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

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`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`
` NDA No. 22-264
`
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
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`NDA NUMBER:
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`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
`PRODUCT:
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`INTENDED CLINICAL POPULATION:
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`SPONSOR:
`AGENT:
`
`22-264 Resubmission
`Sponsor’s responses to FDA’s Complete Response
`letter of August 25, 2008
`
`0000
`February 3, 2009
`Paliperidone palmitate (Invega® Sustenna™)
`adults with schizophrenia (acute and maintenance
`treatment)
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`Johnson & Johnson Pharmaceutical R & D,
`L.L.C., 1125 Trenton-Harbourton Road, P.O. Box
`200, Titusville, NJ 08560
`electronic submission
`Division of Psychiatry Products (HFD-130)
`Elzbieta Chalecka-Franaszek, Ph.D.
`Aisar Atrakchi, Ph.D.
`Barry Rosloff, Ph.D.
`Thomas Laughren, M.D.
`Kimberly Updegraff, R.Ph.
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`DOCUMENTS REVIEWED:
`REVIEW DIVISION:
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`PHARM/TOX REVIEWER:
`PHARM/TOX TEAM LEADER:
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
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`
`Date of review submission to Division File System (DFS): June 17, 2009
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`1
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` NDA No. 22-264
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`Content of submission:
`
`This is a resubmission to the NDA 22-264 addressing comments raised by the Division in
`the Complete Response letter dated August 25, 2008 including items agreed to during the
`Sponsor’s meeting with the Division on November 21, 2008.
`
`In this resubmission reference is made to the original NDA 22-264 for paliperidone
`palmitate
` that was submitted by Johnson & Johnson Pharmaceutical
`Research and Development, L.L.C. on October 25, 2007 for the treatment of
`schizophrenia in adults on behalf of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`Reference is also made to the Division’s Complete Response letter dated August 25, 2008
`and to Sponsor’s meeting with the Division on November 21, 2008 to discuss the content
`of this resubmission.
`
`During the November 21, 2008 meeting, the Sponsor indicated that the paliperidone
`palmitate development program included the use of a clinical 150 mg eq. dose of
`paliperidone palmitate. According to the Sponsor, the nonclinical development program
`provided in the submitted NDA 22-264 was conducted to support the 150 mg eq. dose in
`addition to the 25 to 100 mg eq. dose range. No additional nonclinical studies were
`conducted to further support the 150 mg eq. dose, and no further information or analyses
`were planned to be included in the resubmission;
`
`
`
`
` The Division
`confirmed acceptability of this plan for the Sponsor’s resubmission.
`
`Therefore, no new pharmacology/toxicology data were submitted and/or reviewed at
`present.
`
`
`
`Executive Summary
`
`
`I.
`
`
`Recommendations
`
`A. Recommendation on approvability:
`
`The nonclinical studies submitted in support of the original NDA 22-264 for paliperidone
`palmitate were sufficient to recommend approval of the application from a
`pharmacology/toxicology perspective provided the Sponsor revise the drug substance
`
`specification limiting the dose of each of the genotoxic impurities
` and
`to no more than
` µg per injection
` ppm). This recommendation was communicated
`to the Sponsor in the CMC information request letter dated April 24, 2009.
`
`
`B. Recommendation for nonclinical studies:
`
`No additional nonclinical studies are recommended.
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`2
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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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`(b) (4)
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`

