA-Cleared.pdf?VersionId=sLAhJ4THOBCtVMjgA4kxiFmI2.3LzqIj.

B. Toxicity and Injury Data for XOFLUZA

Toxicity

    CPSC staff reviewed the toxicity of XOFLUZA. XOFLUZA has been 
studied in pediatric patients (Hirotsu, 2019; Heo, 2018; NCT03653364, 
CAPSTONE 2; Hayden, 2018; Dziewiatkowski et al., 2019). Overall, 
clinically relevant doses of XOFLUZA (40 or 80 mg total dose) in humans 
are well tolerated (Dziewiatkowski et al., 2019; Taieb et al., 2019; 
Ng, 2019; Hayden, 2018).
    The analysis of total adverse events (AE) included 10 studies with 
six treatments and 5628 patients. AE did not differ significantly 
between placebo and XOFLUZA. For drug-related vomiting, 3297 patients 
from five studies were included. XOFLUZA did not differ from placebo in 
these studies. (Taieb et al., 2019). The percentage of patients 
experiencing any adverse event \2\ of 610 patients (12 to 64 years old) 
in the CAPSTONE 1 clinical trial was 1.0% grade 3 or grade 4, which can 
be categorized as not serious. Five deaths have been reported by the 
AER System; \3\ however, these deaths have been determined to not be 
related to XOFLUZA.
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    \2\ The adverse events are: Diarrhea, bronchitis, 
nasopharyngitis, nausea, sinusitis, increase in the level of AST, 
headache, vomiting, dizziness, leukopenia and constipation.
    \3\ The Adverse Event Reporting System (AERS) is a computerized 
information database designed to support the FDA's post-marketing 
safety surveillance program for all approved drug and therapeutic 
biologic products. The FDA uses AERS to monitor for new adverse 
events and medication errors that might occur with these marketed 
products.
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    The most common AE of the correct dose of XOFLUZA was diarrhea 
(Heo, 2018; Shionogi prescribing info). The XOFLUZA Product 
Information, 2021 reported that diarrhea (3%), bronchitis (3%), nausea 
(2%), headache (1%) were the most significant adverse events found.
    Treatment of an overdose of XOFLUZA should consist of general 
supportive measures, including monitoring of vital signs and 
observations of the clinical status of the patient. There is no 
specific antidote for overdose with XOFLUZA and it is unlikely to be 
significantly removed by dialysis because it is highly protein bound 
(Prescribing Information for XOFLUZA, 2021; Poisindex, 2021).
    Overall, treatment with XOFLUZA is well tolerated. If accidentally 
ingested, the greatest potential for injury is diarrhea, nausea, and 
headache. For these reasons, CPSC staff determined that XOFLUZA will 
not cause serious injury or death upon acute exposure by a child under 
5 years old.

Injury Data

    CPSC staff searched the Consumer Product Safety Risk Management 
System (CPSRMS), the National Electronic Injury Surveillance System 
(NEISS) databases, and reviewed reports from FDA related to adverse 
events associated with XOFLUZA. CPSC staff found no incidents related 
to XOFLUZA in CPSRMS or NEISS from January 2015 through December 2020. 
CPSC staff also reviewed 12 reports received from FDA related to 
adverse events associated with XOFLUZA. Of the 12 reports, five 
involved XOFLUZA use only. Of these five incidents, two reported 
adverse effects. One patient experienced hallucination, fever, and sore 
throat, and the other patient suffered cardiac failure. Both were 
unrelated to XOFLUZA. Six incidents involved use of multiple drugs and 
were considered out of scope, and one was a duplicate.

C. Action on the Petition

    After considering the information provided by the petitioner and 
other available toxicity and human experience data, the Commission 
concluded preliminarily that the ``lack of toxicity and lack of adverse 
human experience for the substance'' presented by the availability of 
40 mg and 80 mg tablets

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of baloxavir marboxil (currently marketed as XOFLUZA) is such that 
special packaging is not required to protect children from serious 
injury or serious illness from handling, using, or ingesting XOFLUZA. 
16 CFR 1702.17(a). Additionally, the Commission found that the 
petitioner's request for an exemption from special packaging, on the 
basis that it is not technically feasible, practicable, or appropriate 
for XOFLUZA, was not warranted based upon the information provided by 
the petitioner. Therefore, the Commission determined that reasonable 
grounds for an exemption were presented based on toxicity and voted to 
grant the petition and begin a rulemaking proceeding to exempt 
baloxavir marboxil tablets in packages containing not more than 80 mg 
of the drug from the special packaging requirements for oral 
prescription drugs.
    Once the Commission determines that reasonable grounds for an 
exemption are presented by the petition, CPSC regulations require 
publication in the Federal Register of a proposed amendment to the 
listing of substances that require special packaging, stating that the 
substance at issue is exempt. 16 CFR 1702.17. This document proposes to 
amend the listing of substances in 16 CFR part 1700 that require 
special packing to state that baloxavir marboxil tablets in packages 
containing not more than 80 mg of the drug do not require special 
packing.

D. Description of the Proposed Rule

    The proposed rule would amend 16 CFR part 1700 to include a new 
exemption from the special packaging requirements for baloxavir 
marboxil tablets in packages containing not more than 80 mg of the drug 
in proposed Sec.  1700.14(a)(10)(xxiv). The proposed exemption is 
intended to cover baloxavir marboxil tablets for any dosage from 80 mg 
or below. The proposed rule would make no other changes to part 1700.

