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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 22264/S-002
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`Attention: Rodney Malchow, J.D., Associate Director
`Regulatory Affairs
`920 Route 202
`P.O. Box 300
`Raritan, NJ 08869
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`Dear Mr. Malchow:
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`Please refer to your Supplemental New Drug Application (sNDA) dated July 21, 2010, received
`July 21, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Invega Sustenna (paliperidone palmitate) extended-release injectable suspension 37
`mg, 78 mg, 117 mg, 156 mg, and 234 mg.
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`We acknowledge receipt of your amendments dated December 9, 2010, February 23, 2011, and
`May 27, 2011.
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`This “Prior Approval” supplemental new drug application proposes the addition of drug
`interaction information and juvenile rat and dog toxicity information as follows (in red):
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`7.1 Potential for INVEGA to Affect Other Drugs
` Pharmacokinetic interaction between INVEGA® SUSTENNA® and lithium is unlikely.
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`In a drug interaction study, co-administration of oral paliperidone extended-release tablets
`(12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to
`2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of
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` valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of
`valproate had comparable valproate average plasma concentrations when oral paliperidone
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` extended-release tablets 3-15 mg/day was added to their existing valproate treatment.
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`7.2 Potential for Other Drugs to Affect Invega Sustenna
` Pharmacokinetic interaction between lithium and INVEGA® SUSTENNA® is unlikely.
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`8.4 Pediatric Use
`In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a
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`reversible impairment of performance in a test of learning and memory was seen, in females
`only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of
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`Reference ID: 2961342
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` NDA 22264/S-002
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`Page 2
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`paliperidone similar to those in adolescents. No other consistent effects on neurobehavioral or
`reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which
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`produced plasma levels of paliperidone 2-3 times those in adolescents.
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` Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized
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`to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone
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` length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma
`levels (AUC) of risperidone plus paliperidone which were similar to those in children and
`adolescents receiving the maximum recommended human dose of risperidone. In addition, a
`delay in sexual maturation was seen at all doses in both males and females. The above effects
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` showed little or no reversibility in females after a 12-week drug-free recovery period.
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`The long-term effects of paliperidone on growth and sexual maturation have not been fully
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`evaluated in children and adolescents.
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`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert), 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.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
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`Reference ID: 2961342
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` NDA 22264/S-002
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`Page 3
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` REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, please email Ann Sohn, Regulatory Project Manager, at
`ann.sohn@fda.hhs.gov.
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`Sincerely,
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`{See appended electronic signature page}
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`Thomas Laughren, M.D.
`Director
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`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 2961342
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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/
`----------------------------------------------------
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`THOMAS P LAUGHREN
`06/15/2011
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`Reference ID: 2961342
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