May 11, 2001

Clinical Perspective on Citizen Clinical Perspective on Citizen PetitionPetition

NDAC / PADACNDAC / PADAC

Joint MeetingJoint Meeting

Robert J. Meyer, MDRobert J. Meyer, MDDirector, DPADPDirector, DPADP

CDER / FDACDER / FDA

May 11th, 2001May 11th, 2001

May 11, 2001

Clinical PerspectiveClinical Perspective

Important Considerations for OTC Important Considerations for OTC SwitchSwitch::– The ability of the consumer to self-The ability of the consumer to self-

diagnose and/or self-managediagnose and/or self-manage– Safety and effectiveness for drug used Safety and effectiveness for drug used

in OTC setting (i.e., without a “learned in OTC setting (i.e., without a “learned intermediary”)intermediary”)

May 11, 2001

Clinical PerspectiveClinical Perspective

These important considerations are often These important considerations are often addressed byaddressed by::

– OTC actual-use study; and/orOTC actual-use study; and/or– Label comprehension studyLabel comprehension study

May 11, 2001

Clinical PerspectiveClinical Perspective

• Allegra, Claritin and Zyrtec are all antihistamines, Allegra, Claritin and Zyrtec are all antihistamines, all approved to treat allergic rhinitisall approved to treat allergic rhinitis

• FDA accepts allergic rhinitis as an appropriate FDA accepts allergic rhinitis as an appropriate OTC indication, OTC indication, andand

• FDA accepts antihistamines as appropriate for FDA accepts antihistamines as appropriate for OTC use OTC use

• FDA has established appropriate OTC labeling for FDA has established appropriate OTC labeling for antihistamine productsantihistamine products

May 11, 2001

Clinical PerspectiveClinical Perspective

Neither an actual-use study Neither an actual-use study nornor a labeling a labeling comprehension study is comprehension study is necessarynecessary for the for the OTC switch proposedOTC switch proposed

FDA is not seeking advice onFDA is not seeking advice on::– Allergic rhinitis as an OTC indicationAllergic rhinitis as an OTC indication– On the effectiveness of Claritin, Zyrtec or On the effectiveness of Claritin, Zyrtec or

Allegra in OTC settingAllegra in OTC setting

May 11, 2001

Clinical PerspectiveClinical Perspective

• Focus of FDA clinical presentation is on Focus of FDA clinical presentation is on safety and how the safety experiences safety and how the safety experiences bear on the decision for OTC availabilitybear on the decision for OTC availability

• FDA performed full safety reviewFDA performed full safety review– NDA data NDA data – Post-marketing data (AERS)Post-marketing data (AERS)– Other sourcesOther sources

May 11, 2001

Safety Presentation Safety Presentation • Elements of safety presentationElements of safety presentation::

– NDA dataNDA data• Standard safety data, cardiac safety evaluation, Standard safety data, cardiac safety evaluation,

drug-interactionsdrug-interactions

– Post-marketing experiencePost-marketing experience• Case Review, Epidemiology Case Review, Epidemiology

• Focus for NDA on single ingredient compoundsFocus for NDA on single ingredient compounds• AERS reports for include all formulationsAERS reports for include all formulations

May 11, 2001

Safety Presentation - CaveatsSafety Presentation - Caveats

• Safety review is Safety review is notnot intended to be intended to be comparative of the three agents comparative of the three agents

• Safety review will not attempt to Safety review will not attempt to rigorously compare to OTC antihistaminesrigorously compare to OTC antihistamines

• Safety review Safety review willwill help define the safety help define the safety experience with these agents individuallyexperience with these agents individually

May 11, 2001

Safety Presentation - CaveatsSafety Presentation - Caveats

• Most definitive safety data are from NDAMost definitive safety data are from NDA

• Post-marketing data offers less definitive Post-marketing data offers less definitive information about product safetyinformation about product safety

• The use of epidemiology evaluations of The use of epidemiology evaluations of AERS data can help place post-AERS data can help place post-marketing data in perspective, but is not marketing data in perspective, but is not definitivedefinitive

