CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22-264
`22-264
`
`
`
`APPLICA TION NUMBER:
`
`OTHER REVIEW(S)
`OTHER REVIEW! S!
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`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`July 10, 2009
`
`Thomas Laughren, MD, Director
`Division of Psychiatry Products
`
`Laura Pincock, R.Ph, PharmD, Acting Team Leader
`Denise Toyer, PharmD, Deputy Director
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`
`Diane C. Smith, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Label and Labeling Review
`
`
`
`Invega Sustenna (Paliperidone Palmitate) Injection
`25 mg, 50 mg, 75 mg, 100 mg and 150 mg
`NDA 22-264
`
`Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals,
`Inc.
`
`Date:
`
`To:
`
`Through:
`
`From:
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`Subject:
`
`Drug Name(s):
`
`Application Type/Number:
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`Applicant/Sponsor:
`
`OSE RCM #:
`
`2009-286
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`1
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`

`

`Contents
`
` 1
`
`Executive summary............................................................................................................................ 3
`
`Regulatory History............................................................................................................................. 3
`2
`3 Materials Reviewed............................................................................................................................ 3
`4 Discussion .......................................................................................................................................... 3
`5
`RECOMMENDATIONS ................................................................................................................... 4
`5.1
`Comments to the Division......................................................................................................... 4
`
`
`
`
`
`2
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`

`

` 1
`
` EXECUTIVE SUMMARY
`Invega Sustenna (Paliperidone Palmitate) is an extended release intramuscular injection for the
`acute and maintenance treatment of schizophrenia in adults. Invega Sustenna is a product line
`extension of Invega (Paliperidone) oral tablets. Paliperidone palmitate is an ester of
`paliperidone and is dosed based upon the palmitate ester according to CMC. As such, DMEPA
`considered the vulnerability of labeling the product strength based on the ester paliperidone
`palmitate as compared to labeling the product strength in terms of milligram equivalents of
`paliperidone.
`The findings of our Label and Labeling Risk Assessment indicate that improvements can be
`made prior to approval to the presentation of the product strength, proprietary name, established
`name, and the dosage form statement on the container labels and carton labeling to provide
`consistency and reduce the likelihood of confusion. We provide recommendations in Section
`5.2 that aim at reducing the risk of medication errors.
`
`2 REGULATORY HISTORY
`The Division of Medication Error Prevention and Analysis previously reviewed the applicant's
`labels and labeling for the proposed name, Invega Sustenna, in OSE Review # 2008-117, dated
`August 5, 2008. This review noted the expression of strength on the labels and labeling was
`inconsistent with the dose provided in the Dosage and Administration Section of the labeling.
`Specifically, we recommended the Applicant avoid the term "milligram equivalents" or the
`abbreviation "mg eq". Subsequently on October 21, 2008, the applicant submitted a Complete
`Response Briefing Book, which contained justification to present the product strengths in terms
`of milligram (mg) paliperidone equivalent. The applicant noted that confusion could arise if the
`product strengths were presented in terms of paliperidone palmitate versus mg paliperidone
`equivalents.
`
`3 MATERIALS REVIEWED
`Revised container labels and carton labeling were submitted on February 2, 2009. The Division
`of Medication Error Prevention and Analysis (DMEPA) used Failure Mode and Effects
`Analysis (FMEA) in our evaluation of these labels and labeling. We also reviewed the
`justification provided by the Applicant contained in the Complete Response Briefing Book,
`dated October 21, 2008. See Appendix A through E for images.
`
`4 DISCUSSION
`The Applicant was requested to label this product using the “mg” amount of the ester
`paliperidone palmitate rather than the “mg equivalent” amount of paliperidone. Labeling the
`product in this manner would provide for strengths of 39 mg, 78 mg, 117 mg, 156 mg and
`234 mg per syringe.
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` DMEPA does not agree with the
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`3
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`(b) (4)
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`(b) (4)
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`

