Re Docket No. 2002P-012OCPl and SUP 1

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					                 E
  DEPARTMENT OF H’                  & HUMAN SERVICES                         0          Public Health Service



                        AUG 9 2005                                                      Food and Drug Administration
                                                                                        Rockville MD 20857

                                                                   3 ’ 5 6       5     AUG17      p 1   158
  Sidney M. Wolfe, M.D.
  Elizabeth Barbehenn, Ph.D.
  Larry D. Sasich, Pharm.D., M.P.H., FASHP
  Public Citizen Health Research Group
  1600 20th Street, N.W.
  Washington, D.C. 20009- 100 1
                                        Re: Docket No. 2002P-012O/CPl and SUP 1

  Dear Drs. Wolfe, Barbehenn, and Sasich:

  This responds to your citizen petition, dated March 19,2002 (Petition), requesting that
  the Food and Drug Administration (FDA) remove Meridia (sibutramine) from the
  market because of adlverse events associated with the drug. It also responds to the
  supplement you subrnitted on September 3,2003 (Supplement), updating the adverse
  event data for sibutramine covering the 1&month period subsequent to your petition
  (October 1,2001, through March 3 1,2003). The supplement also includes new
  information on fetal <adverseevents. For the reasons discussed below, your petition is
  denied. However, we continue to monitor the safety profile of sibutramine and have
  updated the risk management program for this drug product.

  I.      BACKGROUND

  The Agency approve:d Knoll Pharmaceuticals’ (Knoll) new drug application (NDA) for
  sibutramine (5 milligmms (mg), 10 mg, and 15 mg) for the management of obesity,
  including weight loss and the maintenance of weight loss, in November 1997 (NDA 20-
  632).’ Sibutramine is approved in 72 countries and marketed in 65 countries
  worldwide.2

  In March 2002, the Italian Ministry of Health temporarily suspended the marketing
  license for sibutramine in response to reports of serious adverse reactions, including two
  fatalities. Based on this experience, the Italian health authorities requested that the
  European Agency for the Evaluation of Medicinal Products’ Committee for Proprietary
                                                                              s
  Medicinal Products (CPMP) provide an opinion on whether sibutramine’ marketing
  authorization should be maintained, changed, suspended, or withdrawn.3


  ’ Abbott Laboratories (Abbott) acquired Knoll Pharmaceuticals on March 2,200 1, and currently holds the
  NDA for Meridia.
  ’ Mexico was the fast country to approve sibutramine, in November 1997. In January 1999, Germany
  became the first European country to approve sibutramine. The 10-mg and 1%mg once-daily doses are
  the most commonly marlceted doses worldwide. With the exception of a few countries in Central
  prica,    the 20-mg dose of sib&amine has not been approved.
    Committee for Proprietary Medicinal Products, Opinion Following an Article 3 1 Referral. Sibutramine,
  December 2,2002, available on the Internet at httn://www.emea.eu.int/Ddfs/human/referral/45 1402en.ndf.




2002Mx20
Docket No. 2002P-O12O/CPl

After reviewing availableefficacy and safety data,including the casesreportedin Italy,
the CPMP rendereda favorableopinion on June27,2002, and recommended the    that
marketing authorizationfor sibutraminebe maintained. On August 28,2002, the Italian
                                         s
Ministry of Health reinstatedsibutramine’ marketinglicense.

You submitteda petition requestingthat FDA removesibutraminefrom the U.S. market
basedon the eventsin Italy, other postmarketingadversedrug events,and the FDA
approvalhistory of sibutramine.

II.    DRUG APPROVAL          PROCESS

                                                            s
In the petition, you recountcertain information aboutFDA’ review processfor
sibutramine(Petition at 3). Specifically, you statethat the FDA medical officer
coordinatingthe review of the sibutramineNDA recommended        non-approvalbasedon
an unsatisfactoryrisk-benefit ratio (Petition at 3). You also mention that FDA’ s
Endocrinologicand Metabolic Drugs Advisory Committee(the advisory committee) did
not supportthe approvalof sibutramine(Petition at 5). You claim that a “dangerously
low approvalstandardhas led to needless     deathsand injuries”(Petition at 5). As
demonstrated                                s
               below, we believe that FDA’ review of the NDA for sibutramine
                               and
followed standardprocedures, that the applicationmet the statutoryrequirementsfor
approval.

