CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-264
`
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
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`

`

`
`
`Date:
`To:
`
`Through:
`
`
`
`From:
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`g)
`
`July 31, 2008
`Thomas Laughren, M.D., Director
`)
`Division of Psychiatry Products (DPP
`Claudia Karwoski, Pharm.D., Director (Actin
`)
`Division of Risk Management (DRISK
`OSE Paliperidone Palmitate Review Team
`
`Scientific Lead: Kendra Worthy, Pharm.D., Senior Risk
`)
`Management Analyst (Detail) (DRISK
`
`Team Members:
`Suzanne Berkman, Pharm.D., Senior Drug Risk Managem
`)
`Analyst (Acting) Team Leader (DRISK
`Mary Dempsey, Risk Management Program Coordinator
`(DRISK)
`afety Evaluator , Division of
`Ida-Lina Diak, Pharm.D., S
`Pharmacovigilance (DPV I)
`Laura Pincock, R.Ph., Pharm.D., Safety Evaluator,
` Division of
`edication Error Prevention and Analysis (DMEPA)
`
`
`
`ent
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`M
`
`Subject:
`Drug Name(s):
`
`Application
`Type/Number:
`pplicant/sponsor:
`A
`OSE RCM #:
`
`
`Review of Proposed Risk Management Plan
`nna™ (paliperidone palmitate
`Invega® Suste
`
`NDA 22-264
`
`
`
`Johnson & Johnson
`2008-803
`
`
`
`1
`
`(b) (4)
`
`(b) (4)
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`Contents
`
`1
`
`Introduction and Background.................................................................................................. 3
`1.1 Regulatory History ...................................................................................................... 3
`2 Material Reviewed .................................................................................................................. 3
`3 Results of Review.................................................................................................................... 3
`3.1 Safety Concerns........................................................................................................... 3
`3.2 Sponsor’s Risk Management Proposal........................................................................ 4
`4 Discussion ............................................................................................................................... 4
`5 Conclusion............................................................................................................................... 5
`
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`
`2
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` 1
`
`
`INTRODUCTION AND BACKGROUND
`This review follows the May 16, 2008 request from the Division of Psychiatry products (DPP) for
`the Office of Surveillance and Epidemiology (OSE) to review Johnson & Johnson’s September
`26, 2007 submission containing a proposed pharmacovigilance plan.
`Invega® Sustenna™ (paliperidone palmitate) is an atypical antipsychotic with the proposed
`indication for the treatment of schizophrenia and the prevention of recurrence of symptoms of
`schizophrenia. Paliperidone palmitate is a major active metabolite of risperidone. It is supplied
`as pre-filled syringes for long-acting intramuscular injection containing paliperidone palmitate
`equivalent to 25 mg, 50 mg, 75 mg, and 100 mg paliperidone. It is to be administered by a
`healthcare professional.
`
`1.1 REGULATORY HISTORY
`Invega® (paliperidone) Extended Release Tablet (3 mg, 6 mg, 9 mg, and 12 mg) was first
`approved in the United States on December 19, 2006 for the treatment of schizophrenia (NDA
`21-999). The extended release tablet was then approved for maintenance treatment of
`schizophrenia on April 27, 2007 (NDA 22-043).
`
`2 MATERIAL REVIEWED
`The following materials were reviewed:
`•
`“Paliperidone Palmitate Pharmacovigilance Plan” dated September 26, 2007 by Johnson
`& Johnson and submitted October 26, 2007.
`• Proposed Invega® Sustenna™ package insert submitted February 25, 2008.
`•
`Invega® Extended-Release Tablets package insert. Titusville, NJ: Janssen, L.P.; 2007.
`• Risperdal® package insert. Titusville, NJ: Janssen, L.P.; 2007.
`• Risperdal® Consta® package insert. Titusville, NJ: Janssen, L.P.; 2007.
