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` DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
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`Rockville, MD 20857
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`NDA 21-976/S-006
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`Tibotec, Incorporated
`Attention: Susan Fiordeliso
`Manager, Global Regulatory Affairs
`1020 Stony Hill Road, Suite 300
`Yardley, PA 19067
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`Dear Ms. Fiordeliso:
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`Please refer to your supplemental new drug application dated December 20, 2007, received
`December 21, 2007, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for PREZISTA (darunavir) 300 mg and 600 mg tablets.
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`We acknowledge receipt of your submissions dated February 28, 2008, March 28, 2008, April 18,
`2008, April 30, 2008, May 14, 2008, June 13, 2008, June 17, 2008, July 2, 2008, July 21, 2008,
`September 4, 2008 and October 8, 2008.
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`This supplemental new drug application provides for the use of PREZISTA (darunavir) tablets co-
`administered with 100 mg of ritonavir, for the treatment of human immunodeficiency virus (HIV) in
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` antiretroviral treatment-experienced adult patients.
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`We completed our review of this application, as amended. This application is approved, effective on
`the date of this letter, for use as recommended in the agreed-upon labeling text and patient labeling.
`We approved this NDA (21-976/000) under the 21 CFR 314 Subpart H regulations for accelerated
`approval of new drugs for serious or life-threatening illnesses. Approval of this supplement and NDA
`21-976, supplement 007, fulfills your commitments made under 21 CFR 314.510, listed as PMCs 1
`and 2 in the June 23, 2006, approval letter:
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`1.
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`By December 31, 2007, submit the final study reports and datasets of the 96-week data for the
`ongoing Phase 2b studies TMC114-C202, TMC114-C213, TMC 114-C208, and TMC114-
`C215.
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`2.
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`By December 31, 2007, submit the final study reports and datasets of the 48 week data for the
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`ongoing Phase 3 studies TMC114-C211 and TMC114-C214.
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`Approval of this supplement also fulfills the following postmarketing commitments as numbered in the
`June 23, 2006, approval letter. These commitments are listed below:
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`5.
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`7.
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` Conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and rifabutin.
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` Conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and
`carbamazepine.
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`NDA 21-976/S-006
`Page 2
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`8.
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`Complete the ongoing carcinogenicity study in mice and submit the final report.
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`Complete the ongoing carcinogenicity study in rats and submit the final report.
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`Please conduct a cocktail study to determine the effects of steady state darunavir/rtv
` 600/100 mg b.i.d. on the metabolism of CYP450 probe substrates for the following
` enzymes: CYP2C9, CYP2C19, and CYP2D6.
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`9.
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`10.
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`The following postmarketing commitment acknowledged in our June 23, 2006, approval letter has not
`been completed:
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`6.
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`Conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and
`buprenorphine/naloxone.
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`12.
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`Protocol Submission: by December 31, 2006
`Final Report Submission: by January 31, 2008
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`We acknowledge receipt of your submission of June 25, 2008, in support of fulfillment of the
`following postmarketing commitment listed in our June 23, 2006, approval letter:
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`Conduct a study of darunavir in treatment-experienced female patients to elucidate any
`potential gender differences in efficacy and safety.
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`Protocol Submission: by December 31, 2006
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`Final Report Submission: 24 week data by December 31, 2008
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`The submission of June 25, 2008 is currently under review.
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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 administration
`are required to contain an assessment of the safety and effectiveness of the product for the claimed
`indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.
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`We are waiving the pediatric study requirement for ages 0 to below 3 years of age because of evidence
`strongly suggesting the drug would be unsafe in this pediatric age group. This decision is based on the
`results of juvenile rat toxicology studies that provide evidence of a potential safety risk as a result of
`drug-brain accumulation.
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food and Drug and
`Cosmetic Act (FDCA) are required postmarketing studies. The status of these postmarketing studies
`must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. We
`remind you of the deferred pediatric studies as identified in the June 23, 2006, approval letter for NDA
`21-976/000.
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`We acknowledge receipt of your submission of June 20, 2008 in support of fulfillment of
`postmarketing requirement number 3 acknowledged in our June 23, 2006 approval letter:
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`NDA 21-976/S-006
`Page 3
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`3.
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`Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric patients
`ages 6 to 17 years. Please assess the pharmacokinetics, safety, tolerability and antiviral activity
`of two alternative doses of a suitable pediatric formulation in combination with ritonavir, in
`treatment-experienced pediatric children and adolescents between 6 and 17 years of age.
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`The submission of June 20, 2008 is currently under review.
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`Because we are waiving the pediatric study requirement for ages 0 to below 3 years of age, you are
`released from postmarketing requirement number 4, acknowledged in our June 23, 2006, approval
`letter:
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`4.
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`Protocol Submission:
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`Final Report Submission:
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`Completed
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`June 20, 2008
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`Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric
`patients less than 6 years of age. Please evaluate dose requirements and safety in pediatric
`patients less than 6 years of age with HIV-1 infection after preliminary review of data from
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`the 6 to 17 year olds in trial TMC114-C212 with the Division of Antiviral Products (DAVP).