                                         and
The NDA for sibutramine,a norepinephrine serotoninreuptakeinhibitor with
                                                   s
sympathomimeticactivity, was submittedto the Agency’ Division of Metabolic and
EndocrineDrug Productsin August 1995. The sponsorwas seekingapprovalof 5-mg,
10-mg, 15-mg,20-mg, and 30-mg once-dailydosesof sibutraminefor the treatmentof
obesity.

During the initial regttlatoryreview cycle, the primary medical reviewer expressed
                                s
concernabout sibutramine’effect on blood pressureand eventuallyconcludedthat this
single risk would likely outweigh the documented    benefitsof the drug, which in addition
                                                      improvementsin levels of HDL-
to weight loss itself, at that time, included secondary
cholesteroland triglycerides.

                                         s
Given that the primary reviewing division’ expertisedid not include drugs that affect
blood pressure,a consult on the sibutramineblood pressuredatawas obtainedfrom the
         s
Agency’ Division of Cardio-RenalDrug Products. In a response     datedSeptember11,
                                           that
1996,the consultingdivision acknowledged sibutraminedid causea small pressor
effect, but concludedthat:

                          s                        the
       Were sibutramine’ effects on blood pressure only basis for
       consideringnon-approval,such a decisionwould be a mistake,
       becausepotential long-term benefits of weight reduction could
       outweigh short-termrisks of blood pressureelevation...
                      1
Docket No. 2002P412O/CP

Dr. John Flack, a blood pressureexpertthen at the Bowman Gray School of Medicine,
was retainedby FDA as a consultantand askedto review the sibutramineblood pressure
data. Dr. Flack agreedthat the drug did increaseblood pressureby an averageof 1 to 3
mmHg, and while he did not commenton whethersibutramineshould be approved,he
        that                             s
stressed the balanceof sibutramine’risks vs. benefitswould probably be
unfavorableonly in obesepatientswith uncontrolledhypertension,coronary artery
disease,congestiveheart failure, stroke,or cardiacarrhythmias,as theseconditions
would heightenthe odds for adversecardiovascular                              s
                                                   outcomesrelated to the drug’
sympathomimeticactivity.4

              26,                                               s
On September 1996,the Endocrinologicand Metabolic Drug’ Advisory Committee
convenedto publicly evaluatethe datafrom the sibutramineNDA. Eight of the nine
                                          s
committeemembersagreedthat the drug’ effect on blood pressurewas clinically
important; however,all also believedthat sibutraminewas an effective weight loss drug,
                                                                      s
leadingto a nearly evenly split vote on the questionof whetherthe drug’ benefits
outweighedits risks.

Following the advisory committeemeeting,FDA staff met internally and with Knoll on
a numberof occasionsto discussthe pendingsibutramineapplication.Although a wide
rangeof opinions were expressed   aboutthe relative merits and shortcomingsof the drug,
all FDA staff concludedthat sib&amine was an effective obesity agent,using the
                      s
criteria in the Agency’ draft Guidance the Clinical Evaluation of Weight-Control
                                      for
                                                     s
Drugs.’ Furthermore,FDA staff agreedthat the drug’ major risk was its effect on
blood pressure.Discussionthereforefocusedon whetherit was possibleto identify
                                            risk                   s
practical ways to managethe blood pressure such that the drug’ overall risk-benefit
profile would prove favorable.

To this end, we requestedthat Knoll conductadditional, detailedanalysesof the clinical
trial blood pressuredata, which would be consideredduring a secondregulatoryreview
cycle. Theseanalysesconfirmed two important findings that were crucial to renderinga
final regulatorydecision on the sibutramineNDA: (1) the risk for important elevations
in blood pressureincreasednotably with the 20-mg and 30-mg dosesof sibutramine,and
                                    in
(2) the risk for substantialincreases blood pressurewas confined to a relatively small
             of
percentage patientswho could be identified through regularblood pressure
monitoring.



                                                   and
’ Food andDrug Administration,Endocrinologic MetabolicDrugs Advisory Committeemeeting
transcript,September    1996,availableon the Internetat htto:Nwww.fda.eov/ohrms/dockets/ac/meridia.htm.
5This FDA guidance                                                 effective if at leastone of the following
                        statesthat an obesitydrug will be-considered
                                                        the
criteria is satisfied:(1) the meanweight loss between drug-andplacebo-treated        patientsafter oneyear
              is
of treatment at least5 percent,or (2) the proportionof patientswho lose at least5 percentof their
                                              in
weight after oneyear of lreatmentis greater the drug-andplacebo-treated       group. Available on the
Internetat htto://www.fda.aov/cder/euidance/index.htm.


