[Federal Register Volume 89, Number 77 (Friday, April 19, 2024)]
[Rules and Regulations]
[Pages 28604-28606]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-07651]
[[Page 28604]]
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CONSUMER PRODUCT SAFETY COMMISSION
16 CFR Part 1700
[Docket No. CPSC-2021-0027]
Poison Prevention Packaging Requirements; Exemption of Baloxavir
Marboxil Tablets in Packages Containing Not More Than 80 mg of the Drug
AGENCY: Consumer Product Safety Commission.
ACTION: Final rule.
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SUMMARY: The Consumer Product Safety Commission (Commission or CPSC) is
amending the child-resistant packaging requirements of CPSC's
regulation to exempt baloxavir marboxil tablets, currently marketed as
XOFLUZATM, in packages containing not more than 80 mg of the
drug, from the special packaging requirements. XOFLUZA is used to treat
the flu, and the drug is taken in one dose within 48 hours of
experiencing flu symptoms. The final rule exempts 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: The rule is effective May 20, 2024.
FOR FURTHER INFORMATION CONTACT: Will Cusey, Small Business Ombudsman,
U.S. Consumer Product Safety Commission, 4330 East West Highway,
Bethesda, MD 20814; telephone (301) 504-7945 or (888) 531-9070; email:
[email protected].
SUPPLEMENTARY INFORMATION:
A. Background
1. The Poison Prevention Packaging Act of 1970 and CPSC's 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 required to protect children from
serious personal injury or serious illness resulting from handling,
using, or ingesting 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 of the three ``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\ The 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 a petition presents reasonable
grounds for an exemption, 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
would be 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. The U.S. Food and Drug Administration
(FDA) approved XOFLUZA in October 2018, with a two-tablet dose for
acute uncomplicated flu in patients older than 12 years old showing
symptoms for less than 48 hours. FDA approved single tablet doses 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.
Genentech represents that it intends to continue U.S. production
and packaging of XOFLUZA if the petition is granted. The firm also
states that grant of the petition would allow it to use a packaging
site in Kaiseraugst, Switzerland, as a back-up facility for the U.S.
market in the event there is a spike in demand for XOFLUZA over a short
period of time.
In September 2021, after considering the information provided by
the petitioner up to that date and other available toxicity and human
experience data, the Commission preliminarily concluded in the preamble
of the Notice of Proposed Rulemaking (NPR) 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 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. 86 FR 51640, at 54641-42
(September 16, 2021); 16 CFR 1702.17(a). However, the Commission
preliminarily 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 on the
information provided by the petitioner. Based on the lack of toxicity,
the Commission determined that reasonable grounds for an exemption were
presented 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.
B. Toxicity and Injury Data for XOFLUZA
1. Summary of Data From Proposed Rule
Toxicity
Staff reviewed the toxicity of XOFLUZA. XOFLUZA has been studied in
pediatric patients.\2\ Overall, clinically relevant doses of XOFLUZA
(40 or 80 mg total dose) in humans are well tolerated.\3\
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\2\ Hirotsu N. (2019). Baloxavir Marboxil in Japanese Pediatric
Patients with Influenza: Safety and Clinical and Virologic Outcomes.
Clin Infect Dis Aug 14;71(4):971-981.; Heo Y-A. (2018). Baloxavir:
First Global Approval. Drugs 78:693 697.;https://clinicaltrials.gov/ct2/show/NCT03653364; XOFLUZA Prescribing Information, 2021; Hayden
F.G. (2018). Baloxavir Marboxil for Uncomplicated Influenza in
Adults and Adolescents. The New England Journal of
Medicine.379:(10); Dziewiatkowski N.A., Osmon E.N., Chahine E.B.,
Thornby K.A. (2019). Baloxavir: a novel single-dose oral antiviral
for the treatment of influenza. Sr Care. Pharm; 34:243-52.
\3\ Dziewiatkowski N.A., Osmon E.N., Chahine E.B., Thornby K.A.
(2019). Baloxavir: a novel single-dose oral antiviral for the
treatment of influenza. Sr Care. Pharm; 34:243-52.; Taieb V.,
Ikeoka, Fang-Fang Ma H., Borkowski K., Aballea S., Tone Keiko and
Hirotsu N. (2019). A network meta-analysis of the efficacy and
safety of baloxavir marboxil versus neuraminidase inhibitors for the
treatment of influenza in otherwise healthy patients; Current
Medical Research and Opinion 35:8, 1355-1364.; Hayden F.G. (2018).;
Baloxavir Marboxil for Uncomplicated Influenza in Adults and
Adolescents. The New England Journal of Medicine.379:(10).
