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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 202895/S-01
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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.
`
`Attention: Charles Zezza, Ph.D.
`
`Director, Global Regulatory Affairs
`
`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 January 6,
`2012, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Prezista® (darunavir), Oral suspension.
`
`We acknowledge receipt of your amendments dated February 7, 2012 in response to our
`comments to your January 6, 2012 supplement submission, sent via e-mail on February 3, 2012.
`
`We note that this submission also refers to your NDA 21976/S-022, a prior approval supplement
`(PAS)-labeling submission made in response to our Safety Labeling Change Notification dated
`October 19, 2011 and to your January 6, 2012 response submitted to NDA 21976/S-022 in
`
`response to our General Advice letter of December 12, 2011.
`
`In addition, we refer to non-safety labeling changes in our October 19, 2011 letter sent to your
`NDA 21976 for all antiretroviral products based on recent studies demonstrating decreased
`transmission of HIV when HIV-infected patients or their uninfected partners take antiretroviral
`medication.
`
`This supplemental new drug application provides for revisions to the labeling for Prezista®
`(darunavir) oral solution, 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).
`
`1. The RECENT MAJOR CHANGES in the Highlights section of the labeling has been
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`revised as follows:
`
`
`
` -------RECENT MAJOR CHANGES-------
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` Indications and Usage
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`
`
` Pediatric Patients (1.2)
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` Dosage and Administration
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` Adult Patients (2.1)
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`12/2011
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`12/2011
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`Reference ID: 3089902
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` NDA 202895/S-01
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`Page 2
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`12/2011
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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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`
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` Pediatric Patients (5.11)
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`10/2011
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`02/2012
`12/2011
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`
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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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`
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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.
`
`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.
`
`
`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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`
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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
`
`Drug
`
`
`HMG-CoA Reductase
`Inhibitors:
`
`
`pravastatin
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`atorvastatin
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`rosuvastatin
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`
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`↑ pravastatin
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`↑ atorvastatin
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`↑ rosuvastatin
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`Reference ID: 3089902
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`Other Agents
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`
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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 202895/S-01
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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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`
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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
`opportunistic infections (e.g., pneumonia and herpes virus infections).
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`
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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: 3089902
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`Patients should be advised to avoid doing things that can spread HIV-1 infection to
`others.
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`
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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
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`using a latex or polyurethane condom to lower the chance of sexual contact with
`
`
`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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` NDA 202895/S-01
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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.
`
` 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
`any body fluids such as semen, vaginal secretions, or blood. Never re use or
`share needles.
`
`
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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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`opportunistic infections. You should remain under the care of a doctor when using
`
`PREZISTA.
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`
`
`Avoid doing things that can spread HIV-1 infection.
`
`
`
` 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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`Ask your healthcare provider if you have any questions on how to prevent passing HIV
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`to other people.
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`
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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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`
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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:
`
`
` 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.
`
`
`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: 3089902
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` NDA 202895/S-01
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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
`
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`labeling.
`
`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
`
`
`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:
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`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: 3089902
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` NDA 202895/S-01
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`Page 6
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` REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Kyong Hyon, Safety Regulatory Project Manager, at (301) 796
`0734.
`
`
`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
`
`
`
`ENCLOSURE(S):
`Content of Labeling
`
`Reference ID: 3089902
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`1
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use PREZISTA safely and effectively. See Full Prescribing
`Information for PREZISTA.
`PREZISTA (darunavir) Oral Suspension, for Oral use
`
`
`
`PREZISTA (darunavir) Tablet, Film Coated for Oral use
`Initial U.S. Approval – 2006
`
`---------------------RECENT MAJOR CHANGES--------------------
`
`Indications and Usage
`
`
`
`Pediatric Patients (1.2)
`
`Dosage and Administration
`
`
`Adult Patients (2.1)
`
`
`
`Pediatric Patients (2.2)
`
`
` Warnings and Precautions
`
`Severe Skin Reactions (5.3)
`
`
`Immune Reconstitution Syndrome (5.8)
`
`
`
`Pediatric Patients (5.11)
`
`
`
`
`
`12/2011
`
`12/2011
`12/2011
`
`10/2011
`02/2012
`12/2011
`
`
`---------------------INDICATIONS AND USAGE---------------------
`PREZISTA is a human immunodeficiency virus (HIV-1) protease
`inhibitor indicated for the treatment of HIV-1 infection in adult
`patients. PREZISTA is also indicated for the treatment of HIV-1
`infection in pediatric patients 3 years of age and older. PREZISTA
`must be co-administered with ritonavir (PREZISTA/ritonavir) and
`with other antiretroviral agents. (1)
`
`----------------DOSAGE AND ADMINISTRATION-----------------
`
` Treatment-naïve adult patients and treatment-experienced adult
`patients with no darunavir resistance associated substitutions:
`
`
`800 mg (two 400 mg tablets) taken with ritonavir 100 mg
`
`once daily and with food. (2.1)
`
`
` Treatment-experienced adult patients with at least one darunavir
`
`resistance associated substitution: 600 mg (one 600 mg
`
`tablet) taken with ritonavir 100 mg twice daily and with food.