                                                   3
Docket No. 2002P-012O/CPl

In summary,the 26-,month    regulatoryreview of sibutraminewas a deliberative,open,
interactive, and admittedly complex processinvolving multiple FDA scientistsfrom the
Division of Metabolic and EndocrineDrug Productsand the Division of Cardio-Renal
Drug Products,a blood pressureexpert from the Bowman Gray School of Medicine, and
nine membersof the advisory committee.Therewere certainly differencesof opinion
                        s
regardingsibutramine’ overall risk-benefit profile, but all viewpoints and available
data were taken into consideration before renderinga final regulatorydecision on the
NDA.

While sibutraminewas not consideredan appropriate   drug for all obesepatients,such as
thosewith coronary artery disease,FDA ultimately concludedthat when used in
accordance with the approvedlabeling, the benefitsof the lower dosesof sibutramine
would outweigh the potential increaseof blood pressure,which can be monitored and, if
necessary,treated,im appropriatelyselectedobesepatients.

The 5-mg, lo-mg, and 15-mg(but not the 20-mg and 30-mg) once-daily dosesof
                                                                   of
sibutraminewere approvedon November22, 1997,for the management obesity,
                                     of
including weight loss and maintenance weight loss, in obesepatientswith an initial
                                                       of
body massindex > 30 kg/m2 or 127 kg/m2in the presence other risk factors (e.g.,
hypertension,diabetes,dyslipidemia).

The approvedprofessionaland patient labeling includesprominentwarnings that
sibutraminesubstantiallyincreases  blood pressurein somepatientsand that regular
                             is
monitoring of blood pressure requiredwhen prescribingMeridia.6 The labeling also
clearly warns againstthe use of sibutraminein patientswith uncontrolledhypertension
or histories of coronaryartery disease,stroke,heart failure, or cardiac arrhythmia.
III.    PRE- AND POSTMARKE TING ADVERSE EVENTS

You statethat there was evidenceof a safety risk beforeFDA approvalof sibutramine
(Petition at 3). You point out that in pre-approvalclinical trials, subjectsreceiving
sibutramineshoweda significant increasein blood pressure,      heart rate, and abnormal
electrocardiograms.You expressconcernthat blood pressurescreeningmay not prevent
those at risk for dangerous            in
                            increases blood pressurefrom being prescribed
sibutramine.

You correctly statethat data from the pre-approvaltrials indicatedthat sibutramine,
relative to placebo,causeda l- to 3-mmHg meanincreasein blood pressureand a 4- to
5-beat-per-minute                                                         of
                   averageincreasein pulse rate, with a small percentage patients
                                                in
taking sibutramineexperiencinglarger increases blood pressureor pulse rate or both.
                                        s
Thesechangesresult from sibutramine’pharmacodynamic         action inhibiting the
neuronalreuptake0 Pnorepinephrine,   leadingto stimulation of the sympatheticnervous
system.

6 The approved                                                                             vs.
              labelingincludesa tableof the proportionof patientstreatedwith sibutramine placebo
who developedsubstantial          in
                        increases blood pressure  duringthe pre-approval  clinical trials.

                                               4
Docket No. 2002P-0112O/CPl

                           s
Predictably,sibutramine’ stimulation of the autonomicnervoussystem also led more
sibutramine-than placebo-treated  subjectsto developtachycardia,prematureatria1
contractions,prematureventricular contractions(detectedby electrocardiograms),    and
palpitationsduring tlhepre-approvaltrials. Importantly, however,there was no evidence
that theseevents,or any other electrocardiographic  findings, were associatedwith
clinically significant outcomesor had any clinical relevance,as noted by the primary
medical reviewer of the sibutramineNDA.’

