`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`
` 022264Orig1s015
`
` INVEGA SUSTENNA
`
`
` Paliperidone palmitate
`
`
`
`
`
`
`
`
`
`
`
` Trade Name:
`
`
`
`
`
`
` Approval Date:
`
`
`
`
` Indication:
`
`
`
`
`
`
`
`
` Janssen Pharmaceuticals Inc.
`
` December 20, 2017
`
` INVEGA SUSTENNA® is an atypical antipsychotic
`
`indicated for
`
`  Treatment of schizophrenia in adults.
`
`
`
`
` Treatment of schizoaffective disorder in adults as
`monotherapy and as an adjunct to mood stabilizers or
`
` antidepressant.
`
` Generic or Proper
`
`
` Name:
`
`
`
` Sponsor:
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` 022264Orig1s015
`
`
`
` CONTENTS
`
`
` Reviews / Information Included in this NDA Review.
`
`
`
`
`
`
`
`
` X
`
` X
`
` X
`
`
` X
`
`
`
` X
`
` X
`
`
`
` X
`
` X
`
`
`
` X
`
`
` X
`
`
`
`
` Approval Letter
`
` Other Action Letters
`
`
` Labeling
`
` REMS
` Summary Review
`
`
` Officer/Employee List
`
` Office Director Memo
`
`
` Cross Discipline Team Leader Review
` Medical Review(s)
`
` Chemistry Review(s)
`
`
` Environmental Assessment
`
` Pharmacology Review(s)
` Statistical Review(s)
`
`
` Microbiology / Virology Review(s)
`
` Clinical Pharmacology/Biopharmaceutics Review(s)
`
` Other Reviews
` Risk Assessment and Risk Mitigation Review(s)
`
` Proprietary Name Review(s)
` Administrative/Correspondence Document(s)
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`
`
` 022264Orig1s015
`
`
`
`APPROVAL LETTER
`
`
`

`

`
`
`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`
`
` NDA 022264/S-015
`
`
`
`
`
`
`
`
`
`
`
`
` Janssen Research & Development, L.L.C.
`
` Attention: Beth Geter-Douglass, Ph.D.
`
` Associate Director, Regulatory Affairs
`
` 1125 Trenton-Harbourton Road
`
` E11710
` Titusville, NJ 08560
`
` Dear Dr. Geter-Douglass:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received July 11,
` 2014, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and
`
`
`
` Cosmetic Act (FDCA) for Invega Sustenna (paliperidone palmitate) extended-release injectable
` suspension 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg.
`
`
`
`
`
`
` We acknowledge receipt of your amendment dated June 20, 2017, which constituted a complete
`
`
`
` response to our May 11, 2015, action letter.
`
` This Prior Approval supplemental new drug application proposes revisions to the product label
`
`based on findings from protocol R092670-SCH-3006 titled “A Fifteen-Month, Prospective,
`
`
` Randomized, Active- Controlled, Open-Label, Flexible-Dose Study of Paliperidone Palmitate
`Compared with Oral Antipsychotic Treatment in Delaying Time to Treatment Failure in Adults
`
`
` with Schizophrenia Who Have Been Incarcerated”.
`
` APPROVAL & LABELING
`
` 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.
`
` WAIVER OF HIGHLIGHTS SECTION
`
` Please note that we have previously granted a waiver of the requirements of 21 CFR
`
`
`
`
` 201.57(d)(8) regarding the length of Highlights of prescribing information.
`
` CONTENT OF LABELING
`
` 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
`
`
`
`
`
`
`
`Reference ID: 4198682
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` NDA 022264/S-015
` Page 2
`
`
`
`
`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, and text for
`
`
` 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 titled
`
`
`
`
` “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`
`CM072392.pdf.
`
` The SPL will be accessible from publicly available labeling repositories.
`
`
` Also within 14 days, amend all pending supplemental applications that include labeling changes
`
` 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).
`
` REQUIRED PEDIATRIC ASSESSMENTS
`
`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.
`
` Because none of these criteria apply to your application, you are exempt from this requirement.
`
` 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:
`
`
`
`
`
`
`
`
`
`Reference ID: 4198682
`
`