`(2.1)
`
` Pediatric patients (3 to less than 18 years of age and weighing at
`least 10 kg): dosage of PREZISTA and ritonavir is based on
`body weight and should not exceed the treatment-
`experienced adult dose. Do not use once daily dosing in
`
`
`pediatric patients. PREZISTA should be taken with ritonavir
`twice daily and with food. (2.2)
`
` PREZISTA/ritonavir is not recommended for use in patients
`
`with severe hepatic impairment. (2.3)
`
`
`--------------DOSAGE FORMS AND STRENGTHS---------------
`
`
`100 mg/mL oral suspension (3)
`
`
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`75 mg tablets, 150 mg tablets, 400 mg tablets, and 600 mg
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`tablets (3)
`
`
`-----------------------CONTRAINDICATIONS----------------------
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`Co-administration with alfuzosin, dihydroergotamine, ergonovine,
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`ergotamine, methylergonovine, cisapride, pimozide, oral
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`midazolam, triazolam, St. John’s Wort, lovastatin, simvastatin,
`rifampin and sildenafil (for treatment of pulmonary arterial
`
`hypertension). (4)
`
`
` Due to the need for co-administration of PREZISTA with
`
`ritonavir, please refer to ritonavir prescribing information for a
`
`description of ritonavir contraindications. (4)
`
`-----------------WARNINGS AND PRECAUTIONS-----------------
`
` Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis)
`
`has been reported with PREZISTA/ritonavir. Monitor liver
`function before and during therapy, especially in patients
`with underlying chronic hepatitis, cirrhosis, or in patients
`who have pre-treatment elevations of transaminases. Post-
`marketing cases of liver injury, including some fatalities,
`
`have been reported. (5 2, 6)
`
`
` Skin reactions ranging from mild to severe, including Stevens-
`Johnson Syndrome and toxic epidermal necrolysis, have been
`
`reported. Discontinue treatment if severe reaction develops.
`(5.3, 6)
`
`
` Use with caution in patients with a known sulfonamide allergy.
`(5.4)
`
` Patients may develop new onset diabetes mellitus or
`
`hyperglycemia. Initiation or dose adjustments of insulin or
`
`oral hypoglycemic agents may be required. (5.6)
`
` Patients may develop redistribution/accumulation of body fat
`(5.7) or immune reconstitution syndrome. (5.8)
`
` Patients with hemophilia may develop increased bleeding
`events. (5.9)
`
` PREZISTA/ritonavir should not be used in pediatric patients
`
`below 3 years of age in view of toxicity and mortality
`observed in juvenile rats dosed with darunavir up to days 23
`
`to 26 of age. (5.11)
`
`
`-----------------------ADVERSE REACTIONS-------------------------
`
` The most common clinical adverse drug reactions to
`
`PREZISTA/ritonavir (incidence greater than or equal to 5%)
`of at least moderate intensity (greater than or equal to Grade
`2) were diarrhea, nausea, rash, headache, abdominal pain and
`
`vomiting. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------DRUG INTERACTIONS------------------------
`
` Co-administration of PREZISTA/ritonavir with other drugs can
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`alter the concentration of other drugs and other drugs may
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`alter the concentrations of darunavir. The potential drug-drug
`concentrations must be considered prior to and during
`
`
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`therapy. (4, 5.5, 7, 12.3).
`
`
`------------------USE IN SPECIFIC POPULATIONS---------------
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` Use during pregnancy only if the potential benefit justifies the
`potential risk. (8.1)
`
`
`Pregnancy Registry available. (8.1)
`
`
` Mothers should be instructed not to breastfeed due to the
`potential for HIV transmission and the potential for serious
`
`adverse reactions in nursing infants. (8.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA approved patient labeling.
`
`
`Revised: 02/2012
`
`
`
`
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`Reference ID: 3089902
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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
`
`Reference ID: 3089902
`
`