        A.      Adverse Event Reporting System(AERS) Reports of Death and
                Other Serious Cardiovascular and Stroke Events

With  respectto posbmarketing    adverseeventsassociated   with sibutramine,you statethat
therehave been397 serious“adversereactions”       reportedto the FDA through the end of
 September 2001 (Petition at 2). Of these397 seriousadverseevents,you statethat 152
patientswere hospitalizedand 29 patientsdied, including 19 with cardiovascularcauses
of death(Petition at 2). In addition, you claim that the reportsindicated arrhythmiain
                                                 you
 143 patients(Petition at 2). In the supplement, updateyour analysisof
                                             at
cardiovascularadverseevents(Supplement 1 to 2). Your updatedanalysisincludesan
additional 30 cardiovasculardeathsreportedfrom October 1,2001, through March 3 1,
2003 (Supplementat 2). You statethat the addition of these30 cardiovasculardeathsin
                                                                           a
just 18 months comparedto the numberin the first 44 monthsrepresents significant
increasein the rate of reports to FDA (Supplement 2).at

             to
In response the regulatory action takenby Italian officials and receipt of your petition
                  the                                    for
and supplement, Agency queriedits AERS database’ (1) domesticreports of all-
causefatalities in patientsexposedto sibutraminereceivedduring the time period
November22, 1997,through August 14,2003 (Petition and Supplement);(2) domestic
fatalities associated.witb a cardiovasculareventduring the time period November22,
1997,through August 14,2003 (Petition and Supplement);(3) domesticnonfatal serious
cardiovascular  eventsin patients exposedto sibutraminereceivedduring the time period
November22, 1997,through August 14,2003 (Petition); and (4) domestic fetal or
pregnancy-related   adverseeventsassociated  with the use of sibutraminereceivedduring
the time period November 22, 1997,throughOctober27,2003 (Supplement).’




                                              s                                  of
’Food andDrug Administration,Medical Officer’ Reviewof the Original Submission NDA 20-632
(sibutraminehydrochloride monohydrate), June1996,availableon the Internetat
httn://www.fda.aov/cder~foi/nda/97/20632 meridia.htm.
              we
’ The numbers cite for all-causedeaths,       due                   and
                                         deaths to cardiovascular strokeevents,andnonfatal
              and                                       you
cardiovascular strokeevents,do not matchthe numbers cite for severalpotentialreasons: the  (1)
AERS search  termsthat we usedmay not be the sameas the termsyou used,(2) we limited our searchto
               and
domesticcases, (3) you did not statewhetherthe numberof casesin your petition arelimited to
uniquepatientsor could include duplicates.
                                                                             s
9 The August 14 andOctober27,2003, datesreflect the cutoff datesof the Agency’ AERS database
queries.
Docket No. 2002P-012OKP1

During the reporting period from November22,1997, through August 14,2003, a total
of 54 domesticreports of deathwere submittedto AERS. As shown in the figure
below,” the numberof reportsof deathin patientsexposedto sibutraminewas highest
during the first 2 yearsof marketing,declinedthereafter,and transiently increased
                                                           s
following the publicity over the Italian Ministry of Health’ temporarysuspension of
              s
sibutramine’ marketing licenseand the submissionof your citizen petition to FDA
requestingthat the drug be removedfrom the U.S. market. Theseare well-known
patternsof post-approvaladverseeventreporting to passivedrug safety surveillance
systemssuch as AERS that reflect changesin the reporting environment(e.g., negative
                                      in
publicity) rather than true increases the incidenceof a specific drug-relatedadverse
event 11,12,1X14

Figure - AERS Reportsof Death in PatientsExposed
         to SibutramineAccording to the Year and Quarterthe Reports
         Were Receivedby FDA
10
 9
 8
 7
 8
 5
 4
 3
 2
 1
 0 ~~
        1998   1999   2000   2001   2002   2003


Of the 54 reports of death,30 were reportedlydue to a cardiovascular    causeincluding,
but not limited to, myocardialinfarction, congestiveheart failure, viral cardiomyopathy,
torsadesde pointe, and suddendeath. The remainingcasesof deathwere secondaryto a
                mix
heterogeneous of conditionsincluding, but not limited to, suicide,motor vehicle
accident,respiratoryfailure, serotoninsyndrome,pulmonaryembolism, and “unknown
cause.”