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`Protocol Submission:
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`Final Report Submission:
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`by December 31, 2008
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`by June 30, 2011
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`Postmarketing requirement 4 is now replaced with the following required deferred pediatric study:
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`1.
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`Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric
`patients 3 to 6 years of age. Please evaluate dose requirements and safety in treatment-
`experienced pediatric patients 3 to 6 years of age with HIV-1 infection after preliminary review
`of data from the 6 to 17 year olds in trial TMC114-C212 with the Division of Antiviral
`Products (DAVP).
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`Protocol Submission:
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`Final Report Submission:
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`by December 31, 2008
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`by June 30, 2011
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`Submit final study reports to this NDA. For administrative purposes, all submissions related to this
`required pediatric postmarketing study must be clearly designated “Required Pediatric
`Assessment(s)”.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the FDCA to authorize FDA to require holders of approved drug and biological
`product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA
`makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)). This
`provision took effect on March 25, 2008.
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`Since PREZISTA was approved in June 2006, for the treatment of human immunodeficiency virus
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`(HIV) infection in antiretroviral treatment-experienced adult patients, we have reviewed new data from
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`juvenile rat toxicology studies submitted with this supplement and have re-analyzed data previously
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`NDA 21-976/S-006
`Page 4
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`submitted to FDA from other juvenile toxicology studies. Mortality was observed across all dose
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`groups in the study of juvenile rats directly dosed at post-natal days (PDN) 5, 8 and 11, as well as
`juvenile rats directly dosed on PND 12. As a result of these findings, we also re-analyzed data from
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`reproductive toxicology studies. These re-analyses raise a safety concern about the use of PREZISTA
`in pregnant women and neonates. These re-analyses were not available when PREZISTA was granted
`marketing authorization for the treatment of HIV infection in antiretroviral treatment-experienced adult
`patients. Therefore, we consider this information to be “new safety information” as defined in
`FDAAA.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported under
`subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of serious risk, that is,
`increased mortality and reproductive toxicity in animal studies that may be relevant to pregnant women
`and neonates.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious risk.
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`Therefore, based on appropriate scientific data, we have determined that you are required, pursuant to
`section 505(o) (3) of the FDCA, to conduct the following study:
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`2.
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`Perform a nonclincal reproductive toxicology study in a relevant species which achieves an
`adequate AUC exposure margin (compared to human serum exposure) in order to
`establish the safety profile of darunavir in utero. Submit your protocol for review prior to
`initiation of the reproductive toxicology study.
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`Protocol Submission:
`Final Report Submission:
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`September, 2009
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`April, 2011
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`The timetable you submitted on October 21, 2008, states that you will conduct this study according to
`the following schedule:
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`Submit the protocol to your IND 62,477, with a cross-reference letter to this NDA 21-976. Submit
`all final reports to your NDA 21-976. Use the following designators to prominently label all
`submissions, including supplements, relating to this postmarketing study requirement as
`appropriate:
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`ƒ Required Postmarketing Protocol under 505(o)
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`ƒ Required Postmarketing Final Report under 505(o)
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`ƒ Required Postmarketing Correspondence under 505(o)
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or
`clinical trial required under this section. This section also requires you to periodically report to FDA
`on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section
`506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to report annually on the status of
`any postmarketing commitments or required studies or clinical trials.
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`NDA 21-976/S-006
`Page 5
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`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided
`that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2(vii). We remind you that to
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`comply with 505(o), your annual report must also include a report on the status of any study or clinical
`trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies
`or clinical trials required under 505(o) on the date required will be considered a violation of FDCA
`section 505(o)(3)(E)(ii) and could result in enforcement action.
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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, please submit the content of
`labeling [21 CFR 314.50(1)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/oc/datacouncil/spl/html that is identical to the enclosed labeling (text for the
`package insert and text for the patient package insert). Upon receipt, we will transmit that version to
`the National Library of Medicine for public dissemination. For administrative purposes, please
`designate this submission “SPL for approved NDA 21-976/S-006.”
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`In addition, within 21 days of the date of this letter, amend any pending applications for this NDA with
`content of labeling in structures product labeling (SPL) format to include the changes approved in this
`application.
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`Marketing the product with FPL that is not identical to the approved labeling text and in the required
`format may render the product misbranded and an unapproved new drug.
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`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`the Division of Antiviral Products and two copies of both the promotional materials and the package
`insert directly to:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
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`the following address:
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`MEDWATCH
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`Food and Drug Administration
`Suite 12B05
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`5600 Fishers Lane
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`Rockville, MD 20857
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`NDA 21-976/S-006
`Page 6
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`Please submit one market package of the drug product when it is available.
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
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`If you have any questions, call Stacy Newalu, Regulatory Project Manager, at (301) 796-3978.
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`Enclosure (clean copy of approved labels)
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`Sincerely,
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`{See appended electronic signature page}
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`Debra Birnkrant, M.D.
`Director
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`Division of Antiviral Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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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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`---------------------
`Jeffrey Murray
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`10/21/2008 06:15:29 PM
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