May 11, 2001

NDA Data IntroductionNDA Data Introduction

• Claritin (loratadine)Claritin (loratadine)– approved for marketing April 12, 1993approved for marketing April 12, 1993

• Zyrtec (cetirizine)Zyrtec (cetirizine)– approved for marketing Dec. 8, 1995approved for marketing Dec. 8, 1995

• Allegra (fexofenadine)Allegra (fexofenadine)– approved for marketing July 25, 1996approved for marketing July 25, 1996

May 11, 2001

• Numbers of Patients ExposedNumbers of Patients Exposed

• Safety Experience in Clinical TrialsSafety Experience in Clinical Trials

• Cardiac Safety (in vitro, animals, human)Cardiac Safety (in vitro, animals, human)

• Drug InteractionsDrug Interactions

NDA Safety DataNDA Safety Data

May 11, 2001

NDA Safety Data Introduction NDA Safety Data Introduction

Why the focus on cardiac safety and drug-Why the focus on cardiac safety and drug-drug interactions?drug interactions?

• Issues for Seldane (terfenadine):Issues for Seldane (terfenadine):– ECG / repolarization effects (QT interval) ECG / repolarization effects (QT interval) – Cases of malignant arrhythmias (TdP)Cases of malignant arrhythmias (TdP)

• Problem was clinically manifest due to Problem was clinically manifest due to drug-drug interactionsdrug-drug interactions

• Similar issues with HismanalSimilar issues with Hismanal

May 11, 2001

NDA Safety Data IntroductionNDA Safety Data IntroductionCardiac Investigation of this potential for a Cardiac Investigation of this potential for a

new drug may includenew drug may include::– In vitro studies of ion (KIn vitro studies of ion (K++) channels and ) channels and

repolarization in isolated cardiac musclerepolarization in isolated cardiac muscle– In vivo animal studiesIn vivo animal studies– Clinical dataClinical data

• e.g., high dose and drug interaction studies, clinical e.g., high dose and drug interaction studies, clinical monitoring in clinical trialsmonitoring in clinical trials

May 11, 2001

Claritin NDA DatabaseClaritin NDA Database

• In the NDA database for loratadine over In the NDA database for loratadine over 90,000 patients exposed90,000 patients exposed

• Adverse event profile was consistent for Adverse event profile was consistent for an antihistamine given for allergic an antihistamine given for allergic rhinitisrhinitis

• No significant clinical safety signals in No significant clinical safety signals in original NDAoriginal NDA

May 11, 2001

Claritin NDA DatabaseClaritin NDA Database

AAEE CCllaarriittiinn PPllaacceebboo

HHeeaaddaacchhee 1122%% 1111%%

SSoommnnoolleennccee 88%% 66%%

FFaattiigguuee 44%% 33%%

DDrryy MMoouutthh 33%% 22%%

May 11, 2001

Claritin NDA DatabaseClaritin NDA Database• Somnolence was dose-related, with Somnolence was dose-related, with

reporting of 10% with 20 mg QD, 12% with reporting of 10% with 20 mg QD, 12% with 40 mg QD40 mg QD

• Pediatric studies (6 - 11 years) showed Pediatric studies (6 - 11 years) showed similar AE profilesimilar AE profile– Nervousness, hyperkinesia, wheezing and Nervousness, hyperkinesia, wheezing and

abdominal pain also reported abdominal pain also reported

• No significant safety concerns at the time of No significant safety concerns at the time of approvalapproval

May 11, 2001

Claritin Cardiac SafetyClaritin Cardiac Safety• In vitro testing (ion channel, myocardial In vitro testing (ion channel, myocardial

cells) was negativecells) was negative• No QT or repolarization effects No QT or repolarization effects

documented in animalsdocumented in animals• No significant cardiac AE’s seen in No significant cardiac AE’s seen in

clinical trials (up to 160 mg)clinical trials (up to 160 mg)• No clinically meaningful effect on QTc No clinically meaningful effect on QTc

documented in clinical studiesdocumented in clinical studies

May 11, 2001

Claritin Metabolic Claritin Metabolic ConsiderationsConsiderations

• Loratadine metabolized by CYP3A4, 2D6Loratadine metabolized by CYP3A4, 2D6

• Drug interaction studies with Drug interaction studies with erythromycin, cimetidine and erythromycin, cimetidine and ketoconazole showed some increase in ketoconazole showed some increase in loratadine and desloratadine AUCsloratadine and desloratadine AUCs