During the reporting period from November 1997throughAugust 2003, there were a
                                                            and
total of 224 domesticreportsof seriousnonfatal cardiovascular stroke events


                                                            to
lo The figure depictsthe numberof reportsof deathaccording the datethe reportwas receivedby FDA,
not the dateof the death.
                              of
” WeberJCP. Epidemiallogy adverse              to
                                       reactions nonsteroidal  anti-inflammatorydrugs. In Rainsford
                           in
KD, et al., eds.,Advances InflammationResearch,    Vol. 6, New York: RavenPress,1984,Pages1-7.
                                 of
” Hartnell NR, et al. Relplication the Webereffect usingpostmarketing         eventreports
                                                                        adverse
voluntarily submittedto the United StatesFoodandDrug Administration,Pharmacotherapy     2004;
24~743-749.
                                        in                        In
I3Collet JP, et al. Bias ;md confounding pharmacoepidemiology. Strom,BL, ed.,
                          31d
Pharmacoepidemiology., edition,JohnWiley and SonsLtd, West Sussex        PO19 lUD, England,2000,
Pages 765-769.
I4 SachsRM, et al. An evaluationof spontaneous  adverse drugreactionmonitoringsystems. Am JA4ed
1986;suppl5B:49-55.

                                                  6
                      1
Docket No. 2002P412O/CP

submittedto AERS in associationwith sibutramineuse. Like the reports of death,the
seriousnonfatal cardiovascularand strokereportsincluded a broad mix of event terms,
including viral cardiomyopathy,aphasia,cerebrovascular   accident,ventricular
tachycardia,chestpain, palpitations, anaphylacticshock,myocardial infarction, atria1
                                               and
fibrillation, hypotension,cardiacvalve disease, syncope. The pattern of, and
explanationfor, the reportingover time of the nonfatal cardiovascularand stroke events
are similar to those for the fatal cases.

        B.      Interpretation of the AERS Reports of Death and Other Serious
                Cardiovascular and Stroke Events

Passivepost-approv,al drug safety surveillancesystemssuch as AERS are most reliable
                                                                 rare
and useful for detectingsignalsof serious,previously unrecognized, adverse
events.15For example,through passivesurveillance,a signal for hemolytic anemia- a
serious,rare, and unexpected disorder- was detectedin young women taking the
antibiotic temafloxacinfor urinary tract infections.16

In contrast,passivedrug safety reporting systemsarenot well-suited to assessing
                          the
whether a drug increases risk for commonly-occurringadverseeventsin the
population for which the drug is approved.Myocardial infarction, stroke,heart failure,
and arrhythmiasare very common in patientswith obesity.‘           9*20
                                                             7*18,‘ And despitesome
biological/pharmacological  plausibility of a relationshipbetweena sympathomimetic
drug like sibutramineand certain types of cardiacevents,the high backgroundrisk for
such eventsin the obesepopulation renderAERS reportsof cardiovasculareventsin
patientstaking sibutramineof limited value in assessing   whetherthe drug actually
          the
increases risk for fatal or nonfatal cardiovascular    adverseevents.21In this setting
(i.e., where the eventsof concernare associated   with the underlying disease),
epidemiologicalstudieswould also be limited in providing definitive results.

                       of
Moreover, the degreie documentation     includedin the reportsof death and other
seriouscardiovascularand stroke eventsin subjectsexposedto sibutraminevaried
greatly, fkom a single sentencesubmittedby non-healthcare  professionalsto pagesof
detailedmedical histories,lists of concomitantmedications,results of laboratory and



Is KennedyDL, et al. Spontaneous  reportingin the United States. In Strom,BL, ed.,
                         3d
Pharmacoepidemiology, edition,JohnWiley andSonsLtd, West Sussex           PO19 IUD, England,2000,
Pages151-174.
I6 Blum MD, et al. Temafloxacinsyndrome:   review of 95 cases. Clin Znfect Dis, 1994; 18:946-950.
” Eckel RH, et al. Obesityandheartdisease.  Circulation 1997;96:3248-3250.
 *
‘ Must A, et al. The disease                  with
                            burdenassociated overweightandobesity. JAMA 1999;282:1523-
1529.
I9MansonJE, et al. Body weight and mortality amongwomen. N Engl JMed 1999;333:677-685.
                                            risk
2oHuberHB, et al. Obesityas an independent factor for cardiovascular              a
                                                                         disease: 26-yearfollow-up
of participantsin the FraminghamHeart Study. Circulation 1983;67:968-977.
                                            in
2’RodriquezEM, et al. The role of databases drugpostmarketing      surveillance.Phurmucoepidemiol
Drug Safe2001; 10:407-410.