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`Applicant’s rationale. Using the term ‘mg equivalent’ is confusing and can lead to incorrect
`dosage calculations and conversions. Postmarketing experience with other products that
`express doses/strengths in terms of “equivalents” (e.g., Fosphenytoin equivalents) demonstrates
`such confusion. Furthermore, there is no existing data (of which FDA is aware) that any
`particular ‘even’ strengths, are ‘more identifiable’ than other strengths. Thus, we additionally
`do not agree with the Applicant’s rationale to
`
`
`
`In a meeting with the Division of Psychiatry Products, Office of New Quality Drug Chemistry,
`the Division of Medication Error Prevention and Analysis and the Chair of the CDER Labeling
`and Nomenclature Committee (LNC) on June 8, 2009, the team discussed the Applicant's
`proposal and the differences of opinion as to the preferred expression of strength. ONDQA
`wanted the strength expressed in terms of the ester and clinical liked the whole numbers.
`DMEPA did not have a preference as to how the strength was expressed but did request that
`whichever method was chosen, the container, carton and insert all needed to be consistent.
`Following discussion the group agreed that the product strength should be expressed as the ester
`(paliperidone palmitate) on the container labels, carton and throughout the insert labeling. It
`was agreed that the syringe strengths should be labeled as 39 mg, 78 mg, 117 mg, 156 mg, and
`234 mg of paliperidone palmitate, and not as 25 mg, 50 mg, 75 mg, 100 mg, or 50 mg of
`paliperidone. Additionally, there should not be any references to milligram equivalents, or
`paliperidone equivalents, or any similar terms throughout the labels and labeling, other than in
`the Description section of the Insert Labeling.
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`5 RECOMMENDATIONS
`Our evaluation noted areas of needed improvement on the container labels, carton and insert
`labeling. We noted the use of the inappropriate dosage form,
` and
`provide comments on the insert labeling in Section 5.1 Comments on the Division. Section 5.2,
`Comments to the Applicant, contains our recommendations for the container labels and carton
`labeling. We request the recommendations in Section 5.2 be communicated to the Applicant
`prior to approval.
`Please copy the Division of Medication Error Prevention and Analysis on any communications
`to the Applicant with regard to this review. If you have any further questions or need
`clarification on this review, please contact Abolade Adeolu, OSE Project Manager, at
`301-796-4264.
`
`5.1 COMMENTS TO THE DIVISION
`1.
`The Applicant used the term
` throughout the labels and labeling
`to describe the dosage form of the proposed product throughout the labels and labeling.
`We note this is not an official U.S. Pharmacopeia (USP) dosage form. The chemistry
`review also noted this inappropriate dosage form statement. ONDQA recommended
`that the Applicant to replace the term “
` with the term “Extended-
`release Injectable Suspension” to appropriately reflect the proposed dosage form. We
`concur with this recommendation.
`The syringe strengths should be referred to as 39 mg, 78 mg, 117 mg, 156 mg, and
`
`2.
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`4
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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`234 mg of paliperidone palmitate, and not as 25 mg, 50 mg, 75 mg, 100 mg, or 50 mg of
`paliperidone throughout the insert labeling. Additionally, there should not be any
`references to milligram equivalents, or paliperidone equivalents, or any similar terms
`throughout the labels and labeling, other than in the Description section of the Insert
`Labeling.
`
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`
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`5.2 COMMENTS TO THE APPLICANT
`A.
`All Labels and Labeling
`1. Express the product strength of the prefilled syringes as the ester (paliperidone
`palmitate) throughout the labels and labeling (e.g., 39 mg, 78 mg, 117 mg, 156 mg and
`234 mg). Delete all references to “milligram equivalents”, or “paliperidone
`equivalents”, or any similar terms throughout the labels and labeling, with the exception
`of the Description section of the Insert Labeling.
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`2. Revise the statement
` to read “For Single Use Only - Use Entire
`Content of Syringe”. These statements should be prominently displayed together to
`prevent multiple use/reuse of the syringe and to remind practitioners that one syringe is a
`complete dose.
`3. Revise the established name to read “Paliperidone Palmitate Extended-release Injectable
`Suspension”.
`Carton Labeling
`1. See Comments A 1 through A 3.
`2. Revise the presentation of the proprietary name so that it appears entirely on the same
`line in the same size and font. As currently presented, the "Sustenna" portion of the
`proprietary name appears in a larger font size than the "Invega" portion of the name and
`the two words appear on separate lines. The current presentation may lead health care
`practitioners to believe the name is just "Sustenna", when in fact the full proprietary
`name is Invega Sustenna.
`3. Revise the product strength so that it is proportionate to the font size of the proprietary
`and established names. Although the product strength appears immediately after the
`established name, the font size is small and makes the strength less prominent. Thus it
`may be difficult for practitioners to readily recognize the product strength.
`Container Label
`See Comments A 1 through A 3.
`Professional Sample Carton Labeling
`1. See Comments A 1 through A 3.
`2. Increase the prominence of the statement "Sample. Not for sale or reimbursement.” This
`statement is small and may be overlooked by practitioners. Increasing the size will
`allow healthcare practitioners to clearly identify that this is a professional sample.
`
`B.
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`C.
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`D.
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`5
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`
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`E.
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`F.
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`G.
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`Professional Sample Container Label
`1. See Comments A 1 through A 3.
`2. Increase the prominence of the statement “Sample. Not for sale or reimbursement” by
`bolding or increasing the font size. Increasing the size will allow healthcare
`practitioners to clearly identify that this is a professional sample.
`Insert Labeling
`We have no comments on the prescribing information labeling.
`Information Sheet for Providers
`Revise the statement “Do not administer intravenously or subcutaneously” to read “For
`Intramuscular Injection Only”. Negative statements such as ‘Not for Intravenous
`Injection’ or ‘Not for Subcutaneous Injection’ may actually have the opposite intended
`effect and have inadvertently encouraged wrong routes of administration due to the
`reader's focus on the route of administration and the potential for overlooking the
`negative words ‘not’ or ‘do not’.
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`6
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`7 pp withheld in full immed. after this page as (b)(4) draft labeling.
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Diane Smith
`7/10/2009 01:22:32 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Laura Pincock
`7/10/2009 02:21:15 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Carol Holquist
`7/10/2009 03:03:55 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`M E M O R A N D U M
`
`
`
`
`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`___________________________________________________________________________________________
`
`
`CLINICAL INSPECTION SUMMARY
`August 5, 2008
`
`
`
`DATE:
`
`TO:
`
`Kimberly Updegraff, Regulatory Project Manager
`Jing Zhang, Medical Officer
`Division of Psychiatry Products
`
`
`
`
`
`John Lee, Medical Officer
`Good Clinical Practice Branch II
`Division of Scientific Investigations
`
`
`
`
`
`
`FROM:
`
`
`
`
`
`THROUGH: Tejashri Purohit-Sheth, MD
`
`
` Branch Chief, Good Clinical Practice Branch II
`Division of Scientific Investigations
`
`
`
`
`
`
`
`
`
`Evaluation of Clinical Inspections
`
`22-264
`
`Johnson and Johnson PR&D
`
`Paliperidone palmitate
`
`
`
`No
`
`
`SUBJECT:
`
`NDA:
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`APPLICANT:
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`DRUG:
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`NME:
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`THERAPEUTIC CLASSIFICATION: Standard Review
`
`INDICATIONS: Treatment of schizophrenia and prevention of recurrence of symptoms
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`CONSULTATION REQUEST DATE: January 4, 2008
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`DIVISION ACTION GOAL DATE: August 2, 2008
`
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`PDUFA DATE: August 26, 2008
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`(b) (4)
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`