`

`
`
`
` NDA 022264/S-015
` Page 3
`
`
`
`
`
`
`OPDP Regulatory Project Manager
`
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`5901-B Ammendale Road
`
`
`Beltsville, MD 20705-1266
`
`
`
`
` Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`
`
`For more information about submitting promotional materials in eCTD format, see the draft
`
` Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`
`
` CM443702.pdf ).
`
` 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
`
` FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`
` Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. 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.
`
`
` 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 Shin-Ye Sandy Chang, Regulatory Project Manager, at (301) 796-
`
`
`
`
` 3971, or email shinye.chang@fda.hhs.gov.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Sincerely,
`
` {See appended electronic signature page}
`
` Mitchell V. Mathis, M.D.
`
` Director
`
` Division of Psychiatry Products
`
` Office of Drug Evaluation I
` Center for Drug Evaluation and Research
`
`
`
`
`
`
`
` ENCLOSURE:
` Content of Labeling
`
`
`
`
`Reference ID: 4198682
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MITCHELL V Mathis
`12/20/2017
`
`Reference ID: 4198682
`
`

`

` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
` 022264Orig1s015
`
`
`
`
` OTHER ACTION LETTERS
`
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 22264/S-015
`
`Janssen Pharmaceuticals, Inc.
`Attention: Beth Geter-Douglass, Ph.D.
`Associate Director, Regulatory Affairs
`1125 Trenton-Harbourton Road
`Titusville, NJ 08560
`
`Dear Dr. Geter-Douglass:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received July 11,
`2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Invega Sustenna (paliperidone palmitate) extended-release injectable suspension 39, 78, 117,
`156, 234 mg.
`
`We acknowledge receipt of your amendments dated August 21, 2014, September 24, 2014,
`December 19, 2014, and February 25, 2015.
`
`This “Prior Approval” efficacy supplemental new drug application proposes revisions to the
`
`product label based on findings from study R092670-SCH-3006 titled “A Fifteen-Month,
`Prospective, Randomized, Active-Controlled, Open-Label, Flexible-Dose Study of Paliperidone
`Palmitate Compared with Oral Antipsychotic Treatment in Delaying Time to Treatment Failure
`in Adults with Schizophrenia Who Have Been Incarcerated.”
`
`We have completed the review of your application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this action
`below and, where possible, our recommendations to address these issues.
`
`1.
`
`In our view, study R092670-SCH-3006 does not provide substantial evidence that
`paliperidone palmitate delays time to treatment failure in adults with schizophrenia who
`have been incarcerated, even though the results, on face, seem to demonstrate superiority
`of paliperidone palmitate based on the pre-specified primary endpoint and analysis.
`
`Treatment failure was defined as: 1) arrest/incarceration; 2) psychiatric hospitalization; 3)
`suicide; 4) discontinuation of antipsychotic treatment due to inadequate efficacy or poor
`tolerability; 6) treatment supplementation with another antipsychotic due to inadequate
`efficacy; and/or 7) increase in psychiatric services to prevent imminent psychiatric
`hospitalization.
`
`Reference ID: 3751469
`
`

`

`NDA 22264/S-015
`Page 2
`
`Overall, 39.8% of subjects in the paliperidone palmitate group and 53.7% of subjects in
`the comparator group met the definition for treatment failure (p<0.05). In our view,
`however, these results are not interpretable.
`
`A total of 139 patients (31.3%) discontinued the study early without meeting the
`definition of a treatment failure, and, importantly, there were more discontinuations in the
`paliperidone palmitate group (n=81, 35.8%) than in the oral antipsychotic group (n=58,
`26.6%). Furthermore, in 60 patients (26.5%) in the paliperidone palmitate group and 42
`patients (19.3%) in the oral antipsychotic group, the reasons for discontinuation reported
`in the case report forms were either “lost to follow-up” or “withdrawal by subject” in the
`case report forms. Thus, there is no way to know whether or not these patients
`experienced treatment failure, and the relatively large differences between treatment
`groups undermine the interpretability of the results. To place this problem into
`perspective, in the paliperidone palmitate group, 39.8% of subjects were categorized as
`treatment failures and, as such, had endpoint events, whereas the disposition of a
`relatively large proportion of subjects, 26.5%, was unknown.
`
`To assess the potential impact of the discontinuations, we performed two exploratory
`
`analyses on the explanatory Intent-to-Treat (eITT) set: 1) categorizing all 139 dropouts
`without an event as treatment failures; and 2) categorizing the 102 dropouts assessed as
`“lost to follow-up” or “withdrawal by subject” as treatment failures. Neither analysis
`yielded a statistically significant difference in delaying time to treatment failure (the p-
`values were 0.28 and 0.19, respectively). These analyses underscore the considerable
`uncertainty of the study’s conclusions, given the high numbers of discontinuations and
`the disparity between treatment groups. Thus, we reached the conclusion that study
`
`R092670-SCH-3006 failed to provide substantial evidence in support of the intended
`labeling revisions.
`
`2. We recognize the potential importance of improved compliance with antipsychotic
`treatment, but substantial evidence of effectiveness would be needed to support this
`sNDA approval. We would reconsider the requested labeling revisions if you could
`provide another similar, but more clearly positive, study to address the dropout concern,
`and we strongly encourage you to seek our guidance during the planning stage.
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
`dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`Reference ID: 3751469
`
`

