InnoPharma Licensing LLCAcetaminophen Injection, 10 mg/mL

NDA 206968 COMPLETE RESPONSE

InnoPharma Licensing LLC 275 North Field Dr

Bldg H1-3S

Lake Forest, IL 60045

Attention: Arman Nolledo Manager, Regulatory Affairs

Dear Mr Nolledo:

Please refer to your new drug application (NDA) dated and received May 13, 2014, and your amendments pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Acetaminophen Injection, 10 mg/mL.

We acknowledge receipt of your amendment dated June 30, 2020, which constituted a complete response to our November 9, 2018, action letter.

We also acknowledge receipt of your amendments dated December 7, and 16, 2020, which were not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this 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.

NONCLINICAL

1. You have not provided adequate validated leachable data to permit a substantive toxicological risk assessment for the proposed container closure system.

Information needed to resolve deficiency

Submit a revised toxicological risk assessment based on validated leachable data that characterizes the trends in leachables over the course of the proposed shelf-life. Include later timepoints in your proposed shelf-life to fully inform the trends in leachables, particularly given the observations of novel adducts forming in the drug product solution. The risk assessment should be based on the projected highest level of any leachable over stability. Submit a risk assessment for any compound present over 5 mcg/day taking into consideration the maximum daily dose of your drug product.

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2. You have not provided an adequate toxicological risk assessment for the

acetaminophen adducts detected as leachables in the drug product. Although your risk assessment is based on in silico and read-across evaluations of the

larger fragments of the molecule, there are no data to suggest that this read-

across reliably predicts the toxicological potential of the adduct as a whole.

Information needed to resolve deficiency To address this deficiency, either conduct an intravenous toxicology study with the four adducts or provide data to support the conclusion that these adducts are not stable and rapidly convert back to acetaminophen and the presumed

©® degradants from which they are formed.

PRODUCT QUALITY

3. Your PDE-based approach to selecting targeted leachables is concerning

because not all leachables above the 5 mcg/day threshold may be observed.

Information needed to resolve deficiency

In order to obtain a complete leachables profile for your leachables studies, demonstrate that your validated leachables methods can detect all the extractables above the Analytical Evaluation Threshold (AET) based on an SCT of {mcg /day with LODs/LOQs with acceptable S/N.

Per your response dated October 23, 2020, your validated method will adopt an AET of [i mcg /L based on an SCT of |f}mcg/day and a Maximum daily volume (MDV) of ® L/day without considering a 50% uncertainty factor.

Information needed to resolve deficiency Include a 50% uncertainty factor to the final AET to accommodate variations in response of the compounds with different response factors.

In your response dated November 20, 2020, we note that the newly submitted 9- month leachable data were analyzed by the original semi-quantitative methods.

Information needed to resolve deficiency Reanalyze the 9-month and subsequent stability time points, using the fully validated methods that you are developing.

The non-volatile leachables at the 9-month point are significantly different from those of the 3-month. Some of 3-month leachables disappeared and some new ones appeared in the 9-month time point.

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

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Information needed to resolve deficiency

This can be indicative of either an issue with the analytical method used or the appearance of secondary leachables. Provide a full leachable profile with data collected on a fresh batch of drug product, at 0, 3, 6, 9, and 12-month time points using well-validated methods.

Module P.8.3. states that 6 month accelerated studies under 40° + 2°C/ NMT 25% RH were provided for 2019 batch stability samples 1907059, 1907060, and 1907061. However, we cannot locate this information.

Information needed to resolve deficiency Provide the complete data for at least three batches of drug product stored under accelerated conditions.

Table 2 in the Photostability study report ARL/STDR/0066/19 was not included in the report.

Information needed to resolve the deficiency Provide this information in your resubmission.

PRESCRIBING INFORMATION

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

adequate. We encourage you to review the labeling review resources on the PLR requirements for Prescribing Information’ 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.?

CARTON AND CONTAINER LABELING

10. Submit draft carton and container labeling revised as follows:

’ http:/Awww.fda.gov/Drugs/GuidanceComplianceRequlatoryInformation/LawsActsandRules/ucm08415

9.htm

2 http://www. fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330

7.htm

3 http://www.fda.gow/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

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

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NDA 206968

Page 4 IDENTIFIED ISSUE RATIONALE FOR CONCERN | RECOMMENDATION General Issue 1. | The strength (i.e., 1,000 | Numbers greater than 1,000 | Present numbers greater than or mg) is presented as when presented without a equal to 1,000 with a comma. “1000 mg” (i.e., without | comma may be acomma). misinterpreted as hundreds “100".4 Container Label 1. | The location and format | Clearly defining the Designate an area for inclusion of of the expiration date expiration date will he expiration date and lot number and lot number is not minimize confusion and risk | on the container label. Expiration specified. for deteriorated drug date is required on all container medication errors. Lack of jabels per 21 CFR 201.17, include lot number may result in he expiration date on the label dispensing errors. and ensure it is clearly

differentiated from other numbers on the label. Additionally, identify he expiration date format you intend to use. FDA recommends hat the human-readable expiration date on the drug package label include a year, month, and non-zero day. FDA recommends that the expiration date appear in YYYY-MM-DD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month. If there are space limitations on the drug package, the human-readable text may include only a year and month, to be expressed as: YYYY- MM if only numerical characters

4 ISMP’s List of Error-Prone Abbreviations, Symbols, and Dose Designations [Internet]. Horsham (PA): Institute for Safe Medication Practices. 2015 [cited 2018 NOV 29]. Available from: http://www.ismp.org/tools/errorproneabbreviations.pdf.