                                                 7
                      1
Docket No. 2002P-012OKP

other specializeddiagnostictests,and autopsyfindings, submittedby physicians.A
                                                          or
sizablenumberof the AERS reportscontainedtwo sentences less of descriptive
                                           the
information. This lack of detail compounded difficult and highly subjectiveprocess
of attemptingto assigndrug causalityto commonly-occurringadverseclinical events.22

For thesereasons,it is not possible,basedon AERS data,to rendera conclusion
                                        the
regardingwhether sibutramineincreases rate of deathor seriouscardiovascularand
stroke events.

IV.    THE SIBUTRAMINE           CARDIOVASCULAFt           OUTCOMES        TRIAL

                                     of             s
An unbiased,objectliveassessment sibutramine’cardiovascular           safety profile,
particularly when used in obesepatientswith known or occult cardiovasculardisease,
                                     of
can best be made through analyses data from a large,randomized,controlled trial.
The SibutramineCardiovascularOutcomes,or SCOUT study, is such a trial. SCOUT,
                                                                           trial
underwayin Europe, is a randomized,double-blind,placebo-controlled examining
the incidenceof fatal and nonfatal cardiovascular  outcomesin approximately9,000
obesepatientsat high risk for cardiovascular   disease(e.g., a history of myocardial
infarction) treatedfor up to 5 yearswith diet and exerciseplus sibutramineor placebo.
When completed,this study will provide preciseestimatesof the relative benefits and
risks of sibutraminewhen addedto lifestyle modification in a population of patientsfor
                                                                     of
whom sustainedweight loss is highly desirable,but who, because their underlying
cardiovascular                                                       for
                disease,are not at this time appropriatecandidates use of sibutramine
                     ed
outsideof a controll’ investigationalsetting.

As of April 22,2005, approximately8,000patientshad beenenrolled into SCOUT. An
independent                                           the
             data safety monitoring boardis overseeing conduct of the trial, and
beginning in May 2005, they will be reviewing safety dataon a monthly basis.FDA will
be immediately notified and will take appropriateregulatoryaction if any serioussafety
concernsare identified during the study.

V.     THE OVER&L           BENEFITS VS. RISKS OF SIBUTRAMINE

While our responseto your petition is focusedon risk, it is important to recognizethat
the use of sibutraminein obesepatients- who now represent     nearly a third of all adults
in this counti - is.associatedwith a numberof benefitsin addition to weight loss
                                                             s
itself, many of which have come to light following the drug’ original approvalin 1997.

In the SibutramineTrial of Obesity Reductionand Maintenance(STORM), the longest
study of sibutraminepublishedto date,of 261 obesepatientswho completedthe 2-year



             J.
** Koch-Weser The ambiguityof adverse drug reactions.Eur J Clin Phannacoll977; 11:75-78.
                             and
23Flegal,KM, et al. Prevalence trendsin obesityamongUS adults,1999-2000.  JAMA 2002;
288:1723-1727.

                                              8
Docket No. 2002P-012O/CPl

trial, 70 percenttreatedwith sibutraminelost at least5 percentof their baselineweight
comparedwith approximately48 percentof thosetreatedwith placebo; and 46 percent
of the sibutramine-treatedpatientslost at least 10 percentof their baselineweight vs.
approximately20 percentof placebo-treated    subjects.24Sibutramine-associated  weight
                      ed                                           of
loss was accompani’ by significant reductionsin concentrations serumtriglycerides,
VLDL cholesterol,insulin, C-peptide,and uric acid, as well as clinically meaningful
           in
increases HDL cholesterollevels. The degreeof improvementin thesemetabolic
variableswas proportionalto the amountof weight lost.

Recentstudiesof obesepatientswith type 2 diabetesindicate that treatmentwith
sibutraminefor 12 to 52 weeks is associatedwith averageweight loss ranging from 10
                                                             and, secondarily,with
to 16 pounds,with significant lowering of HbAl, concentrations
                     for
reducedrequirements diabetesmedicationsin patientswho receivedthe drug for 52
weeks.25926

A variety of studiespublishedwithin the past few yearsreinforcesthe findings from the
original NDA that sibutramine-related weight loss improveslevels of HDL cholesterol,
triglycerides, and in somecasesthe ratio of LDL-to-HDL cholesterol.27

Therefore,while sibatramineposesa risk of increased   blood pressurein somepatients,it
also provides a numberof secondarybenefitsin addition to weight loss. Moreover,just
                               with sibutramine,increased
as the principal risk associated                           blood pressure,is readily
monitorable(and treatable),so too are the beneficial effects of the drug. This provides
                                                 on
healthcareprofessionalswith the ability to assess, an ongoing and individual basis,
the balanceof benefits and risks of sibutramineuse and to adjust dose,add adjunctive
risk-modifying therapy,or to discontinuethe drug as necessary.