`

`NDA 22264/S-015
`Page 3
`
` Present new safety data from the studies/clinical trials for the
`using the same format as the original NDA submission.
` Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA with
`
`the retabulated frequencies described in the bullet above.
` For
`, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`
`
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
`
`
`8. Provide English translations of current approved foreign labeling not previously
`
`submitted.
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the supplemental application. A resubmission
`must fully address all the deficiencies listed. A partial response to this letter will not be
`processed as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA Guidance for Industry,
`“Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`Reference ID: 3751469
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22264/S-015
`Page 4
`
`If you have any questions, please email Ann Sohn, Regulatory Project Manager, at
`ann.sohn@fda.hhs.gov.
`
`Sincerely,
`
`{See appended electronic signature page}
`Mitchell V. Mathis, M.D.
`CAPT, USPHS
`Director
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Reference ID: 3751469
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MITCHELL V Mathis
`05/11/2015
`
`Reference ID: 3751469
`
`

`

`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`
` RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
` 022264Orig1s015
`
`
`
` LABELING
`
`
`
`
`
`
`

`

`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` INVEGA SUSTENNA® safely and effectively. See full prescribing
`
`
`
`
`
`
`
` information for INVEGA SUSTENNA®.
`
`
`
`
`
`
`
`
`
`  Mild renal impairment (creatinine clearance  50 mL/min to < 80 mL/min):
`
`
`
`
`
`
`
`
`
`
`
`
`
` Administer 156 mg on treatment day 1 and 117 mg one week later, both
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` administered in the deltoid muscle. Follow with monthly injections of 78
`
`
`
`
`
`
`
`
`
`
` mg in either the deltoid or gluteal muscle. (2.5)
`
`
`
`
`
`
`
`
`
`
`
`
`
` INVEGA SUSTENNA® (paliperidone palmitate) extended-release
`
`
`
` injectable suspension, for intramuscular use
`
`
`
`
` Initial U.S. Approval: 2006
`
`
`
`
`
`
`
`
`
`
` WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`
`
`
`
` WITH DEMENTIA-RELATED PSYCHOSIS
`
`
` See full prescribing information for complete boxed warning.
`
`
`
`
`
`
`
`
` Elderly patients with dementia-related psychosis treated with
`
`
`
`
`
` antipsychotic drugs are at an increased risk of death. (5.1)
`
`
`
`
`
`
`
`
`
` INVEGA SUSTENNA® is not approved for use in patients with
`
`
`
`
`
`
`
` dementia-related psychosis. (5.1)
`
`
`
`
`
`
`
`
`
` 
`
`
`
` 
`
`
`
`
`
` ----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`
`
`
`
`
` Dosage and Administration (2.5)
` 06/2017
` Warnings and Precautions (5.5)
`
`
`
`
` 12/2017
`
`
`
` Warnings and Precautions (5.8)
`
`
`
`
`
` 02/2017
`
` Warnings and Precautions (5.10)
`
`
`
`
` 06/2017
`
`
`
` ----------------------------INDICATIONS AND USAGE---------------------------­
` INVEGA SUSTENNA® is an atypical antipsychotic indicated for
`
`
`
`
`
`
`
