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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 21976/S-022
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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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`Janssen Products, L.P.
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`Attention: Charles Zezza, Ph.D.
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`Director, Global Regulatory Affairs
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`920 Route 202 S
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`Raritan, NJ 08869
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`
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`Dear Dr. Zezza:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received November
`17, 2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Prezista® (darunavir) 75 mg, 150 mg, 400 mg, and 600 mg Tablets
`
`We acknowledge receipt of your amendments dated January 6, and February 7, 2012 in response
`to our General Advice letter dated, December 12, 2011 and our February 3, 2012 e-mail
`comments.
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`We also refer to our letter dated October 19, 2011, notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for
`antiretroviral products. This information pertains to the risk of the autoimmune disorder as
`syndromes that can occur in the setting of immune reconstitution with the use of antiretroviral
`products.
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`In addition, we refer to non-safety labeling changes in our October 19, 2011 letter for all
`antiretroviral products based on recent studies demonstrating decreased transmission of HIV
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`when HIV-infected patients or their uninfected partners take antiretroviral medication.
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`This supplemental new drug application provides for revisions to the labeling for Prezista®
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`(darunavir) 75 mg, 150 mg, 400 mg, and 600 mg Tablets, consistent with our October 19 and
`December 12, 2011 letters and February 3, 2012 e-mail comments, as follows (additions are
`noted by underline and deletions are noted by strikethrough).
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`1. The RECENT MAJOR CHANGES in the Highlights section of the labeling has been
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`revised as follows:
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` -------RECENT MAJOR CHANGES-------
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` Indications and Usage
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`
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` Pediatric Patients (1.2)
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` Dosage and Administration
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`12/2011
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`Reference ID: 3089899
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`

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` NDA 21976/S-022
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`Page 2
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` Adult Patients (2.1)
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` Pediatric Patients (2.2)
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` Warnings and Precautions
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` Severe Skin Reactions (5.3)
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`Immune Reconstitution Syndrome (5.8)
`
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` Pediatric Patients (5.11)
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`12/2011
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`12/2011
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`10/2011
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`02/2012
`12/2011
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`2. The revision date has been changed from 12/2011 to 02/2012 throughout the label.
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`3. The WARNINGS AND PRECAUTIONS/Immune Reconstitution Syndrome sub-
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`section has been revised as follows:
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`Immune reconstitution syndrome has been reported in patients treated with combination
`antiretroviral therapy, including PREZISTA. During the initial phase of combination
` antiretroviral treatment, patients whose immune systems respond,ing to antiretroviral therapy
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`may develop an inflammatory response to indolent or residual opportunistic infections (such
`as Mycobacterium avium infectioncomplex, cytomegalovirus, Pneumocystis jirovecii
`pneumonia (PCP), and/or tuberculosis), which may necessitate further evaluation and
`treatment.
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`Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
`have also been reported to occur in the setting of immune reconstitution; however, the time to
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`onset is more variable, and can occur many months after initiation of treatment.
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`4. The Table 9 in the 7.3 Established and Other Potentially Significant Drug Interactions
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` section of the package insert has been revised as follows:
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`Table 9: Established and Other Potentially Significant Drug Interactions:
`Alterations in Dose or Regimen May Be Recommended
`Based on Drug Interaction Studies or Predicted Interaction
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`[See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 12 and 13]
`Effect on Concentration of
`Clinical Comment
`Concomitant Drug Class:
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`Drug Name
`Lopinavir or Concomitant
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`Drug
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`HMG-CoA Reductase
`Inhibitors:
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`pravastatin
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`atorvastatin
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`rosuvastatin
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`↑ pravastatin
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`↑ atorvastatin
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`↑ rosuvastatin
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`Reference ID: 3089899
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`Other Agents
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`Titrate atorvastatin, pravastatin or
`rosuvastatin dose carefully and Uuse the
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`lowest possiblenecessary dose while
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`monitoring for safety. Caution should be
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`used when theDo not exceed atorvastatin
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`dose exceeds 20 mg/day.of atorvastatin,
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`pravastatin or rosuvastatin with careful
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`monitoring, or consider other HMG CoA
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`reductase inhibitors such as fluvastatin in
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`combination with PREZISTA/ritonavir.
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` NDA 21976/S-022
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`Page 3
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`5. The PATIENT COUNSELING INFORMATION/Information About Therapy with
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` PREZISTA sub-section has been revised as follows:
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`Patients should be informed that PREZISTA is not a cure for HIV infection. Patients
`should stay on continuous HIV therapy to control HIV infection and decrease HIV
`related illnesses.
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`Patients should be told that sustained decreases in plasma HIV RNA have been
`associated with a reduced risk of progression to AIDS and death. Patients should remain
`under the care of a physician while using PREZISTA. Patients should be advised to
`continue to practice safer sex and to use latex or polyurethane condoms to lower the
`chance of sexual contact with any body fluids such as semen, vaginal secretions or blood.
`Patients should be advised never to share personal items that can have blood or body
`fluids on them, like toothbrushes and razor blades. Patients should be advised never to re
`use or share needles. PREZISTA is not a cure for HIV-1 infection and patients may
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`continue to experience illnesses associated with HIV-1infection, including opportunistic
`infections. Patients should remain under the care of a physician when using PREZISTA.
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`Patients should be advised to avoid doing things that can spread HIV-1 infection to
`others.
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` Do not share needles or other injection equipment.
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` Do not share personal items that can have blood or body fluids on them, like
`toothbrushes and razor blades.
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` Do not have any kind of sex without protection. Always practice safe sex by
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`using a latex or polyurethane condom to lower the chance of sexual contact with
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`semen, vaginal secretions, or blood.
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` Do not breastfeed. We do not know if PREZISTA can be passed to the baby
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`through breast milk and whether it could harm the baby. Also, mothers with HIV­
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`1 should not breastfeed because HIV-1 can be passed to the baby in the breast
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`milk.
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`6. Patient Information:
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`a. The “Does PREZISTA cure HIV or AIDS?” section has been revised as follows:
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`Does PREZISTA cure HIV or AIDS?What is PREZISTA?
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`PREZISTA does not cure HIV infection or AIDS. People taking PREZISTA may
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`still develop infections or other conditions associated with HIV infection, including
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`opportunistic infections (e.g., pneumonia and herpes virus infections).
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` Patients must stay on continuous HIV therapy to control infection and decrease
` HIV related illnesses.
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`Reference ID: 3089899
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`

