Shandong Luye Pharmaceutical Co., Ltd.: Rykindo

The January 28, 2020 complete response (CR) letter advised you to conduct a rootcause analysis that would adequately explain the origin of the concentration spikes observed in LY03004/CT-USA-102. We acknowledge that you have re- analyzed the pharmacokinetic (PK) samples of two patients (Subjects 9) and identified the presence of cocaine.

We acknowledge your conclusion that high concentrations of LY03004 were not caused by unanticipated drug release related to the drug product quality but were most likely caused by the extrinsic factor cocaine (which you believe acted as a CYP2D6 inhibitor).

However, we disagree that concomitant use of cocaine adequately explains the high concentrations of LY03004. Labels for risperidone products, which are supported by clinical data, clearly indicate that risperidone concentrations increase less than ~80% in the presence of strong CYP2D6 inhibitors.

To address this safety issue, you must provide us the following data in an NDA resubmission:

Drug, and Cosmetic Act for Rykindo (risperidone) for extended-release injectable suspension.

We also acknowledge receipt of your amendment dated November 22, 2019, which was not fully reviewed for this action.

Your NDA submission provides adequate pharmacokinetic bridging (via the bioequivalence at steady-state) to the listed drug, Risperdal CONSTA.

However, FDA has concluded that there are potential safety issues with the proposed drug product.

Those exposure levels would be significantly higher than the exposure range with the approved oral risperidone dose and could cause serious safety issues for patients.

The following product quality deficiencies will need to be adequately addressed before this application can be approved:

FDA's recommended range and is not acceptable.

The bridging between the proposed commercial drug product and the drug product used in the clinical-BE study has not been adequately established because of the following reasons:

212849 and your Information Request response sent on September 26, 2019 regarding loss of suspension of the microspheres in the syringe after reconstitution.

After resolving the Clinical, Clinical Pharmacology, and Product Quality deficiencies noted above, you must conduct a use-related risk analysis and determine whether a human factors validation study is necessary.

Applications' for the content of a human factors validation study protocol submission.

The requested information should be submitted to the IND. Place the requested information in eCTD Section 5.3.5.4 - Other Study reports and related information.