Unresolved Clinical Safety Concerns: Unexplained Concentration Spikes and Potential Dose Dumping
Severity: criticalThe agency disagreed with the sponsor's root-cause analysis attributing concentration spikes to cocaine as a CYP2D6 inhibitor, stating that CYP2D6 inhibition cannot explain the 300-500% increase in concentration and that cocaine is not a strong CYP2D6 inhibitor. Safety issues with LY03004 remain, and the potential for dose dumping cannot be ruled out. Additional detailed PK data from all clinical trials (including ex-US studies) and adverse event summaries for subjects with spikes/dose-dumping events are required.
Recommended response: Provide detailed study reports including all PK data (mean and individual subject data) for all clinical trials conducted outside the United States (e.g., China, EU). Ensure comprehensive data presentation to unequivocally rule out dose dumping. Include summaries of adverse events, vital signs, and electrocardiogram data for any subject with concentration spikes or suspected dose-dumping events.
Biowaiver Request Denied Due to Unresolved Clinical Concerns
Severity: majorThe biowaiver request for additional strengths (12.5 mg, 37.5 mg, and 50 mg) cannot be granted at this time due to continued clinical concerns related to the results of the pivotal Bioequivalence (BE) study. Satisfactory resolution of the clinical and clinical pharmacology concerns is required to establish adequate BE between the proposed and Listed Drug products.
Recommended response: Address and resolve the underlying clinical and clinical pharmacology concerns to enable the establishment of adequate bioequivalence for the additional strengths.
Labeling Comments Reserved Pending Resolution of Core Deficiencies
Severity: minorComments on the proposed Prescribing Information, Carton, and Container Labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review labeling resources and guidance documents.
Recommended response: Review labeling review resources, regulations, and related guidance documents. Use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure conformity with format items. Update content of labeling per 21 CFR 314.50(l)(1)(i) when resubmitting.
Cited: 21 CFR 314.50(l)(1)(i)
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, Rykindo, was found acceptable pending approval of the application. Resubmission of the proposed proprietary name is required when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name along with the response to the application deficiencies.
Comprehensive Safety Update Required for Resubmission
Severity: majorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included when responding to the deficiencies. This update should cover significant changes/findings in the safety profile, new safety data from studies/trials, retabulations, case report forms for deaths/serious adverse events, updated exposure information, worldwide experience, and English translations of current approved foreign labeling.
Recommended response: Prepare and submit a comprehensive safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b), addressing all specified components including new data, retabulations, case reports, exposure, worldwide experience, and foreign labeling.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
