AOP Orphan Pharmaceuticals GmbHlandiolol injection

NDA 217202 COMPLETE RESPONSE

AOP Orphan Pharmaceuticals GmbH

c/o Strategic Drug Development Services, LLC Attention: Scott A. Oglesby, PhD

US Agent

6518 Green Rise Road

Hillsborough, NC 27278

Dear Dr. Oglesby:

Please refer to your new drug application (NDA) dated May 31, 2022, received May 31, 2022, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for landiolol injection.

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

Drug Product

Reference ID: 5182372

NDA 217202 Page 2

Manufacturing

PRESCRIBING INFORMATION

We acknowledge the draft labeling you submitted on March 15, 2023. We reserve further comment on your labeling until your application is otherwise acceptable.

Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition,

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

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submit updated content of labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.'

To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Word version. The marked-up copy should include annotations that support any proposed changes.

Your proposed Prescribing Information (Pl) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57. As you develop your proposed PI, we encourage you to review the labeling review resources on the Prescription Drug Labeling Resources? and Pregnancy and Lactation Labeling Final Rule? websites, which include:

e The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products

e The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of information in the PI on pregnancy, lactation, and females and males of reproductive potential

e Regulations and related guidance documents

e Asample tool illustrating the format for Highlights and Contents, and

e The Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

e FDA's established pharmacologic class (EPC) text phrases for inclusion in the Highlights Indications and Usage heading.

e Additional resources for the PI, patient labeling, and carton/container labeling.

CARTON AND CONTAINER LABELING

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

PROPRIETARY NAME

Refer to our correspondence dated February 23, 2023, stating that your proposed proprietary name, ®©® is unacceptable. Submit a new proposed proprietary name

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

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

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

U.S. Food and Drug Administration

Silver Spring, MD 20993

www.fda.gov

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when you respond to the application deficiencies if you wish to have a proprietary name for your product.

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 drug 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.

(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 drug. Include an updated estimate of use for drug marketed in other countries.

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

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

POSTMARKETING REQUIREMENTS UNDER 505(0)(3)

Section 505(0)(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute.

Our finding is that you have not investigated the inhibitory effect of landiolol and its metabolite M1 on the activity of multiple drug transporters. Inhibition of these drug ransporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation ransporter (OCT)2, multidrug and toxin extrusion (MATE) proteins (MATE1, MATE2-k), organic anion transporter (OAT)1, and OAT3, by landiolol and/or its M1 metabolite may have an impact on the systemic exposure of concomitantly administered drugs that are sensitive substrates of these transporters.

Based on the above, FDA has determined that if NDA 217202 is approved, an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of he FDCA will not be sufficient to assess a signal of a serious risk of these potential drug interactions.

Furthermore, the active postmarket risk identification and analysis system as available under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.

Therefore, based on appropriate scientific data, FDA has determined that, if NDA 217202 is approved, you will be required to:

Conduct an in vitro assessment to evaluate the potential of landiolol and its M1 metabolite to inhibit drug transporters including P-gp, BCRP, OATP1B1, OATP1B3, OCT2, MATE1, MATE2-K, OAT1, and OAT3.

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 this resubmission a complete response to the deficiencies outlined in this letter. A partial

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

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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 take 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 that this application is approved.

If you have any questions, please call Maryam Changi, Regulatory Project Manager, at (240) 402-2725.

Sincerely,

{See appended electronic signature page}

Hylton V. Joffe, MD, MMSc

Director

Office of Cardiology, Hematology, Endocrinology, and Nephrology

Office of New Drugs

Center for Drug Evaluation and Research

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

Reference ID: 5182372

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.

HYLTON V JOFFE 05/31/2023 02:11:25 PM

Reference ID: 5182372