• No clinically significant impactNo clinically significant impact

• Renal and hepatic insufficiency decrease Renal and hepatic insufficiency decrease clearanceclearance

May 11, 2001

Zyrtec NDA DatabaseZyrtec NDA Database

• An Active metabolite of hydroxyzineAn Active metabolite of hydroxyzine• Over 3900 patients were treated in Over 3900 patients were treated in

clinical trials with Zyrtecclinical trials with Zyrtec• Adverse event profile consistent with an Adverse event profile consistent with an

antihistamine given for allergic rhinitisantihistamine given for allergic rhinitis

May 11, 2001

Zyrtec NDA DatabaseZyrtec NDA Database

AAEE ZZyyrrtteecc PPllaacceebboo

SSoommnnoolleennccee 1133..77%% 66..33%%

FFaattiigguuee 55..99%% 22..66%%

DDrryy MMoouutthh 55..00%% 22..33%%

PPhhaarryynnggiittiiss 22..00%% 11..99%%

DDiizzzziinneessss 22..00%% 11..22%%

May 11, 2001

Zyrtec NDA DatabaseZyrtec NDA Database

• Somnolence was dose-related Somnolence was dose-related • Other AEs reported in children at a rate higher Other AEs reported in children at a rate higher

than placebo in both doses:than placebo in both doses:– abdominal pain, diarrhea, vomiting abdominal pain, diarrhea, vomiting – somnolence in children 1.9% with 5 mg, somnolence in children 1.9% with 5 mg,

4.2% with 10 mg, placebo = 1.3%4.2% with 10 mg, placebo = 1.3%• No significant safety signals from original NDANo significant safety signals from original NDA

May 11, 2001

Zyrtec Cardiac SafetyZyrtec Cardiac Safety• In vitro testing (myocytes, ion channels) In vitro testing (myocytes, ion channels)

revealed no effects at relevant concentrations revealed no effects at relevant concentrations • No significant QT or repolarization effects seen No significant QT or repolarization effects seen

in whole animalsin whole animals• No significant cardiac AE’s seen in clinical No significant cardiac AE’s seen in clinical

trials, including 6 times the recommended dosetrials, including 6 times the recommended dose• 1 of 4 safety-exposure studies showed an effect 1 of 4 safety-exposure studies showed an effect

on the ECG on the ECG – 9.1 msec increase in QTC using Bazett’s correction9.1 msec increase in QTC using Bazett’s correction

May 11, 2001

Zyrtec Metabolic Zyrtec Metabolic ConsiderationsConsiderations

• Renal excretion, the majority unchangedRenal excretion, the majority unchanged

• No significant drug interactions No significant drug interactions

• Renal impairment causes moderate Renal impairment causes moderate decrease in clearancedecrease in clearance

• Hepatic impairment causes small effect Hepatic impairment causes small effect on clearanceon clearance

May 11, 2001

Allegra NDA DatabaseAllegra NDA Database

• Acid metabolite (active) of terfenadineAcid metabolite (active) of terfenadine• Over 2,353 patients exposed to AllegraOver 2,353 patients exposed to Allegra• AE profile was as expected given AE profile was as expected given

Allegra’s drug class and indications Allegra’s drug class and indications studiedstudied

May 11, 2001

Allegra NDA DatabaseAllegra NDA Database

AAEE AAlllleeggrraa

6600 mmgg BBIIDD PPllaacceebboo

VViirraall IInnff.. 22..55%% 11..55%%

NNaauusseeaa 11..66%% 11..55%%

DDyyssmmeennoorrrrhheeaa 11..55%% 00..33%%

DDrroowwssiinneessss 11..33%% 00..99%%

DDyyssppeeppssiiaa 11..33%% 00..66%%

FFaattiigguuee 11..33%% 00..99%%

May 11, 2001

Allegra NDA DatabaseAllegra NDA Database

• Reporting of somnolence not dose-relatedReporting of somnolence not dose-related