`

`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
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`C. Recommendations on labeling:
`
` NDA No. 22-264
`
`
`The Sponsor has accepted the labeling changes proposed by the Division based on the
`recommendations of the pharmacology/toxicology reviewer in sections 8.1 (Pregnancy),
`12.1 (Mechanism of action), 12.2 (Pharmacodynamics), and 13.1 (Carcionogenesis,
`Mutagenesis, Impairment of Fertility).
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`The following labeling text is a version that includes changes proposed by the Division
`and Sponsor and should be considered as final with the exception of paliperidone
`palmitate units (mg eq.) which are still under consideration by the Division.
`
`8.1 Pregnancy
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`In studies in pregnant rats and rabbits in which paliperidone was given orally during the
`period of organogenesis, there were no increases in fetal abnormalities up to the highest
`doses tested (10 mg/kg/day in rats and 5 mg/kg/day in rabbits, which are each 8 times the
`maximum recommended human [12 mg/day] of orally administered paliperidone
`[INVEGA®] on a mg/m2 basis).
`
`In rat reproduction studies with risperidone, which is extensively converted to
`paliperidone in rats and humans, increases in pup deaths were seen at oral doses which
`are less than the maximum recommended human dose of risperidone on a mg/m2 basis
`(see Risperdal package insert).
`
`There are no adequate and well controlled studies of INVEGA® SUSTENNATM
` in
`pregnant women. INVEGA® SUSTENNATM
` should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
`
`Use of first generation antipsychotic drugs during the last trimester of pregnancy has
`been associated with extrapyramidal symptoms in the neonate. These symptoms are
`usually self-limited. It is not known whether paliperidone, when taken near the end of
`pregnancy, will lead to similar neonatal signs and symptoms.
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`3
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`(b) (4)
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`(b) (4)
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` NDA No. 22-264
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`12.1 Mechanism of Action
`
`Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)].
`Paliperidone is the major active metabolite of risperidone. The mechanism of action of
`paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has
`been proposed that the drug's therapeutic activity in schizophrenia is mediated through a
`combination of central dopamine Type 2 (D2) receptor antagonist and a serotonin Type 2
`(5HT2A) receptor antagonist.
`
`12.2 Pharmacodynamics
`
`Paliperidone is a centrally active dopamine Type 2 (D2) receptor antagonist and a
`serotonin Type 2 (5HT2A) receptor antagonist. Paliperidone is also active as an antagonist
`at α1 and α2 adrenergic receptors and H1 histaminergic receptors, which may explain
`some of the other effects of the drug. Paliperidone has no affinity for cholinergic
`muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)-
`and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Carcinogenesis
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` NDA No. 22-264
`
`Summary of nonclinical findings
`
`
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`Mutagenesis
`Paliperidone palmitate showed no genotoxic potential in the Ames reverse mutation test
`or the mouse lymphoma assay. No evidence of genotoxic potential for paliperidone was
`found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo rat
`micronucleus test.
`
`Impairment of fertility
`Fertility studies of paliperidone palmitate have not been performed.
`
`In a study of fertility conducted with orally administered paliperidone, the percentage of
`treated female rats that became pregnant was not affected at doses of paliperidone of up
`to 2.5 mg/kg/day. However, pre- and post-implantation loss was increased, and the
`number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused
`slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg,
`which is half of the maximum recommended human dose (12 mg/day) of orally
`administered paliperidone (INVEGA®) on a mg/m2 basis.
`
`The fertility of male rats was not affected at oral doses of paliperidone of up to 2.5
`mg/kg/day, although sperm count and sperm viability studies were not conducted with
`paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively
`converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg)
`resulted in decreases in serum testosterone and in sperm motility and concentration.
`Serum testosterone and sperm parameters partially recovered, but remained decreased
`after the last observation (two months after treatment was discontinued).
`
`II.
`
`
`A. Brief overview of nonclinical findings
`
`
`Please see Dr. Chalecka-Franaszek’s pharmacology/toxicology review of the NDA 22-
`264 for details.
`
`
`B. Nonclinical safety issues relevant to clinical use
`
`
`The nonclinical studies submitted in support of the original NDA 22-264 for paliperidone
`palmitate were sufficient to recommend approval of the application from a
`pharmacology/toxicology perspective provided the Sponsor sets a specification limiting
`the dose of each of the genotoxic impurities
` and
`
` to
`no more than
` µg per injection
` ppm).
`
` are present in the synthesis batches of
` and
`Two genotoxic impurities
` showed genotoxic properties in an in
` and
`paliperidone palmitate. Both
`vitro Ames bacterial reverse mutation test and an in vitro chromosome aberration assay in
`human lymphocytes. Previous batches have contained impurities
`and
`
`up to levels of and
` ppm, respectively. According to the Sponsor, these values are
`well below the concentration limit of
` calculated on the basis of the maximum
`
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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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`(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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`(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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`(b) (4)
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`

