Download APPENDIX C

APPENDIX C
NDA 21-223
NovartisPharmaceuticals
Corporation
Attention: Ms. EileenRyan
AssociateDirector,Drug RegulatoryAffairs
59Rout.e10
EastHanover,NJ 07936 1O&O
Dear Ms. Ryan:
Pleaserefer to your new drug applicationfr(rDA) datedandreceivedDecember21,1999,submitted
underse&on 505(b)of the FederalFood,Drug, andCosmeticAct for &m&a (zdedrenic acid for
hjection).
We acknowledgereceiptof your submissionsdatedSeptember14,2 1f and29, November6, and
Deeember13 and2 1I 2oo0,andFebruaryf 9, March 26 and29, April 2,9,11 I 25, and 30, May 3,
June1 and 12,July $0,andAugust3,17, a-nd2442001.Your submissionof Februaryt9,2001,
constituteda completeresponseto our September2 f t 21300,
actionfetter.
This new drng appficationprovidesfor theuse of ikmeta (zofedronicacid for injection)for the
treatmentaf hypercalcemiaof malignancy,
We have~rnJ&ed the review CtE
this application,as amended,and havecuncludedthat adequate
informationhasbeenpresentedb demonsttabthat the drugproductis safeand effectivefar useas
rewmmendedirt the agreed-q3cndrai%~a~~~ng
text submittedAugust20,2QOl,vial labelssubmitted
August3,200f i andcartonlabeh~submittedAugust20,2001t for the t&&meat of hprcakemia of
matignsncvwhenadminkteredasa 4 mg doseoverno lessthan 15 minutes. Accordingfy,the
appficationis approvedeffectiveon the dateof this letter. The GnaJprintedlabeling(FPL) mustbe
identkat to the submitteddraft iabdng. Marketingthe productwith FPL that is not identicalto the
appruvedlabelingtext may renderthe productmisbrandedandan unapprovednew dmg.
Pleasesubmitthe FPL electronicallyaccordingto the guidancefor industrytitled &~vk&rg
RegulaloryS~bmi&a~ in &%c&vzS~
Formal - NBA (January1999). Afternatively,you may submit
20 papercopiesof the FPL assoonas it is availablebut no moretharr30 daysafter it is printed. Please
individually mountten of t&ecopies011heap-wei~t paperor simitarmaterial. For administrative
putpases,this submissionshoofdbe designated“FFL for approvedNDA 21-223.”Approvalof this
submissionby FDA is not requiredbeforethe labelingis used,
We remindyou of your postma.rketEng
studycommitmentin your submissiondatedAugust 17,2OOf,in
which you agreea0conducta ~h~~~rne~cs andphok
studyof Zometain patients
with impairedrenalfunction. The studymaybe eithersingle-or multipfe-dose.The finaf studyreport
NDA 21-223
Page2
shouldbe submittedwithin one monthof the dateof tbhisletter.
Submitc2’micalprotoeds to your IND for this product. Submitsturdyfinal reportsto this NDA. In
addition,under21 CFR 3 ~4.3~~b~~2~v~~~
and 314.8~~b~~2~~v~~~~
you &c&d in&de a statussummary
of theimminent in your annualreport20this NDA. The statussummaryshouldin&de expected
studycompletionand final report submissiondates,any changesin planssincethe lastannualreport,
and,the numberof patientsenteredVitoeachstudy. AR submissions,
includingsupplements,
relating
to this postmarketingstudycommitmentmustbe prominentfylabeledT%stmarketig Study
Protwds, ‘Tostmsrketfng Study Ffnal ReporP, or “fostmarketfng StyldyCorrespondenc&*
Validationof the regulatorymethodshasnot beeneampleted,At t&epresenttime, it is the poficy of
the Centernot to withholdapprovalbecausethe meththods
arebeingvalidated.Never&eless,we expect
your continuedcooperationto resolveanyproblemsthat maybe identified.
As of April I, f 999, all appheationsfor new activeingredients,new dosageforms,new indications,
new mutesof a~~n~~~t~on,and new dosingregimensare requiredto cantainan assessment
of the
safetyandeffeetive~ess
afthe pr0duetin @atriG patientsnr&8sthis requ&ementis waivedor
deferred(63 FR 65632). Oa November30, $999,you requesteda waiver f&m conductingpediatric
studiesfor the indication,treatmentof b~er~a~~rn~aof malignancy.The waiver wasgrantedfor
patientaages0 - I6 ye- on February25,2000.
Pleasesubmitthreecopiesof the introductorypromotianalmaterialsthat you proposeto usefor this
product.AH proposedmaterialsshouldbe submittedin draft or mmk-up form, not tInal print. Please
sendonecopy ta the Division of MetabolicandEndocrineDrug Produetsand two copiesof buth the
promotionalmaterialsand the packageinsertdirectlyto:
Divisionof Drug Marketing,Advertising,and ~~~u~~ti~n~, RFD-42
FoobandDrug Administration
5600FishersLane
Roctilfe, Maryland 20857
Pieasesubmitonemarketpackageof the drug productwhenit is availabfe.
We remindyou that you mat complywith the requirementsfur aa approvedNDA set for& under
21 CFR3tQ.gOand314.81.
In additionwe haveconeludedthat theproposalto reGommtrtdan g-mg intravenuuadosefor patients
requiringretnzatment
of hyperealcemia
of rna~~~an~y
is approvable. The similar responserates
fellowing singleinfusionsof Qrng and 8-mg,the Lackof a compariscm
arm in the retreatmentpcntien
of the two ~~n~~l~ed~
mubi~~nterstudies,ad the increasedrisk of renaltoxicity with the g-nagdose
comparedto the 4-rugdose,de not supportthe safetyand ef&acy of the g-mg dosefor retreatment,A
studydemonstrating
that the g-mg doseis superiorto the 4-mg dosein patientsrequiringretre&nent
anddatato supporttbe safetyof the g-mg dosewcmldbe necessaqto supportapprovalof the g-mg
dasefor patientawho requireretreatmentfar bypereafeemia
ofmalignaney~
Within 10 daysafter the dateof this letter,you are requiredto amendthe application,notify us of your
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