VI.     ADVERSE EVENTS INVOLVING FETAL TOXICITY

Your supplementincludes a new categoryof adverseeventsaffecting the fetus,
including spontaneousabortions,stillbirths, and congenitalmalformations,such as heart
and central nervoussystemmalformations.




                                            on                    after
24JamesWP, et al. Effect of sibutramine weight maintancence weight loss: a randomized       trial.
STORM StudyGroup. Sibutramine          Trial of ObesityReductionandMaintenance.Lancet2000;
356:2119-2125.
25                                                for
  Norris SL, et al. Efficacy of pharmacotherapy weightloss in adultswith type 2 diabetesmellitus: a
meta-analysis. Arch Intent Med 2004; 164:1395-1404.
26RedmonJB, et al. One-year                                of                 for
                                  outcomeof a combination weight loss therapies subjectswith type 2
         a
diabetes: randomized     trial. Diabetes Care 2003; 9:2505-25 11.
27FilippatosTD, et al. A review of the metaboliceffectsof sibutramine.Cur Med Res Opin 2005; 3:457-
468.

                                                 9
                       1
Docket No. 2002P-012O/CP

Sibutramineis a CategoryC drug for which the Pregnancysectionof the labeling
reads:28

         Pregnancy

               TeratogenicEficts-Pregnancy CategoryC
               Radiolabeled   studiesin animalsindicatedthat tissuedistribution was unaffectedby
               pregnancy,with relatively low transferto the fetus. In rats, therewas no evidenceof
               teratogenicityat dosesof 1,3, or 10 mg/kg/daygenerating     combinedplasmaAUC’ of s
               the two major active metabolitesup to approximately32 times thosefollowing the
               humandoseof IS mg. In rabbitsdosedat 3, 15, or 75 mg/kg/day,plasmaAUC’ greater s
               than approximately5 times thosefollowing the humandoseof 15 mg causedmaternal
               toxicity. At markedly toxic doses,Dutch Belted rabbitshad a slightly higher than
               control incidenceof pupswith a broadshort snout,short roundedpinnae,short tail and,
               in some,shorterthickenedlong bonesin the limbs; at comparablyhigh dosesin New
               ZealandWhite rabbits,one study showeda slightly higher than control incidenceof
               pupswith cardiovascular   anomalies while a secondstudy showeda lower incidencethan
               in the control group.

                            and
               No adequate well controlledstudieswith MERIDIA havebeenconductedin
               pregnantwomen.The useof MERIDIA during pregnancyis not recommended.         Women
               of childbearingpotentialshouldemploy adequate   contraceptionwhile taking MERIDIA.
               Patientsshouldbe advisedto notify their physicianif they becomepregnantor intendto
               becomepregnantduring therapy.


We                                            and
    have analyzedthe data in your supplement from our AERS database         with
respectto adversedrug experiences                                    with sibutramine.
                                   involving fetal toxicity associated
BetweenNovember22,1997, and October27,2003, ARRS receiveda total of 34
domesticreportsof Ipregnant  women who had beenexposedto sibutramineat some
                               The
point during their pregnancies. 34 reportswere broadly categorizedas spontaneous
abortion,pregnancies  with no outcome,therapeuticabortion, live births, and postnatal
death. The following five birth defectswere reported:

     l Arthrogryposisx 1
     l Aortic stenosisx 1
     0 Preauricularsinus of the right ear x 1
     l Myoplastic left heart syndromex 1
     l Hypoplastic left ventricle x 1

According to the National Vital StatisticsReports,the most common defectsin the
                      were                  and
United Statesin 19919 musculoskeletal connectivetissue defectsat 239.9 per
100,000live births, followed by congenitalheart defectsat 119.8per 100,000live births,




** 21 CFR 201.57,available on the Internetat
http://www.accessd.f&.~ov/scriDts/cd201.57&SearchTe~201%2
&J (May 20,2005).

                                                  10
                      1
Docket No. 2002P-0112OKP

with other circulatory/respiratoryanomaliesat 140.6per 100,000live births2’ Given
that cardiac anomaliesare amongthe most commonbirth defectsin infants born in the
United States,it is not surprisingthat three of the five birth defectsreportedto AERS
involved the heart.

