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`U.S. FOOD & DRUG
`ADMINISTRATION
`
`
` NDA 205552/S-035
`
`NDA 210563/S-011
`
`
`
`
`
` SUPPLEMENT APPROVAL
`
`
`
`Pharmacyclics LLC
`
`Attention: Xi Tian, PhD
`
`Senior Manager, Regulatory Affairs
`
`1000 Gateway Blvd
`
`
`South San Francisco, CA 94080
`
`
`
`Dear Dr. Tian:
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received
`
`November 12, 2021, and your amendments, submitted under section 505(b) of the
`
`
`Federal Food, Drug, and Cosmetic Act (FDCA) for Imbruvica (ibrutinib) capsules and
`
`tablets.
`
`These Prior Approval sNDAs provide for updates to the US Prescribing Information
`
`(USPI) regarding cardiac toxicity, including the following changes:
`
`
`
`
`
`• Warnings and Precautions, Section 5.3 regarding cardiac toxicity – added
`
`information on the risk of sudden death, cardiac death and grade 3 or higher
`
`
`
`tachyarrhythmias using an expanded pooled safety population; renamed from
`
`
`“Cardiac Arrhythmias and Cardiac Failure” to “Cardiac Arrhythmias, Cardiac
`
`Failure, and Sudden Death” and repositioned from fourth to third Warning and
`
`Precaution.
`
`
`• Dosage and Administration, Section 2.2 (Dosage Modifications for Adverse
`
`
`
`Reactions) – added new dosage modification guidelines for cardiac toxicity;
`
`added instruction to evaluate the benefit-risk before resuming treatment for grade
`
`
`
`2 cardiac failure, grade 3 cardiac arrhythmias, and grade 4 non-hematological
`
`toxicities.
`
`
`• Warnings and Precautions, Section 5.4 (Hypertension) – added instruction to
`
`initiate or adjust anti-hypertensive medication.
`
`
`Additional changes were made to Section 17 (Patient Counseling Information) and the
`
`
`
`
`Patient Package Insert regarding cardiac toxicity to align with the updates to the USPI.
`
`
`APPROVAL & LABELING
`
`
`
`We have completed our review of this application, as amended. It is approved, effective
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`
`labeling.
`
`
`Reference ID: 4982387
`
`

`

`
`
`
`
`
`
`
` NDA 205552/S-035
`
` NDA 210563/S-011
`
` Page 2
`
`
` WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
` Please note that we have previously granted a waiver of the requirements of 21 CFR
`
`
` 201.57(d)(8) regarding the length of Highlights of Prescribing Information.
`
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`
`
`
`
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`
`
`
`
`the FDA automated drug registration and listing system (eLIST), as described at
`
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`Prescribing Information, Patient Package Insert), with the addition of any labeling
`
`
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`
`reportable changes not included in the enclosed labeling
`
`
`Information on submitting SPL files using eList may be found in the guidance for
`
`
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`
`
`
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`
`
`
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`
`
`
`
`
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`
`Word version. The marked-up copy should provide appropriate annotations, including
`
`
`
`supplement number(s) and annual report date(s).
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`
`
`new active ingredients (which includes new salts and new fixed combinations), new
`
`
`indications, new dosage forms, new dosing regimens, or new routes of administration
`
`
`are required to contain an assessment of the safety and effectiveness of the product for
`
`
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`
`or inapplicable.
`
`
`Because none of these criteria apply to your application, you are exempt from this
`
`requirement.
`
`
`
`
`
`
` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`
`
`
`
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 4982387
`
`

`

`
`
`
` NDA 205552/S-035
`
` NDA 210563/S-011
`
` Page 3
`
`
`
` PROMOTIONAL MATERIALS
`
` You may request advisory comments on proposed introductory advertising and
`
`
`
` promotional labeling. For information about submitting promotional materials, see the
` final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.3
`
`
`
`
`You must submit final promotional materials and Prescribing Information, accompanied
`
`
`
`by a Form FDA 2253, at the time of initial dissemination or publication
`
`
`
`
`
`
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`
`Instructions for completing the form can be found at FDA.gov.5
`
`
`
`All promotional materials that include representations about your drug product must be
`
`
`promptly revised to be consistent with the labeling changes approved in this
`
`
`
`supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions
`
`
`
`in your promotional materials should include prominent disclosure of the important new
`
`
`safety information that appears in the revised labeling. Within 7 days of receipt of this
`
`
`
`
`letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4).
`
`PATENT LISTING REQUIREMENTS
`
`
`
`
`Pursuant to 21 CFR 314.53(d)(2) and 314.70(f), certain changes to an approved NDA
`
`submitted in a supplement require you to submit patent information for listing in the
`
`Orange Book upon approval of the supplement. You must submit the patent information
`
`required by 21 CFR 314.53(d)(2)(i)(A) through (C) and 314.53(d)(2)(ii)(A) and (C), as
`
`applicable, to FDA on Form FDA 3542 within 30 days after the date of approval of the
`
`supplement for the patent information to be timely filed (see 21 CFR
`
`
`
`
`314.53(c)(2)(ii)). You also must ensure that any changes to your approved NDA that
`
`require the submission of a request to remove patent information from the Orange Book
`
`
`
`
`are submitted to FDA at the time of approval of the supplement pursuant to 21 CFR
`
`
`314.53(d)(2)(ii)(B) and 314.53(f)(2)(iv).
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`
` 3 For the most recent version of a guidance, check the FDA guidance web page at
` https://www.fda.gov/media/128163/download.
`
`
`
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 4982387
`
`

`

`NDA 205552/S-035
`
`NDA 210563/S-011
`
`Page 4
`
`
`
`
`If you have any questions, call CAPT Bernetta Lane, DHS, MBA, RN, Senior Regulatory
`
`Health Project Manager, at (301) 796-0937.
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`
`Nicole Gormley, MD
`
`Director
`
`Division of Hematologic Malignancies II
`
`
`Office of Oncologic Diseases
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Patient Package Insert
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 4982387
`
`

`

`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.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NICOLE J GORMLEY
`05/11/2022 01:53:58 PM
`
`Reference ID: 4982387
`
`■
`
`(
`
`
`
`

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