`  Treatment of schizophrenia in adults. (1)
`
`
`
`
`
`
`
`
`
`  Treatment of schizoaffective disorder in adults as monotherapy and as an
`
`
`
`
`
`
`
`
`
`
`
`
` adjunct to mood stabilizers or antidepressants. (1)
`
`
`
`
`
`
`
`
`
`
`
` -----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`  For intramuscular injection only. (2.1)
`
`
`
`
`
`
`
`
`
`
`
`  Each injection must be administered only by a health care professional.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` (2.1)
`
`  For deltoid injection, use 1-inch 23G needle for patients weighing less than
`
`
`
`
`
`
`
`
`
`
`
` 90 kg or 1½-inch 22G needle for patients weighing 90 kg or more. For
`
`
`
`
`
`
`
`
`
`
`
`
`
` gluteal injection, use 1½-inch 22G needle regardless of patient weight.
`
`
`
`
`
`
`
`
`
`
` (2.1)
`
`
`
`
` Monthly
`
`
`
` Maintenance Dosea
`
`
`
` Maximum
`
`
`
` Monthly
`
`
`
` --------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Extended-release injectable suspension: 39 mg, 78 mg, 117 mg, 156 mg, or
`
`
`
`
` 234 mg (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`
`
`
`
`
`
`
` Known hypersensitivity to paliperidone, risperidone, or to any excipients in
` INVEGA SUSTENNA®. (4)
`
`
`
`
` ---------------------------WARNINGS AND PRECAUTIONS-------------------­
`
`
`  Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients
`
`
`
`
`
`
`
`
`
` with Dementia-Related Psychosis Increased incidence of cerebrovascular
`
`
`
`
`
`
`
`
` adverse reactions (e.g. stroke, transient ischemic attack). (5.2)
`
`
`
`
`
`
`
`
`  Neuroleptic Malignant Syndrome Manage with immediate discontinuation
`
`
`
`
`
`
`
`
`
`
` of drug and close monitoring. (5.3)
`
`
`
`
`
`
`  QT Prolongation Avoid use with drugs that also increase QT interval and
`
`
`
`
`
`
`
`
`
`
`
`
`
` in patients with risk factors for prolonged QT interval. (5.4)
`
`
`
`
`
`
`
`
`
`  Tardive Dyskinesia Discontinue drug if clinically appropriate. (5.5)
`
`
`
`
`
`
`
`
`
`
`
`  Metabolic Changes Monitor for hyperglycemia/diabetes mellitus,
`
`
`
`
`
`
`
` dyslipidemia and weight gain. (5.6)
`
`
`
`
`
`
`  Orthostatic Hypotension and Syncope Monitor heart rate and blood
`
`
`
`
`
`
`
`
`
`
`
` pressure and warn patients with known cardiovascular or cerebrovascular
`
`
`
`
`
`
`
`
` disease, and risk of dehydration or syncope. (5.7)
`
`
`
`
`
`
`
`
`  Leukopenia, Neutropenia, and Agranulocytosis Perform complete blood
`
`
`
`
`
`
`
`
` counts (CBC) in patients with pre-existing low white blood cell count
`
`
`
`
`
`
`
`
`
` (WBC) or history of leukopenia or neutropenia. Consider discontinuing
`
`
`
`
`
`
`
`
` INVEGA SUSTENNA® if clinically significant decline in WBC in the
`
`
`
`
`
`
`
`
`
`
` absence of other causative factors. (5.9)
`
`
`
`
`
`
`  Hyperprolactinemia Prolactin elevations occur and persist during chronic
`
`
`
`
`
`
`
`
`
`
` administration. (5.10)
`
`
`  Potential for Cognitive and Motor Impairment Use caution when
`
`
`
`
`
`
`
`
`
`
`
` operating machinery. (5.11)
`
`
`
`  Seizures Use cautiously in patients with a history of seizures or with
`
`
`
`
`
`
`
`
`
`
`
`
`
` conditions that lower the seizure threshold. (5.12)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Dose
`
`