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[[Page 28605]]
The analysis of total adverse events (AE) included 10 studies \4\
with six treatments and 5,628 patients. AE did not differ significantly
between placebo and XOFLUZA. For drug-related vomiting, 3,297 patients
from five studies were included. XOFLUZA did not differ from placebo in
these studies. The percentage of patients experiencing any AE 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. The
adverse events experienced were diarrhea, bronchitis, nasopharyngitis,
nausea, sinusitis, increase in the level of aspartate aminotransferase
(AST, headache, vomiting, dizziness, leukopenia, and constipation. Five
deaths have been reported by the Adverse Event Reporting System (AERS);
\5\ however, staff assessed that these deaths were not caused by
XOFLUZA.
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\4\ Taieb V., Ikeoka, Fang-Fang Ma H., Borkowski K., Aballea S.,
Tone Keiko and Hirotsu N. (2019). A network meta-analysis of the
efficacy and safety of baloxavir marboxil versus neuraminidase
inhibitors for the treatment of influenza in otherwise healthy
patients. Current Medical Research and Opinion 35:8, 1355-1364.
\5\ 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 is diarrhea.\6\
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.\7\ 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.\8\ Two overdoses of XOFLUZA were reported in children under 5
years old in the FAERS data. Neither overdose resulted in serious
injury or death; one of the children experienced malaise and the other
child experienced a rash.
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\6\ Heo Y-A. (2018). Baloxavir: First Global Approval. Drugs
78:693-697.; Shionogi & Co. Ltd. Xofluza (baloxavir marboxil)
tablets 10 mg/20mg approved for the treatment of influenza types A
and B in Japanese [media release] 23 Feb 2018.
\7\ (PoisIndex, 2021).
\8\ Prescribing Information for XOFLUZA, 2021; Micromedex
Solutions, Poisindex Xofluza search 2/1/2021.
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Overall, treatment with XOFLUZA is well tolerated. In drug trials,
XOFLUZA was well-tolerated as a treatment for flu in otherwise healthy
children age 1 to less than 12 years old. Additionally, two Phase 3
pediatric studies in Japan demonstrate that XOFLUZA is well tolerated
across all pediatric age groups. Finally, the FDA concluded there are
no safety concerns for children from Phase I, Phase 2, and Phase 3
trials of XOFLUZA. If accidentally ingested, the most likely symptoms
are diarrhea, nausea, or headache. For these reasons, staff determined
that XOFLUZA will not cause serious injury or death upon acute exposure
by a child under 5 years old.
Injury Data
The NPR explained that CPSC staff had searched the Consumer Product
Safety Risk Management System (CPSRMS) and the National Electronic
Injury Surveillance System (NEISS) databases, and reviewed reports from
FDA related to adverse events associated with XOFLUZA. Staff found no
incidents related to XOFLUZA in CPSRMS or NEISS from January 2015
through December 2020.
2. Updated Injury Data Since NPR
Since publication of the NPR staff has done an updated search and
found no incidents related to XOFLUZA in the CPSRMS and NEISS databases
from January 2021 through March 2024. CPSC staff also reviewed 26
reports received from FDA related to AEs associated with XOFLUZA
between January of 2018 through March 2024. Of these 26 reports, there
were 8 nonserious reports, such as off-label use of XOFLUZA. There were
also 18 reported AEs. All of these AEs, such as febrile seizures,
delirious behaviors, and gastrointestinal bleeding, were assessed by
staff to be due to the flu disease progression and not due to XOFLUZA.
The staff briefing package on this final rule provides more detailed
information.\9\
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\9\ The staff briefing package is available here: https://www.cpsc.gov/s3fs-public/Briefing-Package-Final-Rule-to-Exempt-Xofluza-from-Special-Packaging-Requirements-in-the-PPPA.pdf?VersionId=rr6qgyEz7Tjc_1AHXq6OndQHRzIaCFgX.
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C. Response to Comments on the Proposed Rule
Two comments were submitted in response to the publication of the
NPR. One comment stated that XOFLUZA should not be exempt from child-
resistant packaging because there is little-to-no existing human
toxicity data for age groups 0-12 years old, and asserted there is a
risk of allergic reactions (including anaphylaxis, angioedema,
urticaria, and erythema multiforme). In response to this comment, CPSC
staff advises that a drug trial demonstrated that XOFLUZA is a well-
tolerated potential treatment for the flu in otherwise healthy children
within the age range of 1 year and over to 12 years and under.