`

` NDA No. 22-264
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`recommended human dose (MRHD) of 100 mg eq. of paliperidone palmitate per person
`given as a monthly i.m. injection (corresponding with 100 mg eq./28 days or
`approximately
`./person/day), and the Threshold of Toxicological Concern
`(TTC) of 1.5 µg/person/day. However, this reviewer concluded in the review of the
`original application that the acceptance criteria for these two impurities in the drug
`substance should be equal to or less than
` ppm because this value should be calculated
`based on monthly (not daily) dose.
`
`In a Complete Response letter dated August 25, 2008, the Sponsor was informed about
`these recommendations and asked to “establish an acceptance criteria equal to or less
`than
` ppm for the two genotoxic impurities,
` and
`”.
`
`It was noted that the Sponsor is reproducibly capable of producing “crude” batches of
`paliperidone palmitate with undetectable
` ppm) levels of both impurities. Therefore,
`the Sponsor should, as the first principle, control both impurities at levels as low as
`reasonably practicable (please see Dr. Chalecka-Franaszek’s pharmacology-toxicology
`review of the NDA 22-264 dated August 25, 2008 for further information regarding
`impurities).
`
`In this resubmission, new clinical data to support the 150 mg eq. dose strength were
`submitted. Based on this change in the MRHD it is recommended at this time that the
`Sponsor sets a specification limiting the dose of each of the genotoxic impurities
` and
` to no more than
` per injection
`
`
`
`In the CMC information request letter dated April 24, 2009, the following
`recommendations were conveyed to the Sponsor:
`
`
`1. The presence of a significant level of impurities
` in sterile
` and
`grade drug substance lots is unlikely as both species are likely to undergo
` Provide evidence that the
` and
`of
` are present at less than
` ppm in the drug substance.
`2. Revise the drug substance specification to include a limit of NMT
` ppm for
`potential genotoxic impurities
` and
` and their respective
`
`3. Provide full details of the analytical method used to detect the potential genotoxic
`impurities (
` and
` and their respective esters).
`
`
`
`
`Please see the CMC letter and CMC review for full list of recommendations and
`information.
`
`The Sponsor responded in a submission dated May 22, 2009. The reviewing chemist will
`evaluate the adequacy of the Sponsor’s response. Please see the CMC review for
`additional information.
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`6
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`(b)
`(4)
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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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`

`

`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`
` NDA No. 22-264
`
`2.6.1 INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22-264
`Review number: 2
`Sequence number/date/type of submission: 0000/February 3, 2009/NDA resubmission
`Information to sponsor: Yes ( x ) No ( )
`Sponsor and/or agent: SPONSOR: Ortho-McNeil-Janssen Pharmaceuticals Inc.
`AGENT: Johnson & Johnson Pharmaceutical R & D, L.L.C., 1125 Trenton-Harbourton
`Road, P.O. Box 200, Titusville, NJ 08560
`Manufacturer for drug substance: Janssen Pharmaceutical Ltd., Cork, Ireland and
`Janssen Pharmceutica N.V., Beerse, Belgium
`Reviewer name: Elzbieta Chalecka-Franaszek, Ph.D.
`Division name: Division of Psychiatry Products
`
`HFD #: 130
`
`Review completion date: June 17, 2009
`
`Drug:
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`Trade name: INVEGA SUSTENNA
`Generic name: paliperidone palmitate
`
`Code name: JNJ16977831; R092670
`Chemical name: (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-
`piperidinyl]ethyl]-6, 7, 8, 9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-
`a]pyrimidin-9-yl hexadecanoate
`CAS registry number: 199739-10-1
`Molecular formula/molecular weight: C39H57FN4O4/664.9
`Structure: Chemical structures of paliperidone palmitate and paliperidone and
`ester hydrolysis of paliperidone palmitate are shown below:
`
`
`
`
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`
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`Relevant INDs/NDAs/DMFs: IND 67,356; DMF 20902; NDA 20-272 for Risperdal
`(risperidone), NDA 21-999 for Invega (paliperidone); NDA 22-043 for Invega
`
`
`
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`7
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`

