`{
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`U.S. FOOD & DRUG
`ADMINISTRATION
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`
` NDA 205552/S-035
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`NDA 210563/S-011
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` SUPPLEMENT APPROVAL
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`
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`Pharmacyclics LLC
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`Attention: Xi Tian, PhD
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`Senior Manager, Regulatory Affairs
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`1000 Gateway Blvd
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`South San Francisco, CA 94080
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`
`
`Dear Dr. Tian:
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`Please refer to your supplemental new drug applications (sNDAs) dated and received
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`November 12, 2021, and your amendments, submitted under section 505(b) of the
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`Federal Food, Drug, and Cosmetic Act (FDCA) for Imbruvica (ibrutinib) capsules and
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`tablets.
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`These Prior Approval sNDAs provide for updates to the US Prescribing Information
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`(USPI) regarding cardiac toxicity, including the following changes:
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`• Warnings and Precautions, Section 5.3 regarding cardiac toxicity – added
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`information on the risk of sudden death, cardiac death and grade 3 or higher
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`tachyarrhythmias using an expanded pooled safety population; renamed from
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`“Cardiac Arrhythmias and Cardiac Failure” to “Cardiac Arrhythmias, Cardiac
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`Failure, and Sudden Death” and repositioned from fourth to third Warning and
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`Precaution.
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`• Dosage and Administration, Section 2.2 (Dosage Modifications for Adverse
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`
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`Reactions) – added new dosage modification guidelines for cardiac toxicity;
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`added instruction to evaluate the benefit-risk before resuming treatment for grade
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`2 cardiac failure, grade 3 cardiac arrhythmias, and grade 4 non-hematological
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`toxicities.
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`• Warnings and Precautions, Section 5.4 (Hypertension) – added instruction to
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`initiate or adjust anti-hypertensive medication.
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`Additional changes were made to Section 17 (Patient Counseling Information) and the
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`Patient Package Insert regarding cardiac toxicity to align with the updates to the USPI.
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`APPROVAL & LABELING
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`
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`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
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`labeling.
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`Reference ID: 4982387
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` NDA 205552/S-035
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` NDA 210563/S-011
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` Page 2
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` WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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` Please note that we have previously granted a waiver of the requirements of 21 CFR
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` 201.57(d)(8) regarding the length of Highlights of Prescribing Information.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`the FDA automated drug registration and listing system (eLIST), as described at
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`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
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`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
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`reportable changes not included in the enclosed labeling
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`Information on submitting SPL files using eList may be found in the guidance for
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`industry SPL Standard for Content of Labeling Technical Qs and As.2
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that include labeling
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`changes for this NDA, including CBE supplements for which FDA has not yet issued an
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`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`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
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`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
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`Word version. The marked-up copy should provide appropriate annotations, including
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`supplement number(s) and annual report date(s).
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
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`new active ingredients (which includes new salts and new fixed combinations), new
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`indications, new dosage forms, new dosing regimens, or new routes of administration
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`are required to contain an assessment of the safety and effectiveness of the product for
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`the claimed indication in pediatric patients unless this requirement is waived, deferred,
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`or inapplicable.
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`Because none of these criteria apply to your application, you are exempt from this
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`requirement.
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` 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
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`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`U.S. Food and Drug Administration
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`
`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4982387
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` NDA 205552/S-035
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` NDA 210563/S-011
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` Page 3
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` PROMOTIONAL MATERIALS
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` You may request advisory comments on proposed introductory advertising and
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` promotional labeling. For information about submitting promotional materials, see the
` final guidance for industry Providing Regulatory Submissions in Electronic and Non-
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`Electronic Format-Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.3
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`You must submit final promotional materials and Prescribing Information, accompanied
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`by a Form FDA 2253, at the time of initial dissemination or publication
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`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
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`Instructions for completing the form can be found at FDA.gov.5
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`All promotional materials that include representations about your drug product must be
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`promptly revised to be consistent with the labeling changes approved in this
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`supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions
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`in your promotional materials should include prominent disclosure of the important new
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`safety information that appears in the revised labeling. Within 7 days of receipt of this
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`letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4).
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`PATENT LISTING REQUIREMENTS
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`Pursuant to 21 CFR 314.53(d)(2) and 314.70(f), certain changes to an approved NDA
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`submitted in a supplement require you to submit patent information for listing in the
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`Orange Book upon approval of the supplement. You must submit the patent information
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`required by 21 CFR 314.53(d)(2)(i)(A) through (C) and 314.53(d)(2)(ii)(A) and (C), as
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`applicable, to FDA on Form FDA 3542 within 30 days after the date of approval of the
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`supplement for the patent information to be timely filed (see 21 CFR
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`314.53(c)(2)(ii)). You also must ensure that any changes to your approved NDA that
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`require the submission of a request to remove patent information from the Orange Book
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`are submitted to FDA at the time of approval of the supplement pursuant to 21 CFR
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`314.53(d)(2)(ii)(B) and 314.53(f)(2)(iv).
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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` 3 For the most recent version of a guidance, check the FDA guidance web page at
` https://www.fda.gov/media/128163/download.
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`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
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`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
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`
`
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`Reference ID: 4982387
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`
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`NDA 205552/S-035
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`NDA 210563/S-011
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`Page 4
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`If you have any questions, call CAPT Bernetta Lane, DHS, MBA, RN, Senior Regulatory
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`Health Project Manager, at (301) 796-0937.
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`
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`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
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`ENCLOSURE(S):
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`• Content of Labeling
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`o Prescribing Information
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`o Patient Package Insert
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`
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`Reference ID: 4982387
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`
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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.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NICOLE J GORMLEY
`05/11/2022 01:53:58 PM
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`Reference ID: 4982387
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