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`Page 3 CLINICAL INSPECTION SUMMARY, NDA 22-264, paliperidone palmitate
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`
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`I. BACKGROUND
`Johnson and Johnson submitted NDA 22-264 to support the use of paliperidone in the
`treatment of schizophrenia and prevention of recurrence of symptoms.
`Schizophrenia
`Schizophrenia is a chronic debilitating mental illness which affects 0.5 to 1% of the United
`States (US) population. The risk for schizophrenia has been found to be generally consistent
`across diverse geographic, ethnic, cultural, and socioeconomic groups. Schizophrenia affects
`men and women with equal frequency but appears about 10 years earlier in men than in
`women, typically in late teens or early twenties.
`Non-compliance is a major problem in using antipsychotic agents to treat schizophrenia.
`Medication gaps as short as 1 to 10 days have been shown to be associated with an increased
`risk of hospitalization and suicide attempts. The cumulative relapse rate in schizophrenia has
`been estimated to be about 80% by 5 years. Discontinuing drug therapy has been shown to
`increase the relapse risk five-fold. The use of long-acting injectable agents has been shown to
`reduce the relapse rate by about one-third at one year (from 40 to 25%).
`Paliperidone palmitate
`Paliperidone is a monoaminergic antagonist that exhibits the characteristic dopamine type 2
`antagonism combined with predominant serotonin (5-hydroxytryptamine type 2A) antagonism
`of the second-generation antipsychotic drugs. The oral paliperidone extended release
`formulation was approved by the Food and Drug Administration on 19 December 2006 for the
`treatment of schizophrenia and on 27 April 2007 for maintenance treatment of schizophrenia.
`Paliperidone ER tablets are also approved and marketed in the European Union for the
`treatment of schizophrenia.
`Paliperidone palmitate is a long-acting injectable with a long duration of action and acceptable
`systemic and local tolerance. Relatively constant plasma concentrations are achieved using
`monthly dosing. Given that paliperidone has been extensively investigated in the oral tablet
`program, it is expected that its documented safety and efficacy will extend to the injectable
`formulation, paliperidone palmitate.
`Study Protocol
`R092670-PSY-3003 was a multicenter, randomized, double-blind, placebo-controlled, parallel-
`group, dose response study in adults with a diagnosis of schizophrenia for at least one year and
`severely symptomatic at screening. The study consisted of a screening period (up to 7 days)
`followed by a 13-week double-blinded treatment period (four treatment groups, paliperidone
`palmitate 50, 100, or 150 mg equivalent or placebo). Each subject received an intramuscular
`injection on Days 1, 8, 36, and 64, and end-of-study assessments were performed on Day 92.
`349 randomized subjects received the study medication, had baseline and post baseline
`efficacy assessments, and received the same study treatment for the duration of the study. The
`primary efficacy endpoint was the change from baseline in Positive and Negative Syndrome
`Scale for Schizophrenia (PANSS) total score. Major safety assessment consisted of noting the
`incidence, severity, and relationship of treatment-emergent adverse events and changes from
`baseline in clinical laboratory tests, vital signs, physical examination, body weight, body mass
`index, electrocardiograms (ECGs), and extrapyramidal symptom scale scores. The inspected
`
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`(b) (4)
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`