`

` NDA No. 22-264
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`(paliperidone; for prevention of recurrence of schizophrenia), NDA 21-346 for Risperdal
`Consta (risperidone i.m.)
`
`Drug class: Paliperidone palmitate injected intramuscularly is hydrolized to
`paliperidone, an atypical antipsychotic drug, which is an antagonist on serotonin 5-HT2A
`and dopamine D2 receptors.
`
`Intended clinical population: adults with schizophrenia
`
`Clinical formulation: An aqueous nanosuspension for injection with low solubility
`leading to extended release properties; strength: 25, 50, 75, 100, and 150 mg eq.
`
`Route of administration: intramuscular injection (i.m.)
`
`Studies reviewed within this submission: none
`
`This resubmission includes a “Complete Response Document” that addresses the
`comments raised by the Division in the Complete Response letter dated August 25, 2008.
`It also includes a Chemistry, Manufacturing, Control (CMC) reviewer’s guide that
`provides an overview of Module 3 updates presented in this Resubmission. As discussed
`during the November 21, 2008 meeting, this submission includes resubmission of the
`Pediatric Waiver request, an update to include Cork, Ireland, as an additional sterile drug
`substance manufacturing site and new clinical data to support the 150 mg eq. dose
`strength and the proposed initiation dosing regimen. It also contains a Safety Update
`document, patient case report forms, clinical study reports for R092670-PSY-3007 and
`R092670-PSY-3001, summaries of published clinical safety data, and updated draft
`Package Insert and package labeling. The package labeling also includes an Instruction
`For Use leaflet
` that is planned as a packaging component
`within each sample carton. That this updated draft labeling is intended to replace the
`labeling provided in the original NDA submission.
`
`All pivotal studies submitted to the NDA 22-264 except toxicology and other studies
`were reviewed previously by Dr. Aisar Atrakchi under INDs 67,356 for paliperidone
`palmitate and Dr. Elzbieta Chalecka-Franaszek under the NDA 21-999 for paliperidone.
`Their reviews are available in the Division’s file and DARRTS. In addition, the
`summaries of pivotal studies and conclusions taken directly from Dr. Atrakchi’s and
`Chalecka-Franaszek’s reviews are included in relevant sections of the review of the NDA
`22-264.
`
`Studies not reviewed within this submission: none
`
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`8
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`(b) (4)
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`

`

`
`
` NDA No. 22-264
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS
`
`Conclusions: Please see Executive Summary on page 2 of this review.
`
`Unresolved toxicology issues (if any): Two genotoxic impurities
`and
`are present in the
` of paliperidone palmitate. Please see page 5 of this
`review for additional information.
`
`Recommendations: The nonclinical studies submitted in support of the original NDA
`22-264 for paliperidone palmitate were sufficient to recommend approval of the
`application from a pharmacology/toxicology perspective provided the Sponsor revise the
`drug substance specification limiting the dose of each of the genotoxic impurities
` and
` to no more than
` µg per injection
` ppm). This
`recommendation was communicated to the Sponsor in the CMC information request
`letter dated April 24, 2009. The reviewing chemist will evaluate the adequacy of the
`Sponsor’s response. Please see the CMC review for additional information.
`
`
`
`
`
`Reviewer Signature: Elzbieta Chalecka-Franaszek, Ph.D. (signed electronically)
`
`Supervisor Signature Aisar Atrakchi, Ph.D. (team leader) (signed electronically)
`
`Concurrence Yes _ x__ No ___
`
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`9
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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/
`---------------------
`Elzbieta Chalecka-Franaszek
`6/17/2009 12:08:57 PM
`PHARMACOLOGIST
`
`Aisar Atrakchi
`6/18/2009 08:58:25 AM
`PHARMACOLOGIST
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
`
`
`
`
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`
`
`
`
`NDA NUMBER:
`
`
`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
`PRODUCT:
`
`
`
`INTENDED CLINICAL POPULATION:
`
`
`
`
`
`
`22-264
`0000
`10/26/2007
`Paliperidone palmitate (Invega Sustenna)
`adults with schizophrenia
`
`
`
`SPONSOR:
`AGENT:
`
`
`Ortho-McNeil-Janssen Pharmaceuticals Inc.
`Johnson & Johnson Pharmaceutical R & D,
`L.L.C. 1125 Trenton-Harbourton Road, P.O. Box
`200, Titusville, NJ 08560
`electronic submission
`Division of Psychiatry Products (HFD-130)
`Elzbieta Chalecka-Franaszek, Ph.D.
`Aisar Atrakchi, Ph.D.
`Thomas Laughren, M.D.
`Kimberly Updegraff, R.Ph.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DOCUMENTS REVIEWED:
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`
`Date of review submission to Division File System (DFS): July 31, 2008
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`
`TABLE OF CONTENTS
`
`
`
`EXECUTIVE SUMMARY .............................................................................................. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................. 16
`
`2.6.1 INTRODUCTION AND DRUG HISTORY................................................................. 16
`
`2.6.2 PHARMACOLOGY....................................................................................................... 18
`2.6.2.1
`Brief summary ...................................................................................................................... 18
`2.6.2.2
`Primary pharmacodynamics ................................................................................................. 18
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................. 18
`2.6.2.4
`Safety pharmacology ............................................................................................................ 18
`2.6.2.5
`Pharmacodynamic drug interactions..................................................................................... 19
