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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 205834/S-2
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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` Gilead Sciences, Inc.
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` Attention: Prachi Shah, MBS, RAC
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` Associate Manager, Regulatory Affairs
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` 333 Lakeside Drive
` Foster City, CA 94404
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`Dear Ms. Shah:
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`Please refer to your Supplemental New Drug Application (sNDA) dated and received May 14,
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`2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Harvoni® (ledipasvir/sofosbuvir), fixed-dose combination tablet, 90 mg/400 mg.
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`This Prior Approval supplemental new drug application proposes the following changes:
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`1. To expand the patient population to include patients with chronic hepatitis C virus
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`infection who are co-infected with HIV-1 and to update various sections of the labeling
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`based upon the results from GS-US-337-0115 (ION 4) study.
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`2. To update DRUG INTERACTIONS, Drugs without Clinically Significant Interactions
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`subsection with information related to dolutegravir, and
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`elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide combination therapy.
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`3. To update DRUG INTERACTIONS, Table 4 with information regarding drug
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`interactions between Harvoni and regimens containing tenofovir DF without a HIV
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`protease inhibitor/ritonavir or cobicistat, and drug interaction between Harvoni and
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`antimycobacterials.
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`4. To update CLINICAL PHARMACOLOGY, Table 5 and Table 6 with drug interaction
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`information between Harvoni and elvitegravir/cobicistat/emtricitabine/tenofovir
`alafenamide, atazanavir/ritonavir/emtricitabine/tenofovir DF, darunavir/ritonavir/
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`emtricitabine/tenofovir DF, or rifampin.
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`5. To update the NONCLINICAL TOXICOLOGY, Carcinogenesis, Mutagenesis,
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`Impairment of Fertility subsection with carcinogenicity data from the ledipasvir 6-month
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`rasH2 transgenic mouse study and to remove the Animal Toxicology and/or
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`Pharmacology section.
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`Reference ID: 3846141
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` NDA 205834/S-2
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` Page 2
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`Reference ID: 3846141
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`6. To update the “What should I tell my healthcare provider before taking Harvoni?” and
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` “Especially tell your healthcare provider if you take any of the following medicines”
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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`text.
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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 content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert and text for the
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`patient package insert), with the addition of any labeling changes in pending “Changes Being
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`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
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`labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
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`“SPL Standard for Content of Labeling Technical Qs and As at
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
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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 includes labeling changes
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`changes approved in this supplemental application, as well as annual reportable changes and
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`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`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 new
` active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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` administration are required to contain an assessment of the safety and effectiveness of the
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` product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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` deferred, or inapplicable.
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` Because none of these criteria applies to your application, you are exempt from this requirement.
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` NDA 205834/S-2
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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 promotional
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` labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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` OPDP Regulatory Project Manager
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` Food and Drug Administration
` Center for Drug Evaluation and Research
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` Office of Prescription Drug Promotion (OPDP)
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` 5901-B Ammendale Road
` Beltsville, MD 20705-1266
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` Alternatively, you may submit a request for advisory comments electronically in eCTD format.
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` For more information about submitting promotional materials in eCTD format, see the draft
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` Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
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`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
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`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`All promotional materials that include representations about your drug product must be promptly
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`revised to be consistent with the labeling changes approved in this supplement, including any
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`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
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`should include prominent disclosure of the important new safety information that appears in the
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`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
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`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
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`electronically in eCTD format. For more information about submitting promotional materials in
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`eCTD format, see the draft Guidance for Industry (available at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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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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`Reference ID: 3846141
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` NDA 205834/S-2
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` Page 4
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` If you have any questions, call Mammah Sia Borbor, Regulatory Project Manager, at (301) 796
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`Sincerely,
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`{See appended electronic signature page}
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`Debra Birnkrant, MD
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`Director
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`Division of Antiviral Products
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`Office of Antimicrobial Products
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`Content of Labeling
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`Reference ID: 3846141
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`DEBRA B BIRNKRANT
`11/12/2015
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`Reference ID: 3846141
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`(
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