`
` Initiation Dosing
`
`
`
`
`
`
`
` Indication
`
`
`
` (deltoid)
`
` Day 1
`
`
`
` Day 8
`
`
`
` (deltoid or gluteal)
`
`
`
`
`
`
`
`
`
`
`
` 234 mg
`
`
`
`
`
` 156 mg
`
`
`
`
`
` 234 mg
`
`
`
`
`
` 156 mg
`
`
`
` Schizophrenia
`
`
`
` (2.2)
`
`
`
` Schizoaffective
`
`
`
`
`
` disorder (2.2)
`
`
`
` 39-234 mgb
`
`
`
`
`
` 78-234 mgc
`
`
`
`
`
`
`
` 234 mg
`
`
`
`
`
` 234 mg
`
`a
`
`b
`
`
`c
`
`
`
`
`
`
`
`
` Administered 5 weeks after the first injection.
`
`
`
` The recommended maintenance dose for treatment of schizophrenia is 117
`
`
`
`
`
`
` mg. Some patients may benefit from lower or higher maintenance doses
`
`
`
`
`
`
`
` within the additional available strengths (39 mg, 78 mg, 156 mg, and 234
`
`
`
`
`
`
`
`
`
`
`
`
` mg).
`
`
`
`
`
`
`
`
`
` Adjust dose based on tolerability and/or efficacy using available strengths.
`
` The 39 mg strength was not studied in the long-term schizoaffective
`
`
`
`
`
`
`
`
`
` disorder study.
`
`
`  For patients naïve to oral paliperidone or oral or injectable risperidone,
`
`
`
`
`
`
`
`
`
`
`
`
` establish tolerability with oral paliperidone or oral risperidone prior to
`
`
`
`
`
`
`
`
`
`
`
` initiating treatment with INVEGA SUSTENNA®. (2.2)
`
`
`
`
`
`
`  Missed Doses: To manage either a missed second initiation dose or a
`
`
`
`
`
`
`
`
`
`
`
`
` missed monthly maintenance dose, refer to the Full Prescribing
`
`
`
`
`
`
`
`
` Information. (2.3)
`
`
`
`  Moderate to severe renal impairment (creatinine clearance < 50 mL/min):
`
`
`
`
`
`
`
`
`
`
`
`
` INVEGA SUSTENNA® is not recommended. (2.5)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------------ADVERSE REACTIONS-----------------------------­
`
` The most common adverse reactions (incidence ≥ 5% and occurring at least
`
`
`
`
`
`
`
`
`
`
` twice as often as placebo) were injection site reactions, somnolence/sedation,
`
`
`
`
`
`
`
`
` dizziness, akathisia, and extrapyramidal disorder. (6)
`
`
`
`
`
`
`
`
`
`
`
`
` To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`
`
`
` Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at
`
`
`
`
` 1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`
`
`---------------------------------DRUG INTERACTIONS---------------------------­
`
`  Drugs that may cause orthostatic hypotension An additive effect may
`
`
`
`
`
`
`
`
`
`
`
`
` occur when co-administered with INVEGA SUSTENNA®. (7.1)
`
`
`
`
`
`
`
`
`  Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong
`
`
`
`
`
`
`
` inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s
`
`
`
`
`
`
`
`
`
` Wort) during a dosing interval for INVEGA SUSTENNA®. If
`
`
`
`
`
`
`
`
` administering a strong inducer is necessary, consider managing the patient
`
`
`
`
` using paliperidone extended release tablets. (2.5, 7.1, 12.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` -----------------------USE IN SPECIFIC POPULATIONS----------------------­
` Pregnancy May cause extrapyramidal and/or withdrawal symptoms in
`
`
`
`
`
`
`
`
` neonates with third trimester exposure. (8 1)
`
`
`
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA-
` approved patient labeling.
`
`
`
`
`
`
`
`
` Revised: 12/2017
`
`
`
`
`
`
`
`Reference ID: 4198682
`
`
`
`
`
`
`
`