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 19
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 19
`2.6.4.1
`Brief summary ...................................................................................................................... 19
`2.6.4.2
`Methods of Analysis............................................................................................................. 23
`2.6.4.3
`Absorption ............................................................................................................................ 23
`2.6.4.4
`Distribution........................................................................................................................... 23
`2.6.4.5
`Metabolism........................................................................................................................... 23
`2.6.4.6
`Excretion............................................................................................................................... 23
`2.6.4.7
`Pharmacokinetic drug interactions........................................................................................ 23
`2.6.4.8
`Other Pharmacokinetic Studies............................................................................................. 23
`2.6.4.9
`Discussion and Conclusions ................................................................................................. 23
`2.6.4.10
`Tables and figures to include comparative TK summary ................................................. 23
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY............................................... 23
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`2.6.6 TOXICOLOGY............................................................................................................... 32
`2.6.6.1
`Overall toxicology summary ................................................................................................ 32
`2.6.6.2
`Single-dose toxicity .............................................................................................................. 37
`2.6.6.3
`Repeat-dose toxicity ............................................................................................................. 40
`2.6.6.4
`Genetic toxicology................................................................................................................ 53
`2.6.6.5
`Carcinogenicity..................................................................................................................... 60
`2.6.6.6
`Reproductive and developmental toxicology........................................................................ 83
`2.6.6.7
`Local tolerance ..................................................................................................................... 96
`2.6.6.8
`Special toxicology studies .................................................................................................... 98
`2.6.6.9
`Discussion and Conclusions ............................................................................................... 101
`2.6.6.10
`Tables and Figures.......................................................................................................... 109
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`2.6.7 TOXICOLOGY TABULATED SUMMARY ............................................................ 109
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`OVERALL CONCLUSIONS AND RECOMMENDATIONS............................................. 109
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`APPENDIX/ATTACHMENTS ............................................................................................... 109
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`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
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` NDA No. 22-264
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`EXECUTIVE SUMMARY
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`I.
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`Recommendations
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`A. Recommendation on approvability:
`The preclinical studies submitted in support of the NDA for paliperidone palmitate are
`sufficient to recommend approval of the application from a pharmacology/toxicology
`perspective provided the Sponsor sets a specification limiting the dose of each of the
`genotoxic impurities
`and
` to no more than
` per injection
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`ppm). We note that the Sponsor is reproducibly capable of producing “crude” batches of
`paliperidone palmitate with undetectable (< 1 ppm) levels of both impurities. Therefore,
`the Sponsor should, as the first principle, control both impurities at levels as low as
`reasonably practicable (please see page 15 of the Executive Summary for further
`information regarding impurities).
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`B. Recommendation for nonclinical studies:
`No additional preclinical studies are recommended.
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`C. Recommendations on labeling:
`Note to the Sponsor: We have deleted the safety factor of 27 from the “Pregnancy”
`section and the safety factor of 1.7 from the “Impairment of fertility” section of the
`labeling. To help determine the validity of comparing the animal oral doses with i.m.
`doses in humans, please provide comparisons of exposure in humans receiving the
`maximum recommended oral and i.m. doses.
`
`Note: All the doses of paliperidone palmitate are expressed as mg eq./kg, referring to mg paliperidone
`(base) equivalents (eq.)/kg body weight (f = 1.56). In the plasma and tissue samples, concentrations of
`paliperidone were measured unless stated otherwise.
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`8.1 Pregnancy
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`Sponsor’s proposal:
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`3 pp withheld in full immed. after this page as (b)(4) draft labeling.
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`

