Clinical Perspective on Citizen Petition

1
Clinical Perspective on Citizen Petition

• NDAC / PADAC
• Joint Meeting
• Robert J. Meyer, MD
• Director, DPADP
• CDER / FDA
• May 11th, 2001

2
Clinical Perspective

• Important Considerations for OTC Switch
• The ability of the consumer to self-diagnose
  and/or self-manage
• Safety and effectiveness for drug used in OTC
  setting (i.e., without a learned intermediary)

3
Clinical Perspective

• These important considerations are often
  addressed by
• OTC actual-use study and/or
• Label comprehension study

4
Clinical Perspective

• Allegra, Claritin and Zyrtec are all
  antihistamines, all approved to treat allergic
  rhinitis
• FDA accepts allergic rhinitis as an appropriate
  OTC indication, and
• FDA accepts antihistamines as appropriate for OTC
  use
• FDA has established appropriate OTC labeling for
  antihistamine products

5
Clinical Perspective

• Neither an actual-use study nor a labeling
  comprehension study is necessary for the OTC
  switch proposed
• FDA is not seeking advice on
• Allergic rhinitis as an OTC indication
• On the effectiveness of Claritin, Zyrtec or
  Allegra in OTC setting

6
Clinical Perspective

• Focus of FDA clinical presentation is on safety
  and how the safety experiences bear on the
  decision for OTC availability
• FDA performed full safety review
• NDA data
• Post-marketing data (AERS)
• Other sources

7
Safety Presentation

• Elements of safety presentation
• NDA data
• Standard safety data, cardiac safety evaluation,
  drug-interactions
• Post-marketing experience
• Case Review, Epidemiology
• Focus for NDA on single ingredient compounds
• AERS reports for include all formulations

8
Safety Presentation - Caveats

• Safety review is not intended to be comparative
  of the three agents
• Safety review will not attempt to rigorously
  compare to OTC antihistamines
• Safety review will help define the safety
  experience with these agents individually

9
Safety Presentation - Caveats

• Most definitive safety data are from NDA
• Post-marketing data offers less definitive
  information about product safety
• The use of epidemiology evaluations of AERS data
  can help place post-marketing data in
  perspective, but is not definitive

10
NDA Data Introduction

• Claritin (loratadine)
• approved for marketing April 12, 1993
• Zyrtec (cetirizine)
• approved for marketing Dec. 8, 1995
• Allegra (fexofenadine)
• approved for marketing July 25, 1996

11
NDA Safety Data

• Numbers of Patients Exposed
• Safety Experience in Clinical Trials
• Cardiac Safety (in vitro, animals, human)
• Drug Interactions

12
NDA Safety Data Introduction

• Why the focus on cardiac safety and drug-drug
  interactions?
• Issues for Seldane (terfenadine)
• ECG / repolarization effects (QT interval)
• Cases of malignant arrhythmias (TdP)
• Problem was clinically manifest due to drug-drug
  interactions
• Similar issues with Hismanal

13
NDA Safety Data Introduction

• Cardiac Investigation of this potential for a new
  drug may include
• In vitro studies of ion (K) channels and
  repolarization in isolated cardiac muscle
• In vivo animal studies
• Clinical data
• e.g., high dose and drug interaction studies,
  clinical monitoring in clinical trials

14
Claritin NDA Database

• In the NDA database for loratadine over 90,000
  patients exposed
• Adverse event profile was consistent for an
  antihistamine given for allergic rhinitis
• No significant clinical safety signals in
  original NDA

15
Claritin NDA Database
16
Claritin NDA Database

• Somnolence was dose-related, with reporting of
  10 with 20 mg QD, 12 with 40 mg QD
• Pediatric studies (6 - 11 years) showed similar
  AE profile
• Nervousness, hyperkinesia, wheezing and
  abdominal pain also reported
• No significant safety concerns at the time of
  approval

17
Claritin Cardiac Safety

• In vitro testing (ion channel, myocardial cells)
  was negative
• No QT or repolarization effects documented in
  animals
• No significant cardiac AEs seen in clinical
  trials (up to 160 mg)
• No clinically meaningful effect on QTc documented
  in clinical studies

18
Claritin Metabolic Considerations

• Loratadine metabolized by CYP3A4, 2D6
• Drug interaction studies with erythromycin,
  cimetidine and ketoconazole showed some increase
  in loratadine and desloratadine AUCs
• No clinically significant impact
• Renal and hepatic insufficiency decrease
  clearance

19
Zyrtec NDA Database

• An Active metabolite of hydroxyzine
• Over 3900 patients were treated in clinical
  trials with Zyrtec
• Adverse event profile consistent with an
  antihistamine given for allergic rhinitis

20
Zyrtec NDA Database
21
Zyrtec NDA Database

• Somnolence was dose-related
• Other AEs reported in children at a rate higher
  than placebo in both doses
• abdominal pain, diarrhea, vomiting
• somnolence in children 1.9 with 5 mg, 4.2 with
  10 mg, placebo 1.3
• No significant safety signals from original NDA