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` NDA 21976/S-022
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`Page 4
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` Avoid doing things that can spread HIV 1 infection.
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`
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`  Do not share needles or other injection equipment.
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` Do not share personal items that can have blood or body fluids on them,
`like toothbrushes and razor blades.
`
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` Do not have any kind of sex without protection. Always practice safe sex by
`using a latex or polyurethane condom to lower the chance of sexual contact with
`any body fluids such as semen, vaginal secretions, or blood. Never re use or
`share needles.
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`
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` Ask your healthcare provider if you have any questions on how to prevent passing
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` HIV to other people. PREZISTA does not cure HIV infection or AIDS and you may
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`continue to experience illnesses associated with HIV-1infection, including
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`
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`opportunistic infections. You should remain under the care of a doctor when using
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`
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`PREZISTA.
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`
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`Avoid doing things that can spread HIV-1 infection.
`
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` Do not share needles or other injection equipment.
`
`
` Do not share personal items that can have blood or body fluids on them,
`like toothbrushes and razor blades.
`
`
` Do not have any kind of sex without protection. Always practice safe sex by
`
`
`using a latex or polyurethane condom to lower the chance of sexual contact with
`
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`semen, vaginal secretions, or blood.
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`
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`Ask your healthcare provider if you have any questions on how to prevent passing HIV
`to other people.
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`b. The “Does PREZISTA reduce the risk of passing HIV to others?” section has been
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`deleted.
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`c. The sixth bulleted paragraph in the “What should I tell my doctor before taking
`PREZISTA?/ PREZISTA may not be right for you. Before taking PREZISTA, tell
`your doctor or healthcare provider if you:” section has not been revised as follows:
`
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` are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking
`PREZISTA. You should not breastfeed if you have HIV because of the chance
`of passing HIV to your baby. Talk with your healthcare provider about the best
`way to feed your baby. The Centers for Disease Control and Prevention (CDC)
`recommends that HIV infected mothers not breastfeed to avoid the risk of
`passing HIV infection to your baby. Do not breastfeed. We do not know if
`PREZISTA can be passed to your baby in your breast milk and whether it could
`harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV­
`1 can be passed to the baby in the breast milk.
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`
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`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
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`Reference ID: 3089899
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`

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` NDA 21976/S-022
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`Page 5
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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
`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
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`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
`labeling.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`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 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 MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, 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).
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`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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`Food and Drug Administration
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`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
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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/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Office of Prescription Drug Promotion (OPDP), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`Reference ID: 3089899
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`

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` NDA 21976/S-022
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`Page 6
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` REPORTING REQUIREMENTS
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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 Kyong Hyon, Safety Regulatory Project Manager, at (301) 796­
`0734.
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`
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`Sincerely,
`
` {See appended electronic signature page}
`
` Kendall A. Marcus, MD
`
`Deputy Director for Safety
`Division of Antiviral Products
`Office Antimicrobial Products
`Center for Drug Evaluation and Research
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`
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`ENCLOSURE(S):
`Content of Labeling
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`Reference ID: 3089899
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`

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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/
`----------------------------------------------------
`
`KENDALL A MARCUS
`02/17/2012
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`Reference ID: 3089899
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`