Becauseof the small numberof AERS reportsof birth defectsin infants born to women
exposedto sibutramine,the limited documentation   included in the reports,and the lack
of data regardingthe numberof pregnantwomen in the United Stateswho have been
exposedto sibutramine,it is not possible,basedon this information, to rendera
                                                                     the
conclusionregardingwhetherin utero sibutramineexposureincreases risk for birth
                                      basedon preclinical data reviewed before the
defectsor fetal toxicity. Nevertheless,
approval of the sibutramineNDA (thesedata form the basis of the languagein the
Pregnancysectionof the current labeling) and information from two recently published
caseseriesof pregnantwomen exposedto sibutraminewho deliveredhealthy infants, we
believe that sibutramineis appropriatelylabeledas CategoryC and is not recommended
for use during pregnancy.30’ ’

VII.    RISK MANAGEMENT

During our review of the sibutramineAERS reportsof deathsand seriouscardiovascular
and stroke events,we noted that somepatientswith a history of cardiovasculardisease
                                                                   that
were prescribedsibutraminedespitethe labeledrecommendation such patientsnot
receive the drug. While the prescribingof drugs at variancewith the approvedlabeling
                                            s
is a practice that falls outsidethe Agency’ regulatorypurview, FDA has askedthe
sponsorto address tlhe use of sibutraminein patientsfor whom there are limited efficacy
and safety data in an updatedrisk management     plan. This plan includes (1) a Dear
Healthcare Professionalletter stressingthat patientswith known cardiovasculardisease
                                                           the
should not be prescribedsibutramineand re-emphasizing importanceof monitoring
blood pressure(and pulse) in all patientstaking the drug; (2) revisions to the physician
labeling and patient labeling to reinforce the properuse of the drug; and (3) an
educationaloutreachprogramthat is aimed at physiciansto reinforce the message
                                                         for
regardingwhich patientsarenot appropriatecandidates sibutramine.




29VenturaSJ, et al. Birlhs: final datafrom 1999.NationalVital StatisticsReports,49: 1, April 17,2001,
                               of
page83; from the Department HealthandHumanServices,                   for
                                                               Centers DiseaseControl andPrevention,
National Centerfor Heatlth  Statistics,NationalVital StatisticsSystem.
                               to
soEinarsonA, et al. Exposure sibutramine                        a
                                             duringpregnancy: caseseries. Eur J of ObstetGynecol
ReprodBiol2004; 116:112.
                                   use
3’Kadioglu M, et al. Sibutrarnine in pregnancy:      Reportof two cases.Birth DefectsA Clin Mol
Teratol 2004;70:545-5,46.

                                                 11
Docket No. 2002P-012OKPl

VIII.   CONCLUSION

Following a 2-year rlegulatoryreview, FDA concludedthat the benefits of sibutramine
outweighedits risks for certain obesepatientsand approvedthe drug for the treatmentof
obesity on November 22, 1997,with labeling to warn physiciansof the risks to certain
patientsand the needto monitor patients.

In our ongoing effort to maximize the safe and effective use of sibutramine,we have
                          to
worked with the spo:nsor updatethe physicianand patient labeling to reinforce the
appropriatepopulation for and properuse of sibutramine(i.e., the needto regularly
monitor blood pressure).An additionalcomponentof the risk management       program
includesan educationaloutreachprogramaimedat physicianswho are likely to
prescribesibutramine.

                                                  of
Basedon the previously describedreassessment the original drug review process,an
evaluationof data from AERS, and recentlypublishedstudies,we continueto believe
                 s
that sibutramine’ overall risk-benefit profile supportsit remaining available as a
prescriptiondrug for the treatmentof appropriatelyselectedobesepatients. Your
requestthat we remove sibutraminefkom the market is thereforedenied.

                                            Sincerely,



                                            StevenK. Galson,M.D., M.P.H.
                                            Acting Director
                                            Centerfor Drug Evaluation and Research




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