[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