[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
[[Page 51642]]
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]
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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).
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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