• AE profile in Children additionally AE profile in Children additionally showed:showed:– headaches, accidental injuries, cough, fever, headaches, accidental injuries, cough, fever,

pain, otitis media and URIspain, otitis media and URIs

• No significant safety signals in original No significant safety signals in original NDANDA

May 11, 2001

Allegra Cardiac SafetyAllegra Cardiac Safety• In vitro testing (ion channels, isolated In vitro testing (ion channels, isolated

myocytes) showed no evidence of repolarization myocytes) showed no evidence of repolarization effects effects

• No whole animal effects even at high exposuresNo whole animal effects even at high exposures• No significant cardiac events reported in No significant cardiac events reported in

clinical trialsclinical trials• No clinical ECG interval effects seen, even at No clinical ECG interval effects seen, even at

doses up to 690 mg BIDdoses up to 690 mg BID

May 11, 2001

Allegra Metabolic Allegra Metabolic ConsiderationsConsiderations

• Fexofenadine minimally metabolizedFexofenadine minimally metabolized

• Drug interaction studies showed small Drug interaction studies showed small increase in AUCincrease in AUC

• No evidence of important changes in No evidence of important changes in metabolism in special populationsmetabolism in special populations

May 11, 2001

NDA summaryNDA summary

• All three drugs with acceptable safety in All three drugs with acceptable safety in NDAsNDAs

• Work-up for cardiac effects reassuringWork-up for cardiac effects reassuring

• Claritin with some drug-drug Claritin with some drug-drug interactions, but no apparent clinical interactions, but no apparent clinical consequencesconsequences

May 11, 2001

POST-MARKETINGPOST-MARKETING

• Duration of marketing will affect total Duration of marketing will affect total numbers of reportsnumbers of reports

• Extent of use will affect total number of Extent of use will affect total number of reportsreports

• Heightened sensitivities may affect Heightened sensitivities may affect number of reportsnumber of reports

May 11, 2001

POST-MARKETINGPOST-MARKETING

• Databases first extensively queried up to Databases first extensively queried up to 4/2000, updated for serious events 4/2000, updated for serious events

• Overall, this assessment shows all 3 drugs Overall, this assessment shows all 3 drugs to have a good post-marketing safety to have a good post-marketing safety profile, though a few signals seenprofile, though a few signals seen

• No issues found in review that would No issues found in review that would warrant reconsideration of approvalwarrant reconsideration of approval

May 11, 2001

POST-MARKETING - OTC POST-MARKETING - OTC antihistaminesantihistamines

• Review of literature, AERS database also Review of literature, AERS database also performedperformed

• OTC antihistamines have acceptable OTC antihistamines have acceptable safety profilesafety profile

• CNS and anticholinergic AEs commonCNS and anticholinergic AEs common

• Rare cases of seizures, liver failure, Rare cases of seizures, liver failure, serious cardiac adverse events and other serious cardiac adverse events and other rare events have been noted rare events have been noted

May 11, 2001

4081 Spontaneous AEs for all loratadine products4081 Spontaneous AEs for all loratadine products

Most commonly reported events were:Most commonly reported events were:

Drug ineffective Drug ineffective TachycardiaTachycardia

Drug interaction Drug interaction Insomnia Insomnia

Headache Headache Sedation Sedation

Palpitations Palpitations Dermatitis Dermatitis

Dizziness Dizziness Nervousness Nervousness

POST-MARKETING – ClaritinPOST-MARKETING – Claritin

May 11, 2001

Serious Cardiac events:Serious Cardiac events:• 86 cases were reviewed in depth86 cases were reviewed in depth• Patient ages ranged from 2 to Patient ages ranged from 2 to

87 years87 years• 38% of reports were for 38% of reports were for

patients less than 50patients less than 50 years old years old• Large majority of cases occurred in Large majority of cases occurred in

setting of confounding factorssetting of confounding factors

POST-MARKETING – ClaritinPOST-MARKETING – Claritin

May 11, 2001

POST-MARKETING – ClaritinPOST-MARKETING – Claritin

• Some hepatic terms are included in Some hepatic terms are included in listing of in Claritin labelinglisting of in Claritin labeling