`

`
`
` 7.1
`
`
`
` 7.2
`
`
`
` Drugs Having Clinically Important Interactions
`
`
`
`
`
`
`
`
` with INVEGA SUSTENNA®
`
`
`
`
`
`
` Drugs Having No Clinically Important
`
`
`
`
`
`
`
`
`
` Interactions with INVEGA SUSTENNA®
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
` Pregnancy
`
`
`
` 8.1
`
`
`
`
` 8.2
`
` Labor and Delivery
`
`
`
`
`
`
` 8.3
`
` Nursing Mothers
`
`
`
`
`
`
` 8.4
`
` Pediatric Use
`
`
`
`
`
`
` 8.5
`
` Geriatric Use
`
`
`
`
`
`
`
` 8.6
`
` Renal Impairment
`
`
`
`
`
` 8.7
`
` Hepatic Impairment
`
`
`
`
` 8.8
`Patients with Parkinson’s Disease or Lewy Body
`
`
`
`
`
`
`
`
`
`
`
`
`Dementia
`
`
`
`
` 9 DRUG ABUSE AND DEPENDENCE
`
`
`
`
` Controlled Substance
`
`
` 9.1
`
`
`
`
`
` 9.2
`
`
` Abuse
`
`
`
`
`
` 9.3
`
` Dependence
`
`
`
`10 OVERDOSAGE
`
`
`
` 10.1 Human Experience
`
`
`
`
`
`
`
`
` 10.2 Management of Overdosage
`
`
`
`
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
` 12.1 Mechanism of Action
`
`
`
`
`
`
`
` 12.2 Pharmacodynamics
`
`
`
`
`
` 12.3 Pharmacokinetics
`
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`
`
`
`
`
`
`
`
` Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`
` 14.1 Schizophrenia
`
`
`
`
`
`
`
` 14.2 Schizoaffective Disorder
`
`
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.2
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
` WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
` WITH DEMENTIA-RELATED PSYCHOSIS
`
`
`
`
`
` INDICATIONS AND USAGE
`1
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
` Administration Instructions
`
`
` 2.1
`
`
`
`
`
`
` 2.2
`
` Schizophrenia and Schizoaffective Disorder
`
`
`
`
`
`
` 2.3
`
` Missed Doses
`
`
`
`
`
`
`
` 2.4
`
` Use with Risperidone or with Oral Paliperidone
`
`
`
`
`
`
`
`
`
` 2.5
`
` Dosage Adjustments
`
`
`
`
`
`
`
` 2.6
`
` Switching from Other Antipsychotics
`
`
`
`
`
`
`
` 2.7
`
` Instructions for Use
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
` Increased Mortality in Elderly Patients with
`
`
` 5.1
`
`
`
`
`
`
`
`
` Dementia-Related Psychosis
`
`
`
`
`
` Cerebrovascular Adverse Reactions, Including
`
`
`
`
`
`Stroke, in Elderly Patients with Dementia-
`
`
`
`
`
`
`
`
`
`
`Related Psychosis
`
`
`
`
`
`
` Neuroleptic Malignant Syndrome
`
`
` 5.3
`
`
`
`
`
` QT Prolongation
`
`
`
` 5.4
`
`
`
`
` Tardive Dyskinesia
`
`
` 5.5
`
`
`
`
` Metabolic Changes
`
`
`
` 5.6
`
`
`
`
`
` Orthostatic Hypotension and Syncope
`
`
` 5.7
`
`
`
`
`
`
`
` Falls
`
`
` 5.8
`
`
`
`
` Leukopenia, Neutropenia, and Agranulocytosis
`
`
` 5.9
`
`
`
`
`
`
` 5.10 Hyperprolactinemia
`
`
`
`
`
`
`
` 5.11 Potential for Cognitive and Motor Impairment
`
`
`
`
`
`
`
`
`
` 5.12 Seizures
`
`
`
`
`
`
`
` 5.13 Dysphagia
`
`
`
`
`
` 5.14 Priapism
`
`
`
`
`
`
`
` 5.15 Disruption of Body Temperature Regulation
`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
` Clinical Trials Experience
`
`
` 6.1
`
`
`
`
`
`
` 6.2
`
` Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`
` listed.
`
`Reference ID: 4198682
`
`
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA­
`
`
`
`
`
` RELATED PSYCHOSIS
`
`
`
`  Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at
`
`
`
` an increased risk of death [see Warnings and Precautions (5.1)].
`
`
`
` INVEGA SUSTENNA® is not approved for use in patients with dementia-related
`
` psychosis [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
`
`
` INVEGA SUSTENNA® (paliperidone palmitate) is indicated for the treatment of:
`
`
`
`  Schizophrenia in adults [see Clinical Studies (14.1)].
`
`
`
`
`
`
`
`
`  Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or
`
`
`
`
`
`
`
`
` antidepressants [see Clinical Studies (14.2)].
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
` 2.1 Administration Instructions
`
`
`
`
`
`
`
` Each injection must be administered only by a healthcare professional.
`
`
`
`
`
`
`
`
`
` Parenteral drug products should be inspected visually for foreign matter and discoloration prior to
`
`
`
`
`
`
`
` administration, whenever product and container permit.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` INVEGA SUSTENNA® is intended for intramuscular use only. Do not administer by any other
`
`
`
`
`
`
`
`
`
` route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection;
`
`
`
`
`
`
`
`
`
`
`
` do not administer the dose in divided injections. Inject slowly, deep into the deltoid or gluteal
`
`
`
`
`
` muscle.
`
` INVEGA SUSTENNA® must be administered using only the needles that are provided in the
`
`
` INVEGA SUSTENNA® kit.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` The recommended needle size for administration of INVEGA SUSTENNA® into the deltoid
`
`
`
`
`
` muscle is determined by the patient’s weight:
`
`
`
`
`  For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.
`
`
`
`
`
`
`  For patients weighing 90 kg or more, the 1½-inch, 22 gauge needle is recommended.
`
`
`
`
`
`
`
`
`
` Deltoid injections should be alternated between the two deltoid muscles.
`
`
`
`
`
`
`
`
`
` The recommended needle size for administration of INVEGA SUSTENNA® into the gluteal
`
`
`
`
`
` muscle is the 1½-inch, 22 gauge needle regardless of patient weight.
`
`
`
`
`
`
`
`
`
` Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be
`
`
`
`
`
`Reference ID: 4198682
`
`
`
`