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` NDA No. 22-264
`
`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
`
`paliperidone. There were no separate primary pharmacodynamics, secondary
`pharmacodynamics, safety pharmacology, or pharmacodynamic drug interaction studies
`submitted to the NDA 22-264 for paliperidone palmitate since pharmacology profile of
`paliperidone was evaluated during the development of p.o. paliperidone. Please see
`pharmacology/toxicology reviews of the NDA 21-999 for paliperidone (INVEGA) for
`more information.
`
`General toxicology: The nonclinical toxicology program in support of paliperidone
`palimitate intramuscular formulation consisted of single-dose toxicity studies in dogs,
`pigs, and minipigs, repeat-dose toxicity studies in rats (3 months and two 6 months
`studies), dogs (6 months and 12 months studies), and minipigs (3 months study). These
`studies addressed both local tolerance at the i.m. injection site and systemic toxicity.
`Moreover, several nonclinical toxicology studies were previously conducted with p.o.
`paliperidone. The NDA 22-264 for i.m. paliperidone palmitate cross-references the
`toxicology study reports and nonclinical summaries submitted previously under NDA 21-
`999 for p.o. paliperidone (INVEGA). All pivotal toxicity studies were conducted in full
`compliance with the OECD Good Laboratory Practice guidelines.
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`Rats: In the 3 months and two 6 months repeat-dose toxicity studies in rats, paliperidone
`palimitate was injected i.m. once monthly at 0, 20 (LD), 80 (MD), and 160 mg eq./kg
`(HD). Test article related mortalities occurred only in two HD females in the 3 months
`study; all animals survived in the 6 months studies. The following description is based on
`observations in the 6 months study in rats. However, in general, test article related effects
`were comparable in all studies. Clinical signs included ptosis and sedation at all dose
`levels. Body weight and body weight gain decreased in males and increased in females,
`with the greatest increases in the LD female group. Changes in food consumption in
`general paralleled changes in body weights in both sexes. Test article related changes in
`hematology and clinical chemistry parameters that reached statistical significance were
`small and may not have any toxicological significance. Mean weight of several
`organs/tissues were affected and correlated with histopathology findings: spleen weight
`was significantly and dose dependently increased in both sexes, kidney weight was
`significantly increased in HD males (but decreased in LD males), absolute adrenal weight
`was significantly and dose dependently increased in males (but relative weight decreased
`in females), and gonads weight of females were significantly reduced in the MD and HD
`groups compared to control. Gross morphological exam showed a white powdery deposit
`at injection site in all dose groups of both sexes. Mammary gland stimulation was
`observed in all female drug groups and occasionally in males. Histopathological exam
`revealed findings in the following organs/tissues: injection site, adrenals, kidneys,
`mammary glands, ovaries, prostate, seminal vesicles, spleen, testes, and pituitary. Similar
`to other toxicity studies, findings at injection site were those of inflammatory
`immunoreactive changes. In the adrenals, swollen cortical cells of zona fasiculata and
`reticularis were markedly increased in all male drug groups compared to control.
`Increased dilation of cortical renal collecting tubules was observed in HD males and
`females, and in all female drug groups relative to corresponding controls. There was
`female appearance (alveolar development) with increased secretion observed in
`mammary glands in all male drug groups; similarly, alveolar development and secretion
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` NDA No. 22-264
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`Reviewer: Elzbieta Chalecka-Franaszek, Ph.D.
`
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`were increased in mammary glands of all female groups compared to controls. Focal
`hyperplasia of alveolar epithelium of mammary glands was seen in MD and HD males
`and in all female test article groups. Reduced cyclic activity was noted in the uterus. Male
`accessory sex organs showed low epithelium of ventral prostate, seminal vesicles, and
`coagulation gland. Increase in prolactin-immunoreactivie cells was observed in males.
`However, a decrease in these cell was seen in females. Serum prolactin was increased in
`all male test article treated groups and in HD females. The MTD was achieved in this
`study and in all repeat-dose toxicity studies in rats. Based on these results, the NOEL
`could not be determined due to presence of injection site reactions as well as other effects
`including histopathology at the LD of 20 mg eq./kg. However, 20 mg eq./kg may be
`considered the NOAEL.
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`Dogs: In the 6 months and 12 months repeat-dose toxicity studies in dogs, paliperidone
`palimitate was injected i.m. once monthly at 0, 5 (LD), 20 (MD), and 80 (HD) mg eq./kg.
`However, the test article related injection site reactions led to decreasing the doses of 20
`and 80 mg eq./kg to 10 and 40 mg eq./kg, respectively. The findings from pivotal 12
`months repeat-dose toxicity study are described below. However, in general, test article
`related effects were comparable in all studies in dogs. The monthly injections were
`administered in the m. semimembranosus/m. semitendinosus of both hind legs using a 21
`G needle. From the second dose onwards, the injections were given in the m. biceps
`femoris of both hind legs, because the m. semitendinosus m. semimembranosus were not
`healed yet.
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`Transient sedation was noted dose-dependently in all test article dosed groups. An acute,
`transient anaphylactic reaction (i.e., swollen eyelids, head and paws, red spots, sedation,
`decubitus, cyanosis and hyperpnea), probably related to the polysorbate 20 present in the
`vehicle, was seen in all animals of the vehicle and HD group after each injection. Some
`animals also had a slight anaphylactic reaction (i.e., swollen eyelids and/or sedation) after
`the first dose of 20 mg eq./kg/month. Slight decreases in body weight and food
`consumption were noted after single doses of 20 or 80 mg eq./kg/month.
`There were no treatment-related effects on ECG, heart rate, ophthalmoscopy, and
`urinalysis. Systolic and diastolic blood pr