• 5 cases of hepatic failure in AERS 5 cases of hepatic failure in AERS databasedatabase

• 3 of 5 had confounding factors3 of 5 had confounding factors

• 2 of 5 not otherwise explained, without 2 of 5 not otherwise explained, without clear causalityclear causality

May 11, 2001

3096 Spontaneous AEs in database for cetirizine3096 Spontaneous AEs in database for cetirizine

Most commonly reported events were:Most commonly reported events were:

Drug ineffective Drug ineffective PruritusPruritus

Sedation Sedation Drug InteractionDrug Interaction

Thrombocytopenia Thrombocytopenia AstheniaAsthenia

Urticaria Urticaria HeadacheHeadache

Dermatitis Dermatitis HypersensitivityHypersensitivity

POST-MARKETING – ZyrtecPOST-MARKETING – Zyrtec

May 11, 2001

POST-MARKETING – ZyrtecPOST-MARKETING – Zyrtec

Thrombocytopenia (low blood platelets):Thrombocytopenia (low blood platelets):

• 1 case in NDA database1 case in NDA database

• 170 cases in the AERS database170 cases in the AERS database

• All but 11 cases were not plausibly linked All but 11 cases were not plausibly linked to cetirizine useto cetirizine use

• Review of the 11 cases do not provide a Review of the 11 cases do not provide a clear link to the drugclear link to the drug

May 11, 2001

POST-MARKETING – ZyrtecPOST-MARKETING – Zyrtec

• Seizures - 64 casesSeizures - 64 cases

• 26 cases discounted as implausibly linked 26 cases discounted as implausibly linked

• 38 cases were reviewed in depth, 5 were 38 cases were reviewed in depth, 5 were not seizure eventsnot seizure events

• Ages ranged from 3 to 79 yearsAges ranged from 3 to 79 years

• 21 new onset / 12 pre-existing seizure21 new onset / 12 pre-existing seizure

May 11, 2001

POST-MARKETING – ZyrtecPOST-MARKETING – Zyrtec

Serious cardiac eventsSerious cardiac events• 37 cases were reviewed in depth37 cases were reviewed in depth

• Patient ages ranged from 3 to 80 Patient ages ranged from 3 to 80 yearsyears

• More than half under 50 yearsMore than half under 50 years • Majority of cases with confounding featuresMajority of cases with confounding features

May 11, 2001

POST-MARKETING – AllegraPOST-MARKETING – Allegra

1768 Spontaneous AEs for fexofenadine products1768 Spontaneous AEs for fexofenadine products

Most commonly reported events were:Most commonly reported events were:Drug ineffective Drug ineffective Sedation Sedation Nausea Nausea Insomnia Insomnia Dizziness Dizziness Palpitations Palpitations Dermatitis Dermatitis Diarrhoea Diarrhoea Headache Headache Dyspnoea Dyspnoea

May 11, 2001

POST-MARKETING – AllegraPOST-MARKETING – Allegra

Serious cardiac events Serious cardiac events • 39 cases reviewed 39 cases reviewed

• Age range from 15 to 81 yearsAge range from 15 to 81 years• Of the most serious cases, the Of the most serious cases, the

majority had a prior cardiac history majority had a prior cardiac history and/or concomitant drugsand/or concomitant drugs

May 11, 2001

POST-MARKETING – AllegraPOST-MARKETING – Allegra

SeizuresSeizures

• 17 of 30 cases were reviewed in depth17 of 30 cases were reviewed in depth

• ages ranged from 22 to 80years oldages ranged from 22 to 80years old• 9 patients with no previous history9 patients with no previous history• 10 patients on drugs known to 10 patients on drugs known to

cause seizurescause seizures• 8 with dechallenge, 1 possible 8 with dechallenge, 1 possible

rechallengerechallenge

May 11, 2001

POST-MARKETINGPOST-MARKETING

• Some signals arise in AERS databaseSome signals arise in AERS database

• After careful review, each drug has some After careful review, each drug has some cases of cardiac events and seizures that cases of cardiac events and seizures that cannot be otherwise explainedcannot be otherwise explained