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

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IDENTIFIED ISSUE

RATIONALE FOR CONCERN

RECOMMENDATION

are used or YYYY-MMM if alphabetical characters are used to represent the month. FDA recommends that a hyphen or a space be used to separate the portions of the expiration date.

Overwrap Labeling

1| The format of the expiration date is not specified.

Clearly defining the expiration date will minimize confusion and risk for deteriorated drug medication errors.

Identify the expiration date format you intend to use. FDA recommends that the human- readable expiration date on the drug package label include a year, month, and non-zero day. FDA recommends that the expiration date appear in YYYY-MM-DD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month. If there are space limitations on the drug package, the human-readable text may include only a year and month, to be expressed as: YYYY- MM if only numerical characters are used or YYYY-MMM if alphabetical characters are used to represent the month. FDA recommends that a hyphen or a space be used to separate the portions of the expiration date.

N

The net quantity (100 mL) statement highlighted by a red box competes for

The net quantity statement should not compete in size or prominence with important information

Reduce the prominence of the net quantity statement.

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

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IDENTIFIED ISSUE

RATIONALE FOR CONCERN

RECOMMENDATION

prominence with the product strength.

isted on the label. For more information see draft guidance, Guidance for ndustry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize M edication Errors April 2013)5. As written, the net quantity statement could be misinterpreted as a strength statement (i.e., 00 mg).

Carton Labeling (Shipper Label)

1

As currently presented, he units o ‘emperature measurement Centigrade and Fahrenheit) following he first numbers in the ‘emperature ranges e.g., Centigrade symbols (C) following he 20 and the Fahrenheit symbols (F) ollowing the 68) are

missing.

he lower temperatures in he ranges may be overlooked.

Add the Centigrade symbol (C) ‘ollowing the 20 and the Fahrenheit symbol (F) following the 68 within he storage statement.

For example, “Stored at controlled room temperature 20°C to 25°C 68°F to 77°F).”

5 When final, this guidance will represent FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search- fda-guidance-documents

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

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2. As currently presented, the product strength (i.e., 1,000 mg per 100 mL) is not included on the carton labeling. Only the quantity per milliliter is included (i.e., “10 mg/mL")

The “strength or potency of

the dosage form in metric system” is required by 21 CFR 201.57(c)(17)(i).

Add the proposed product strength, “1,000 mg per 100 mL” to the carton labeling.

For example, “1,000 mg per 100 mL 0 mg/mL)”

3. The route of administration is missing.

Missing route of administration statement could pose risk of product administration errors.

Add the route of administration statement without the use of abbreviations to the carton labeling. For consistency, use the same statement that is on the container label, per 21 CFR 201.100(b)(3).

S

For example: “For Intravenous Use

Only”.

4. A quantity statement, we may be

interpreted as one

infusion bag per carton.

This quantity statement is misleading and incorrect.

(b) (4)

Delete the quantity statement,

5. The carton labeling does not contain an “Rx Only” statement.

The “Rx Only” statement is required on the drug label and the outside container by Section 503(b)(4)(A) of

the Federal Food, Drug, and

Cosmetic Act.

Consider including an “Rx Only” statement on the carton labeling.

We recommend adding the “Rx Only” statement to an area on the carton label that does not interfere with important product identifying information (i.e. product name, product strength).

6. The carton labeling

The DSCSA requires certain

In September 2018, FDA released

includes a 2D data prescription drugs to have a | the draft guidance, Product matrix barcode, lot human-readable and Identifiers under the Drug Supply number, and expiration | machine-readable (2D data | Chain Security Act - Questions and date. However, it isnot | matrix barcode) product Answers.® The Act requires

® When final, this guidance will represent FDA's current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-

fda-quidance-documents

U.S. Food and Drug Administration

Silver Spring, MD 20993 www.fda.gov

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NDA 206968 Page 8

clear if a serial number is included.

identifier on the smallest saleable unit (usually the carton) for tracking and tracing purposes.

manufacturers and repackagers, respectively, to affix or imprint a product identifier to each package and homogenous case of a product intended to be introduced in a transaction in(to) commerce beginning November 27, 2017, and November 27, 2018, respectively. We recommend that you review the draft guidance to determine if the product identifier requirements apply to your product's labeling.

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 c

1.

inical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

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.

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.

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

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4. Provide case report forms and narrative summaries for each patient 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.

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

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.

If you have any questions, call Kimberly Compton, RPh, RAC, Senior Regulatory Project Manager, at (301) 796-1191.

Sincerely,

{See appended electronic signature page}

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

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Rigoberto Roca, MD

Director

Division of Anesthesiology, Addiction Medicine, and Pain Medicine

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.

RIGOBERTO A ROCA 12/22/2020 10:03:57 PM

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