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`Page 4 CLINICAL INSPECTION SUMMARY, NDA 22-264, paliperidone palmitate
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`site, which contributed approximately 9% of the subjects in this study, was selected for
`inspection based on enrollment of large numbers of study subjects.
`Four sites were originally targeted for inspection by the Division of Psychiatry Products, which
`were selected due to high enrollment. However, this audit only covered one of the four
`originally requested sites, as the Division of Psychiatry Products withdrew their request for
`inspection of three of the four sites (Litman, Lowy, and Chaganti). The request for the
`inspection of Drs. Litman and Lowy’s sites was withdrawn based on recent inspectional
`history, since these sites were inspected within 4 months of consult request date and no major
`deficiencies were observed. The request for the inspection of Dr. Chaganti’s site was
`withdrawn since he was recently inspected, received a recent Warning Letter, and the data
`from the site did not significantly affect the overall efficacy and safety analysis outcome.
`
`II.
`
`INSPECTION RESULTS
`
`Clinical Site
`
`Protocol
`Subjects
`
`Inspection
`Dates
`
`Classification
`
`Interim
`
`Final
`
`Steven Glass, MD
`CNS Research Institute, PC
`Clementon, New Jersey
`
`R092670-PSY-3003
`(31 subjects)
`
`7/7 - 7/21
`2008
`
`VAI
`
`VAI
`
`NAI = no action indicated (no deviations from regulations); VAI = voluntary action indicated (no
`significant deviations from regulations); OAI = official action indicated (significant deviations from
`regulations); NA = not applicable
`
`Steven Glass, MD
`CNS Research Institute, PC
`130 White Horse Pike
`Clementon, NJ 08021
`a. What was inspected:
`• Scope of inspection: subject eligibility, informed consent, test article accountability and
`disposition, adherence to protocol and applicable regulations.
`• Data verification: primary efficacy endpoint data, adverse events, concomitant
`medication use, and subject discontinuation
`• Subjects: 35 subjects were screened, 31 enrolled, and 14 completed the study. Consent
`forms, randomization information, termination dates and reasons, and source PANSS
`scores were reviewed for all subjects. Concomitant medications, adverse events, ECGs
`(limited visits), laboratory tests, and subject selection criteria were reviewed for all
`subjects who received the study drug. Drug accountability was evaluated for 9
`randomly selected subjects.
`b. General observations and commentary:
`• Cited deficiencies (Form FDA 483): Delayed signing of Addendum I to the consent
`
`
`
`(b) (4)
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`

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`Page 5 CLINICAL INSPECTION SUMMARY, NDA 22-264, paliperidone palmitate
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`form (3 subjects), which described updated safety information not contained in the
`original consent form
`• Other significant findings:
`o Patient evaluation visits out of protocol-specified time window (most approved by
`the sponsor)
`o Minor discrepancies between source data (which matched electronic case report
`forms) and data listings
`c. Assessment of data integrity: Although minor regulatory violations were noted, it is
`unlikely that these would affect data integrity. Data from this site are considered
`reliable.
`
`III. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS
`Serious deficiencies were not observed at inspection of this clinical site. Minor deficiencies
`consisted of suboptimal informed consent procedures for signatures on addendum to the
`informed consent documents and a limited number of protocol violations that are not expected
`to importantly impact data integrity. The data generated from this site are considered
`acceptable in support of the proposed indication.
`
`
`{See appended electronic signature page}
`John Lee, M.D.
`Good Clinical Practice Branch II
`Division of Scientific Investigations
`
`{See appended electronic signature page}
`Tejashri Purohit-Sheth, M.D.
`Branch Chief
`Good Clinical Practice Branch II
`Division of Scientific Investigations
`Office of Compliance
`
`
`
`CONCURRENCE:
`
`
`
`
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`John Lee
`8/6/2008 03:10:24 PM
`MEDICAL OFFICER
`
`Tejashri Purohit-Sheth
`8/6/2008 03:50:34 PM
`MEDICAL OFFICER
`
`