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`February 27, 2006
`March 21, 2006
`March 29, 2006
`April 14, 2006
`June 1, 2006
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`September 23, 2005
`November 4, 2005
`November 17, 2005
`December 22, 2005
`February 9, 2006
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`NDA 21-976
`
`Tibotec, Inc.
`Attention: Jenny Z. Lin, PharmD
`Manager, Global Regulatory Affairs
`1020 Stony Hill Road, Suite 300
`Yardley, PA 19067
`
`Dear Dr. Lin:
`
`Please refer to your new drug application (NDA) dated December 22, 2005, received December
`23, 2005, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`PREZISTA (darunavir) tablets, 300 mg.
`
`We acknowledge receipt of your submissions dated:
`
`
`
`
`
`
`
`
`This new drug application provides for the use of PREZISTATM (darunavir) tablets, co-
`administered with 100 mg of ritonavir, for the treatment of human immunodeficiency virus
`(HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1
`strains resistant to more than one protease inhibitor.
`
`We completed our review of this application, as amended. It is approved under the provisions of
`accelerated approval regulations (21 CFR 314.510), effective on the date of this letter, for use as
`recommended in the enclosed labeling text and patient labeling. Marketing of this drug product
`and related activities must adhere to the substance and procedures of the referenced accelerated
`approval regulations.
`
`The final printed labeling (FPL) must be identical to the agreed upon enclosed labeling (text for
`the package insert and patient package insert). Marketing the product with FPL that is not
`identical to the approved labeling text may render the product misbranded and an unapproved
`new drug.
`
`Please submit final printed labeling (FPL) electronically according to the guidance for industry
`titled Providing Regulatory Submissions in Electronic Format - NDA. Alternatively, you may
`submit 20 paper copies of the FPL, as soon as it is available but no more than 30 days after it is
`printed. Please individually mount 15 of the copies on heavy-weight paper or similar material.
`
`June 12, 2006
`June 19, 2006
`June 21, 2006
`June 22, 2006
`
`
`
`

`

`
`
`For administrative purposes, designate this submission “FPL for approved NDA 21-976.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Submit 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 in content to the
`enclosed labeling. Upon receipt and verification, we will transmit that version to the National
`Library of Medicine for posting on the DailyMed website.
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled studies to verify and describe clinical benefit. We remind you of
`your postmarketing study commitments specified in your submission dated June 22, 2006.
`These commitments, along with any completion dates agreed upon, are listed below.
`
`1. 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.
`
`
`2. By December 31, 2007, submit the final study reports and datasets of the 48 week data for
`the ongoing Phase 3 studies TMC114-C211 and TMC114-C214.
`
`
`Please submit final study reports to NDA 21-976 as supplemental applications. For
`administrative purposes, all submissions relating to these postmarketing study commitments
`must be clearly designated “Subpart H Postmarketing Study Commitments.”
`
`Furthermore, all applications for new active ingredients, new dosage forms, new indications, new
`routes of administration, and new dosing regimens are required to contain an assessment of the
`safety and effectiveness of the product in pediatric patients unless this requirement is waived or
`deferred. We are deferring submission of your pediatric studies for ages 6 to 17 years until June
`30, 2008. Also, we are deferring submission of your pediatric studies for less than 6 years of age
`until June 30, 2011.
`
`Your deferred pediatric studies required under Section 2 of the Pediatric Research Equity Act
`(PREA) are considered required postmarketing study commitments. The status of these
`postmarketing studies shall be reported annually according to 21 CFR 314.81. These
`commitments are listed below.
`
`3. 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.
`
`
`Protocol Submission:
`Final Report Submission:
`
`Completed
`24 week data by June 30, 2008
`
`
`
`
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`

