Laboratorios Farmaceuticos Rovi, S.A.Risvan (risperidone ISM) intramuscular injectable suspension

NDA 214835 COMPLETE RESPONSE

Laboratorios Farmaceuticos Rovi, S.A.

c/o PharmaLex

Attention: Nick Palmer

Senior Manager, Consulting and Scientific Affairs 1700 District Avenue, Suite 100

Burlington, MA 01803

Dear Mr. Palmer:

Please refer to your new drug application (NDA) dated and received November 24, 2020, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Risvan (risperidone ISM) intramuscular injectable suspension.

We acknowledge receipt of your amendment dated January 18, 2022, which constituted a complete response to our September 24, 2021, action letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

PRODUCT QUALITY

a Your application referenced the Drug Master File (DMF) This DMF was found inadequate to support your submission and a deficiency letter was sent to the DMF holder on July 15, 2022. These deficiencies must be adequately addressed before this application can be approved. As part of your response to this letter, include the date the DMF holder amended their DMF to address the deficiencies.

FACILITY INSPECTIONS

(b) (4) During a recent inspection of the manufacturing facility for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

During a recent inspection of the Laboratorios Farmacéuticos ROVI, S.A. (FEI: 3010705046) manufacturing facility for this application, our field investigator conveyed

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deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved. MICROBIOLOGY

Sterile Drug Substance Risperidone

The referenced DMF for sterile drug substance risperidone has been reviewed and determined to be inadequate. The DMF holder has been notified.

Solvent DMSO We acknowledge the new validation study plan provided on paaes 56-57 of 76 (1 wah 4,4 Multiple Information Amendment, Seq-0038) regarding the

© ou indicate that the new validation study runs will be performed March 1 to May 31, 2022. Provide the a] validation study summary and data demonstrating a minimum of fglog of endotoxin reduction.

Sterile excipient PLGA We acknowledge the responses provided on pages 57-68 of 76,(4.11.4 Multiple

Information Amendment, Seq-0038) regarding the validation of the excipient PLGA. Address the following issues:

a. You indicate that the | based validation studies (verification cycles of sterilizing capacity) were performed using “ Note that the microbiological efficacy studies should be performed using a dose of < the minimum, ose specified for the production sterilization process. If you decide to choose the based validation strategy, provide three validation studies and data using a dose of < the minimum specified production dose demonstrating a minimum sterility assurance level of | Requalification should be also performed using a dose of < the minimum specified production dose. Alternatively, provide data for validation studies using the © approach with @ dose audits per

b. Page 61 of 76 indicates” growth in the first “revalidation” batch performed in 2015 with the treatment No. 15T02296T. Additionally, the maximum dose for the first batch of 2020 “revalidation” with the treatment No. 20T01769T, ™® exceeds the maximum dose of ©® Provide a summary of investigations, the root cause identified, potential impact on routine production, and corrective and preventative actions.

c. Page 66 of 76 indicates that the |

wey

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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NDA 214835 Page 3

(©) (4)

d. Pages 67-68 of 76 provide requalification data from the 0O3SEP2019 run (study code:

UDMI-PVP-18-018/00). However, exposed” provided and should be described. Specify the posi

HUMAN FACTORS

We acknowledge your response to our complete respo

2021, and your response to our in submissions addressed some of o

Ss after incubation are not ive control result.

resul

nse letter dated September 24, ‘ormation request dated September 10, 2021. These ur Human Factors concerns; however, our review of

the instructions for use identified an area of vulnerability that may lead to medication errors. We note that two participants in your HF validation study had difficulty injecting

the full dose due to the viscosity o!

the medication. Additionally, we note that your root

cause analysis states that the proposed product requires the user to maintain the force

for a longer time to inject the medi

Furthermore, in your response dat “THICK MEDICATION. MAKE SU

longer than usual due to the viscosity of the medication,”

the user to inject the medication s

ication.

‘ed September 10, 2021, although your IFU states: RE TO FULLY INJECT,” and “The injection time is it does not explicitly instruct lowly and steadily. Revise the IFU to include

instructions for users to inject the medication slowly and steadily. PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources! and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.3

https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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NDA 214835 Page 4

CARTON AND CONTAINER LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate.

MEDICATION GUIDE

Add the following bolded statement or appropriate alternative to the carton and

container labeling per 21 CFR 208.24(d): “|

(0) 4)

PROPRIETARY NAME

Please refer to correspondence dated, April 12, 2022, which addresses the proposed proprietary name, Risvan. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the product under consideration regardless of indication, dosage form, or dose level.

(1) Describe in detail any significant changes or findings in the safety profile. (2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data

as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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NDA 214835 Page 5

(3) Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

(4) Provide case report forms and narrative summaries for each subject who died during a Clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

(5) Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

(6) Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

(7) Provide a summary of worldwide experience on the safety of this product. Include an updated estimate of use for product marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider

his resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to ‘ake before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The drug product may not be legally marketed until you have been notified in writing hat this application is approved.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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If you have any questions, contact Eugene Lee, Regulatory Project Manager, at C.Eugene.Lee@fda.hhs.gov.

Sincerely, {See appended electronic signature page}

Tiffany R. Farchione, MD

Director

Division of Psychiatry

Office of Neuroscience

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

TIFFANY R FARCHIONE 07/15/2022 05:47:51 PM

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