AbbVie Inc.Vyalev (foscarbidopa and foslevodopa) injection for subcutaneous use

NDA 216962 COMPLETE RESPONSE

AbbVie Inc.

Attention: Grace Chun, PharmD Associate Director, Regulatory Affairs 5 Giralda Farms

Madison, NJ 07940

Dear Dr. Chun:

Please refer to your new drug application (NDA) dated May 19, 2022, received May 19, 2022, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Vyalev (foscarbidopa and foslevodopa) injection for subcutaneous use.

We acknowledge receipt of your amendment dated December 19, 2023, which constituted a complete response to our March 17, 2023, 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.

FACILITY INSPECTIONS

Following a CGMP inspection of OO (FEI

®() listed in this application, FDA conveyed deficiencies to the representative of the facility. The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA 483 prior to your complete response. The facility's satisfactory responses are dependent on FDA’s determination that the facility has come into compliance with CGMP and may require re-inspection of the facility. The deficiencies identified during the inspection may not be specific to your pending application; therefore, you should coordinate with the facility for timely resolution. Your complete response should include the date(s) of the facility's response(s) to the FDA Form 483. Please refer to Compliance Program CP 7356.002 for guidance on post inspection activities. Following resolution of the CGMP inspection, FDA may need to conduct a pre-approval inspection (PAI) of the facility. Satisfactory outcomes of both the PAI and the CGMP surveillance inspections will be needed prior to an approval of the application.

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PRESCRIBING INFORMATION

Submit draft labeling that is responsive to our electronic communication dated June 17, 2024, when you respond to the application deficiencies.

Prior to resubmitting the labeling, use the Selected Requirements of Prescribing Information (SRPI) checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition, 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 (PI) 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.

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

2 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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NDA 216962 Page 3

CARTON AND CONTAINER LABELING

Submit draft carton and container labeling revised, based on our recommendations noted below under Additional Comments, when you respond to the application deficiencies.

PROPRIETARY NAME

Please refer to correspondence dated, May 14, 2024, which addresses the proposed proprietary name, Vyalev. 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 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.

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

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(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.

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

ADDITIONAL COMMENTS We have additional comments/recommendations that are not approvability issues.

We recommend the following be implemented for the carton labeling, container labels, and the Instructions for Use for Vyalev:

Identified Issue

Rationale for Concern

Recommendation

Carton labeling

Based on our review of your response submitted on May 20, 2024, it appears that the front opening panel is the principal display panel (PDP).

However, we note the Medication Guide (MG) statement is located on the

© instead of on the PDP.

Per 21 CFR 208.24(d), the label of each container or package, where the container label is too small, of drug product for which a MG is required under this part shall instruct the authorized dispenser to provide a MG to each patient to whom the drug product is dispensed, and shall state how the MG is provided. These statements shall appear on the label ina prominent and conspicuous manner.

Ensure the MG statement appears in accordance with 21 CFR 208.24(d). To ensure its prominence, we recommend relocating the MG statement to the PDP.

Container label

The container label does not include the container closure term (i.e., vial).

Omission of the container closure term after the package type term may lead to confusion.

Revise the statement “10 mL single-dose” to now read “10 mL single-dose vial”.

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

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Identified Issue

Rationale for Concern

Recommendation

Patient Instructions for Use

(IFU) and Healthcare provi

ider (HCP) IFU

You revised the patient IFU and HCP IFU to include the following statements to indicate patients should carry an alternative treatment option.

Patient IFU: |

HCP IFU: a

OTHER

We acknowledge immediate release carbidopa-levodopa tablets are a reasonable alternative treatment option if Vyalev infusion is unavailable. However, there are additional alternative treatment options that can be considered (e.g., COMT inhibitors, etc.) if patients are unable to receive Vyalev infusion.

Revise the patient IFU

statement |

(b) (4)

to now read “Talk with your healthcare provider about what to do in case you are unable to use VYALEV infusion. Keep a supply of backup oral Parkinson’s Disease medicines with you at all times”.

Revise the HCP IFU statement |

to now read “Instruct the patient to keep a supply of backup oral Parkinson’s Disease medicines with them at all times in case they are unable to use VYALEV infusion”.

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

U.S. Food and Drug Administration

Silver Spring, MD 20993 www.fda.gov

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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.

If you have any questions, please contact Stacy Metz, PharmD, Senior Regulatory Project Manager, at stacy. metz@fda.hhs.gov.

Sincerely, {See appended electronic signature page}

Emily Freilich, MD

Director

Division of Neurology 1

Office of Neuroscience

Center for Drug Evaluation and Research

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

Reference ID: 5400209

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.

LAURA A JAWIDZIK on behalf of EMILY R FREILICH 06/18/2024 03:28:48 PM

Reference ID: 5400209