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Federal Register / Vol. 86, No. 177 / Thursday, September 16, 2021 / Proposed Rules Pharmacology and Physiology Assessment, Directorate for Health Sciences, Consumer Product Safety Commission, 5 Research Place, Rockville, MD 20850; telephone 301
9872572; cscorpio@cpsc.gov.
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. 14711476, 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. 1472a. 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
1700.14a10. 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 1702.17a and b.
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 1A

third reasonable ground for an exemption is that special packaging is incompatible with the particular substance. 16 CFR 1702.17c. The petitioner has not requested an exemption on this basis so it is not relevant here.

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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. Staffs briefing memorandum provides a detailed assessment of the petitioners claims regarding a request for an exemption from the special packing requirements for XOFLUZA. https
cpsc-d8-mediaprod.s3.amazonaws.com/s3fs-public/
Petition-to-Exempt-Baloxavir-MarboxilXOFLUZA-in-40-mg-and-80-mg-TabletDoses-from-Special-PackagingRequirements-of-the-PPPA-Cleared.pdf?
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jgA4kxiFmI2.3LzqIj.
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 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
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been determined to not be related to XOFLUZA.
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 support the FDAs 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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