E. Regulatory Flexibility Act

    Under the Regulatory Flexibility Act (RFA; 5 U.S.C. 601 et seq.), 
an agency that engages in rulemaking generally must prepare initial and 
final regulatory flexibility analyses describing the impact of the rule 
on small businesses and other small entities. Section 605 of the Act 
provides that an agency is not required to prepare a regulatory 
flexibility analysis if the head of an agency certifies that the rule 
will not have a significant economic impact on a substantial number of 
small entities.
    CPSC staff prepared a preliminary assessment of the impact of the 
proposed rule to exempt baloxavir marboxil in 40 mg and 80 mg tablet 
form, currently marketed as XOFLUZA, from special packaging 
requirements. Genentech, Inc., is a subsidiary of, and owned in its 
entirety by the multinational corporation, Roche Group, the company 
that markets XOFLUZA. Roche Group employs 97,735 workers worldwide, of 
which 26,176 are located in North America. As of February 2020, 
Genentech employed 13,638 people. Roche Group's operating businesses 
are organized into two divisions: Pharmaceuticals and Diagnostics. 
Genentech, as the former third segment, has been integrated into Roche 
Pharmaceuticals. Sales in the Pharmaceuticals Division were $48.1 
billion in 2019.
    There are two main economic reasons for why granting the petition 
would not result in the exemption having a significant economic impact 
on a substantial number of small entities. First, the exemption for 
this drug is not likely to impact a large number of firms, therefore it 
is unlikely that granting the petition would impact a substantial 
number of small entities. Second, CR packaging for XOFLUZA tablets is 
unlikely to be a significant amount of any firm's business, therefore 
granting the petition would not have a significant economic impact on 
any small entity. However, if the petitioner relocates packaging to 
another country, it could potentially result in some minor negative 
impacts for small domestic firms. Based on this assessment, we 
preliminarily conclude that the proposed amendment exempting baloxavir 
marboxil tablets in packages containing not more than 80 mg of the drug 
would not have a significant impact on a substantial number of small 
businesses or other small entities. We seek public comment on any small 
business impacts that might result from the exemption in the proposed 
rule.

F. Effective Date

    The Administrative Procedure Act (APA) generally requires that a 
substantive rule must be published not less than 30 days before its 
effective date. 5 U.S.C. 553(d)(1). The NPR proposes an effective date 
of 30 days after publication of the final rule in the Federal Register, 
because the proposed rule would provide an exemption from the 
requirement to use special packaging for baloxavir marboxil tablets in 
packages containing not more than 80 mg of the drug.

G. Environmental Considerations

    The Commission's regulations provide a categorical exclusion for 
the Commission's rules from any requirement to prepare an environmental 
assessment or an environmental impact statement where they ``have 
little or no potential for affecting the human environment.'' 16 CFR 
1021.5(c)(3). Rules exempting products from poison prevention packaging 
rules fall within the categorical exclusion, so no environmental 
assessment or environmental impact statement is required.

H. Preemption

    The PPPA provides that, generally, when a special packaging 
standard issued under the PPPA is in effect, ``no State or political 
subdivision thereof shall have any authority either to establish or 
continue in effect, with respect to such household substance, any 
standard for special packaging (and any exemption therefrom and 
requirement related thereto) which is not identical to the [PPPA] 
standard.'' 15 U.S.C. 1476(a). A state or local standard may be 
excepted from this preemptive effect if: (1) The state or local 
standard provides a higher degree of protection from the risk of injury 
or illness than the PPPA standard; and (2) the state or political 
subdivision applies to the Commission for an exemption from the PPPA's 
preemption clause and the Commission grants the exemption through a 
process specified at 16 CFR part 1061. 15 U.S.C. 1476(c)(1). In 
addition, the federal government, or a state or local government, may 
establish and continue in effect a nonidentical special packaging 
requirement that provides a higher degree of protection than the PPPA 
requirement for a household substance for the federal, state, or local 
government's own use. 15 U.S.C. 1476(b).
    Thus, with the exceptions noted above, the proposed rule exempting 
baloxavir marboxil tablets in packages containing not more than 80 mg 
of the drug from special packaging requirements, if finalized, would 
preempt nonidentical state or local special packaging standards for the 
substance.

List of Subjects in 16 CFR Part 1700

    Consumer protection, Drugs, Infants and children, Packaging and 
containers, Poison prevention, Toxic substances.

    For the reasons given above, the Commission proposes to amend 16 
CFR part 1700 as follows:

PART 1700--[AMENDED]

0
1. The authority citation for part 1700 continues to read as follows:


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    Authority:  15 U.S.C. 1471--76. Secs. 1700.1 and 1700.14 also 
issued under 15 U.S.C. 2079(a).

0
2. Section 1700.14 is amended by adding paragraph (a)(10)(xxiv) to read 
as follows:


Sec.  1700.14   Substances requiring special packaging.

    (a) * * *
    (10) * * *
    (xxiv) Baloxavir marboxil tablets in packages containing not more 
than 80 mg of the drug.
* * * * *

Alberta E. Mills,
Secretary, U.S. Consumer Product Safety Commission.
[FR Doc. 2021-19953 Filed 9-15-21; 8:45 am]
BILLING CODE 6355-01-P