Additionally, two Phase 3 pediatric studies conducted in Japan
demonstrate that XOFLUZA is well tolerated across all pediatric age
groups. Finally, the FDA concluded there are no safety findings of
concern for children from Phase 1, Phase 2, or Phase 3 trials of
XOFLUZA. Indeed, as compared to adults, drugs are less common triggers
of anaphylaxis in children, with a frequency which is increasing from
infancy to adolescence.\10\ Of the 26 adverse reactions in the FDA
FAERS data, there were no hypersensitivity reactions in children under
5 years of age.\11\
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\10\ Cardinale F, Amato D, Mastrototaro MF, Caffarelli C.,
Crisafulli D., Franceshini F., Liotti L., Bottau P., Saretta F.,
Mori F. and Bernardini R. Drug-induced anaphylaxis in children. Acta
Biomed. 2019 90 (3-S): 30-35.; Atanaskovic-Markovic M, Gomes E,
Cernadas JR, du Toit G, Kidon M, Kuyucu S, Mori F, Ponvert C,
Terreehorst I, Caubet JC. Diagnosis and management of drug-induced
anaphylaxis in children: An EAACI position paper. Pediatric Allergy
Immunol. 2019 May;30(3):269-276.). In the pediatric population the
average age of diagnosis for drug-induced hypersensitivity was 8.7
years old. The most common causative drugs included antiepileptics
(50%) and antibiotics (30.8%) (Metterle L, Hatch L, Seminario-Vidal
L. Pediatric drug reaction with eosinophilia and systemic symptoms:
A systemic review of the literature, with a focus on relapsing
cases. Pediatric Dermatol. 2020 Jan;37(1):124-129. doi: 10.1111/
pde.14044. Epub 2019 Nov 5., Oberlin KE, Rahnama-Moghadam S, Alomari
AK, Haggstrom AN. Drug reaction with eosinophilia and systemic
symptoms: Pediatric case series and literature review. Pediatric
Dermatol. 2019 Nov;36(6):887-892.). Pediatric drug reaction with
eosinophiliea and systemic symptoms is an uncommon disease with a
mean age of 11.5 years of age presenting with the syndrome (Oberlin
KE, Rahnama-Moghadam S, Alomari AK, Haggstrom AN. Drug reaction with
eosinophilia and systemic symptoms: Pediatric case series and
literature review. Pediatric Dermatol. 2019 Nov;36(6):887-892.).
\11\ https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.
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The second comment stated that people should use zinc instead of
XOFLUZA for treatment of the flu. The use of other substances to treat
the flu is not relevant to whether baloxavir marboxil should be given
an exemption from the special packing requirements and, therefore, is
outside the scope of this rulemaking.
D. Description of the Final Rule
The final rule amends 16 CFR part 1700 to include a new exemption
from the special packaging requirements for baloxavir marboxil tablets
in packages
[[Page 28606]]
containing not more than 80 mg of the drug in proposed
1700.14(a)(10)(xxiv).\12\ The exemption is intended to cover baloxavir
marboxil tablets in a dosage of 80 mg or less. The text of the final
rule is unchanged from the proposed rule. The final rule makes no other
changes to part 1700.
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\12\ The Commission voted 4-1 to publish this final rule. The
Record of Commission Action can be viewed here: https://www.cpsc.gov/s3fs-public/RCA-Draft-Final-Rule-to-Exempt-Baloxavir-Marboxil-XOFLUZA-from-Packaging-Requirements-in-PPPA.pdf?VersionId=TR31D0KETbniRXpLZHUqI_9R28VqffJo.
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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(b) of the Act
provides that an agency is not required to prepare an RFA if the head
of an agency certifies that the rule will not have a significant
economic impact on a substantial number of small entities.
As noted in the preamble to the proposed rule (86 FR 51640 at
51642), the Commission's Directorate for Economic Analysis prepared a
preliminary assessment of the impact of the proposed rule. Based on
this assessment, the Commission preliminarily concluded that the
proposed rule would not have a significant impact on a substantial
number of small businesses or other small entities. We received no
comments on this assessment or any additional information. Therefore,
we certify that the rule will not have a significant economic impact on
a substantial number of small entities. 5 U.S.C. 605(b).
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 proposed an effective date
of 30 days after publication of the final rule in the Federal Register.
We received no comments on the proposed effective date. Therefore, the
effective date for the final rule will be May 20, 2024.
G. Environmental Considerations
The Commission's regulations provide a categorical exclusion from
any requirement to prepare an environmental assessment or an
environmental impact statement the Commission rules ``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 significantly 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 that government's own use. 15
U.S.C. 1476(b).
Thus, with the exceptions noted above, the final rule exempting
baloxavir marboxil tablets in packages containing not more than 80 mg
of the drug from special packaging requirements preempts 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 amends 16 CFR part 1700
as follows:
PART 1700--[AMENDED]
0
1. The authority citation for part 1700 continues to read as follows:
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. 2024-07651 Filed 4-18-24; 8:45 am]
BILLING CODE 6355-01-P