• All these events occur with some All these events occur with some background rate in the general background rate in the general populationpopulation

May 11, 2001

Epidemiology AssessmentEpidemiology Assessment

• The epidemiology staff within OPDRA The epidemiology staff within OPDRA estimated reporting rates for these 3 drugs estimated reporting rates for these 3 drugs vs. expected background incidencesvs. expected background incidences

• Events examined Events examined – serious cardiac eventsserious cardiac events– seizuresseizures– hepatotoxicity for loratadinehepatotoxicity for loratadine

May 11, 2001

Epidemiology AssessmentEpidemiology Assessment

• Background incidence rates were Background incidence rates were estimated for comparison purposes estimated for comparison purposes

• Drug experience comes from a mixed-Drug experience comes from a mixed-risk population risk population

• ““Denominator” for rates inferred from Denominator” for rates inferred from actual use dataactual use data

May 11, 2001

Epidemiology AssessmentEpidemiology Assessment

• Serious Cardiac Events Serious Cardiac Events – estimated incidence of 44 per million person-estimated incidence of 44 per million person-

yearsyears• New Onset Solitary Seizures New Onset Solitary Seizures

– Estimated incidence of 90 per millionEstimated incidence of 90 per million person-yearsperson-years

• Hepatic Failure Hepatic Failure – Estimated incidence of 1 to 2.3 per million Estimated incidence of 1 to 2.3 per million

person-yearsperson-years

May 11, 2001

Epidemiology Conclusions:Epidemiology Conclusions:• The calculated reporting rates for all three The calculated reporting rates for all three

drugs were comparable for serious cardiac drugs were comparable for serious cardiac events and seizuresevents and seizures

• Reporting rates are below background rate Reporting rates are below background rate for all three drugs and all eventsfor all three drugs and all events

• Due to limitations of the data and these Due to limitations of the data and these analyses, a safety problem for one or more analyses, a safety problem for one or more of these drugs cannot be excludedof these drugs cannot be excluded

May 11, 2001

Overall Clinical/Regulatory Overall Clinical/Regulatory ConclusionsConclusions

May 11, 2001

Overall ConclusionsOverall Conclusions• Loratadine, fexofenadine, cetirizine have Loratadine, fexofenadine, cetirizine have

extensive, favorable marketing histories extensive, favorable marketing histories and safety profilesand safety profiles

• FD&C Act sets criteria for when a drug FD&C Act sets criteria for when a drug should be Rx-only vs. OTCshould be Rx-only vs. OTC

• The US market has OTC antihistamines The US market has OTC antihistamines available to treat symptoms of allergic available to treat symptoms of allergic rhinitisrhinitis

May 11, 2001

Overall ConclusionsOverall Conclusions• BC/BS petition requests FDA to initiate a BC/BS petition requests FDA to initiate a

switch of three Rx antihistamines to OTC switch of three Rx antihistamines to OTC statusstatus

• Available data for these drugs supports Available data for these drugs supports them being effective for allergic rhinitis them being effective for allergic rhinitis

• Some low-frequency safety “signals” do Some low-frequency safety “signals” do arise from the post-marketing experiencearise from the post-marketing experience

• Weight of safety evidence is that all three Weight of safety evidence is that all three drugs have a favorable safety profile drugs have a favorable safety profile

May 11, 2001

Advice Sought from Advice Sought from NDAC/PADACNDAC/PADAC

• Given the current OTC status of certain Given the current OTC status of certain antihistamines for the treatment for allergic antihistamines for the treatment for allergic rhinitis and the safety information discussed rhinitis and the safety information discussed todaytoday::– Should each individual drug be available OTC?Should each individual drug be available OTC?– If not, what other safety studies or other If not, what other safety studies or other

information would be recommended?information would be recommended?– If yes, what modifications to the existing OTC If yes, what modifications to the existing OTC

antihistamine labeling would be recommend?antihistamine labeling would be recommend?