`

`
`
`4. 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
` the 6 to 17 year olds in trial TMC114-C212 with the Division of Antiviral Products (DAVP).
`
`
`
`
`Protocol Submission:
`Final Report Submission:
`
`by December 31, 2008
`by June 30, 2011
`
`
`Submit final study reports to this NDA. For administrative purposes, all submissions related to
`this/these pediatric postmarketing study commitments must be clearly designated “Required
`Pediatric Study Commitments.”
`
`In addition, we note the following postmarketing study commitments, specified in your
`submission dated June 22, 2006, that are not a condition of the accelerated approval. These
`commitments are listed below:
`
`Drug-Drug Interaction Trials
`
`5. Conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and rifabutin.
`
`
`by July 31, 2006
`by June 30, 2007
`
`Protocol Submission:
`Final Report Submission:
`
`6. Conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and
` buprenorphine/naloxone.
`
`
`Protocol Submission:
`Final Report Submission:
`
`by December 31, 2006
`by January 31, 2008
`
`
`7. Conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and
` carbamazepine.
`
`
`Protocol Submission:
`Final Report Submission:
`
`by December 31, 2006
`by January 31, 2008
`
`
`Pharmacology/Toxicology
`
`8. Complete the ongoing carcinogenicity study in mice and submit the final report.
`
`Protocol Submission:
`Final Report Submission:
`
`9. Complete the ongoing carcinogenicity study in rats and submit the final report.
`
`Protocol Submission:
`Final Report Submission:
`
`Completed
`by December 31, 2007
`
`Completed
`by December 31, 2007
`
`
`
`

`

`
`
`Pharmacokinetics
`
`10. 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.
`
`
`Protocol Submission:
`Final Report Submission:
`
`by December 31, 2006
`by January 31, 2008
`
`
`Special Populations
`
`11. Evaluate the pharmacokinetics of darunavir/rtv in HIV-negative subjects with Child-Pugh A
` and Child-Pugh B liver disease in order to determine dosing recommendations.
`
`
`Protocol Submission:
`Final Report Submission:
`
`by July 31, 2006
`by March 31, 2007
`
`
`12. Conduct a study of darunavir in treatment-experienced female patients to elucidate any
` potential gender differences in efficacy and safety.
`
`
`
`
`
`Protocol Submission:
`Final Report Submission:
`
`by December 31, 2006
`24 week data by December 31, 2008
`
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under
`21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last
`annual report, and, for clinical studies, number of patients entered into each study. All
`submissions, including supplements, relating to these postmarketing study commitments must be
`prominently labeled “Postmarketing Study Commitment Protocol”, “Postmarketing Study
`Commitment Final Report”, or “Postmarketing Study Commitment Correspondence.”
`
`The following are not postmarketing study commitments; however, we request the
`following information be submitted:
`
`Drug-Drug Interaction Trials
`
`1. Please submit the results from your planned study TMC114-C127, a drug-drug interaction
` study between darunavir/rtv b.i.d. and methadone.
`
`Clinical
`
`2. In addition to the required periodic adverse drug experience reports [21 CFR 314.80(c)(2)],
` please submit a separate periodic adverse drug experience report for rash.
`
`
`
`
`

`

`Microbiology
`
`3. Determine response rates based upon presence of specific cleavage site mutations at baseline
` and submit this analysis with the PREZISTA traditional approval application.
`
`4. Determine the protease cleavage site mutations that occur most frequently (>10%) in
` virologic failure isolates and submit this analysis with the PREZISTA traditional approval
` application.
`
`5. Determine if the most frequently occurring protease cleavage site mutations contributed to
` decreases in darunavir susceptibility through site-directed mutagenesis and submit this
` analysis with the PREZISTA traditional approval application.
`
`
`As required by 21 CFR 314.550, submit all promotional materials at least 30 days before the
`intended time of initial distribution of labeling or initial publication of the advertisement. Send
`two copies of all promotional materials directly to:
`
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`Food and Drug Administration
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`
`
`
`
`Please submit one market package of the drug product when it is available.
`
`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with the reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at www.fda.gov/medwatch/report/mmp.htm.
`
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`

`
`
`If you have any questions, call Elizabeth Thompson, M.S., Regulatory Project Manager, at (301)
`796-0824.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mark Goldberger, M.D., M.P.H.
`Director
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`
`
`Attachment: approved draft labeling and patient package insert
`
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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/
`---------------------
`Edward Cox
`6/23/2006 04:12:29 PM
`for Mark J. Goldberger, MD MPH
`
`