`• Email correspondence from Dr. Jing Zhang, medical officer, DPP. Dated June 4, 2008.
`
`3 RESULTS OF REVIEW
`
`3.1 SAFETY CONCERNS
`
`3.1.1 Sponsor’s Safety Concerns
`
`Johnson & Johnson did not identify any safety risks in the proposed pharmacovigilance plan.
`However, the proposed labeling1 includes the following risks:
`• Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-
`related psychosis.
`• Neuroleptic malignant syndrome
`
`
`•
`1 Proposed Invega® Sustenna™ package insert submitted February 25, 2008. Warnings and Precautions.
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`3
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`• QT prolongation
`• Tardive dyskinesia
`• Hyperglycemia and diabetes mellitus
`• Orthostatic hypotension and syncope
`• Potential for cognitive and motor impairment
`• Seizures
`• Suicide
`• Administration (For intramuscular injection only. Avoid inadvertent injection into a
`blood vessel.)
`Further, atypical antipsychotics as a class have a Boxed Warning which states (in pertinent part)
`that “[e]lderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
`are at an increased risk of death compared to placebo.”2
`The safety risks noted above are also included in the Warnings and Precautions section of the
`Invega® Extended-Release Tablets label. Hyperprolactinemia is listed in the Warnings and
`Precautions section of the Invega® label; however, it is listed in the full prescribing information
`section of the Invega® Sustenna™ label. Gastrointestinal narrowing is listed in the Invega® label,
` If this adverse reaction is unrelated to the oral
`route of administration, it should also be included in Invega® Sustenna™ labeling. Additionally,
`the safety risks noted above, with the exception of QT prolongation and administration, are
`included in the Warnings and Precautions section of the Risperdal label.3
`
`3.1.2 DMEPA Safety Concerns
`
`The Division of Medication Error Prevention and Analysis (DMEPA) has concerns regarding the
`dosing and administration of this product which will be communicated in a separate forthcoming
`review from DMEPA.
`
`3.2 SPONSOR’S RISK MANAGEMENT PROPOSAL
`
`The sponsor proposes a routine pharmacovigilance strategy with the following two objectives:
`1. To systematically collect adverse events (AE) from multiple sources, and
`2. To conduct real time and periodic medical assessments of single and aggregate cases to
`identify potential safety signals.
`The sponsor plans to submit aggregate reports, i.e. Periodic Safety Update Reports (PSURs), as
`required by regulations.
`
`4 DISCUSSION
`The sponsor’s proposal is consistent with a routine pharmacovigilance program. Based on the e-
`mail communication with the medical officer4 and review of the proposed label, the adverse event
`
`
`2 Proposed Invega® Sustenna™ package insert submitted February 25, 2008. Boxed Warning.
`3 Risperdal® package insert. Titusville, NJ: Janssen, L.P.; 2007.
`4 Email correspondence from Dr. Jing Zhang, medical officer, DPP. Dated June 4, 2008.
`
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`4
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`(b) (4)
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`profile of paliperidone palmitate injection is very similar to the paliperidone oral formulation as
`well as risperidone. None of the approved risperidone products nor the approved paliperidone
`oral formulation employ additional risk management measures beyond routine pharmacovigilance
`and labeling.
`
`5 CONCLUSION
`Routine pharmacovigilance of spontaneous adverse event reporting and routine labeling appears
`appropriate at this time and is consistent with measures employed for other similar drug products
`(risperidone and the approved paliperidone oral formulation).
`
`Should DPP raise further concerns with the risks outlined above or identify additional risks
`associated with paliperidone palmitate warranting more extensive risk mitigation or a formal risk
`evaluation and mitigation strategy (REMS), please send a consult to OSE Division of Risk
`Management.
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`5
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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/
`---------------------
`Mary Dempsey
`7/31/2008 07:44:58 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Claudia Karwoski
`7/31/2008 08:49:03 AM
`DRUG SAFETY OFFICE REVIEWER
`
`