Insufficient Scientific Bridge and Inadequate Long-Term Safety Data for Carbidopa Component
Severity: criticalBased on relative bioavailability studies, an adequate scientific bridge for carbidopa pharmacokinetic (PK) exposure between Crexont and Sinemet or Rytary was not established at the highest proposed dosage. Carbidopa exposure from Crexont is substantially higher, preventing reliance on FDA's safety findings for Sinemet or cross-referencing Rytary. The long-term safety database is insufficient to characterize Crexont's safety, specifically lacking data from 100 patients with 12-month continuous exposure, with a substantial proportion at the highest dose based on modal dose, as previously discussed in pre-NDA meetings.
Recommended response: Provide long-term safety data from 100 patients with continuous exposure to Crexont for at least 12 months, with a substantial proportion using the highest dose intended for labeling, based on modal dose. Alternatively, consider reformulating the product to reduce carbidopa exposure to levels comparable to a listed drug, which may still require additional clinical studies.
Requirement for Thorough QT Study
Severity: majorDue to the inability to rely on Sinemet or cross-reference Rytary for the safety of carbidopa in Crexont, a thorough QT study is required to assess potential effects of Crexont on QTc, as per ICH E14 section 1.3.
Recommended response: Conduct a thorough QT study to assess potential effects of Crexont on QTc.
Cited: ICH E14 section 1.3
Prescribing Information and Labeling 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 FDA's Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, including regulations, guidance documents, and the Selected Requirements for Prescribing Information (SRPI) checklist.
Recommended response: Review FDA labeling resources and guidance documents. Address labeling once other critical deficiencies are resolved and the application is otherwise adequate.
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, Crexont, was found acceptable pending approval of the application in the current review cycle. The sponsor must resubmit the proposed proprietary name when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name, Crexont, concurrently with the response to other application deficiencies.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required when responding to deficiencies, as described at 21 CFR 314.50(d)(5)(vi)(b). This includes detailing significant changes in the safety profile, presenting new safety data from studies/clinical trials (for proposed and other indications), tabulating combined new and original data, comparing frequencies of adverse events, providing case report forms and narrative summaries for deaths/SAEs, describing changes in common adverse events, updating exposure information, summarizing worldwide safety experience, and providing English translations of current approved foreign labeling.
Recommended response: Provide a detailed safety update including all specified elements: significant changes, new data tabulations, comparisons, case report forms for deaths/SAEs, updated exposure, worldwide experience, and translated foreign labeling, as per 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