`

`
` alternated between the two gluteal muscles.
`
`
`
`
`
` 2.2 Schizophrenia and Schizoaffective Disorder
`
`
`
`
`
`
`
` For patients who have never taken oral paliperidone or oral or injectable risperidone, it is
`
`
`
`
`
` recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating
`
` treatment with INVEGA SUSTENNA®.
`
`
`
`
`
`
`
`
`
`
` The recommended dosing of INVEGA SUSTENNA® for each approved indication is displayed in
`
`
`
`
`
`
` Table 1. The recommended initiation of INVEGA SUSTENNA® is with a dose of 234 mg on
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. Following
`
`
`
`
`
`
`
`
`
` the second initiation dose, monthly maintenance doses can be administered in either the deltoid or
`
`
`
`
`
` gluteal muscle.
`
`
`
`
` Table 1:
`
`
`
`
`Recommended Dosing of INVEGA SUSTENNA for Adults with Schizophrenia or
`
`
`
`
`
`
`
`
`Schizoaffective Disorder
`
`
`
`
`
` Indication
`
` Schizophrenia
`
`
`
` Initiation Dosing
`
`
`
` (deltoid)
`
`
`
` Day 1
`
`
`
` Day 8
`
`
`
` 234 mg
`
`
`
`
`
` 156 mg
`
`
`
` Monthly
`
` Maintenance Dosea
`
`
`
`
`
` (deltoid or gluteal)
`
`
`
`
`
` Maximum
`
`
`
` Monthly Dose
`
`
`
`
`
` 234 mg
`
`
`
`
`
`
`
` Schizoaffective disorder
`
`
`
` 234 mg
`
`
`
`
` 39-234 mgb
`
`
`
`
` 78-234 mgc
`
`
`
`
`
` 156 mg
`
`
`
`
`
` 234 mg
`
`
`
`
`
` b
`
`
`
`
` a Administered 5 weeks after the first injection.
`
`
`
`
`
`
`
`
`
` The recommended maintenance dose for treatment of schizophrenia is 117 mg. Some patients may benefit
`
`
`
`
` from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg,
`
`
`
`
`
`
`
`
`
`
`
`
`
` and 234 mg).
`
`
`
` c Adjust dose based on tolerability and/or efficacy using available strengths. The 39 mg strength was not
`
`
`
`
`
`
`
`
`
` studied i