22
Zyrtec Cardiac Safety

• In vitro testing (myocytes, ion channels)
  revealed no effects at relevant concentrations
• No significant QT or repolarization effects seen
  in whole animals
• No significant cardiac AEs seen in clinical
  trials, including 6 times the recommended dose
• 1 of 4 safety-exposure studies showed an effect
  on the ECG
• 9.1 msec increase in QTC using Bazetts correction

23
Zyrtec Metabolic Considerations

• Renal excretion, the majority unchanged
• No significant drug interactions
• Renal impairment causes moderate decrease in
  clearance
• Hepatic impairment causes small effect on
  clearance

24
Allegra NDA Database

• Acid metabolite (active) of terfenadine
• Over 2,353 patients exposed to Allegra
• AE profile was as expected given Allegras drug
  class and indications studied

25
Allegra NDA Database
26
Allegra NDA Database

• Reporting of somnolence not dose-related
• AE profile in Children additionally showed
• headaches, accidental injuries, cough, fever,
  pain, otitis media and URIs
• No significant safety signals in original NDA

27
Allegra Cardiac Safety

• In vitro testing (ion channels, isolated
  myocytes) showed no evidence of repolarization
  effects
• No whole animal effects even at high exposures
• No significant cardiac events reported in
  clinical trials
• No clinical ECG interval effects seen, even at
  doses up to 690 mg BID

28
Allegra Metabolic Considerations

• Fexofenadine minimally metabolized
• Drug interaction studies showed small increase in
  AUC
• No evidence of important changes in metabolism in
  special populations

29
NDA summary

• All three drugs with acceptable safety in NDAs
• Work-up for cardiac effects reassuring
• Claritin with some drug-drug interactions, but no
  apparent clinical consequences

30
POST-MARKETING

• Duration of marketing will affect total numbers
  of reports
• Extent of use will affect total number of reports
• Heightened sensitivities may affect number of
  reports

31
POST-MARKETING

• Databases first extensively queried up to 4/2000,
  updated for serious events
• Overall, this assessment shows all 3 drugs to
  have a good post-marketing safety profile, though
  a few signals seen
• No issues found in review that would warrant
  reconsideration of approval

32
POST-MARKETING - OTC antihistamines

• Review of literature, AERS database also
  performed
• OTC antihistamines have acceptable safety profile
• CNS and anticholinergic AEs common
• Rare cases of seizures, liver failure, serious
  cardiac adverse events and other rare events have
  been noted

33
POST-MARKETING Claritin

• 4081 Spontaneous AEs for all loratadine products
• Most commonly reported events were
• Drug ineffective Tachycardia
• Drug interaction Insomnia
• Headache Sedation
• Palpitations Dermatitis
• Dizziness Nervousness

34
POST-MARKETING Claritin

• Serious Cardiac events
• 86 cases were reviewed in depth
• Patient ages ranged from 2 to 87 years
• 38 of reports were for patients less than 50
  years old
• Large majority of cases occurred in setting of
  confounding factors

35
POST-MARKETING Claritin

• Some hepatic terms are included in listing of in
  Claritin labeling
• 5 cases of hepatic failure in AERS database
• 3 of 5 had confounding factors
• 2 of 5 not otherwise explained, without clear
  causality

36
POST-MARKETING Zyrtec

• 3096 Spontaneous AEs in database for cetirizine
• Most commonly reported events were
• Drug ineffective Pruritus
• Sedation Drug Interaction
• Thrombocytopenia Asthenia
• Urticaria Headache
• Dermatitis Hypersensitivity

37
POST-MARKETING Zyrtec

• Thrombocytopenia (low blood platelets)
• 1 case in NDA database
• 170 cases in the AERS database
• All but 11 cases were not plausibly linked to
  cetirizine use
• Review of the 11 cases do not provide a clear
  link to the drug

38
POST-MARKETING Zyrtec

• Seizures - 64 cases
• 26 cases discounted as implausibly linked
• 38 cases were reviewed in depth, 5 were not
  seizure events
• Ages ranged from 3 to 79 years
• 21 new onset / 12 pre-existing seizure

39
POST-MARKETING Zyrtec

• Serious cardiac events
• 37 cases were reviewed in depth
• Patient ages ranged from 3 to 80 years
• More than half under 50 years
• Majority of cases with confounding features

40
POST-MARKETING Allegra

• 1768 Spontaneous AEs for fexofenadine products
• Most commonly reported events were
• Drug ineffective Sedation
• Nausea Insomnia
• Dizziness Palpitations
• Dermatitis Diarrhoea
• Headache Dyspnoea

41
POST-MARKETING Allegra

• Serious cardiac events
• 39 cases reviewed
• Age range from 15 to 81 years
• Of the most serious cases, the majority had a
  prior cardiac history and/or concomitant drugs

42
POST-MARKETING Allegra

• Seizures
• 17 of 30 cases were reviewed in depth
• ages ranged from 22 to 80years old
• 9 patients with no previous history
• 10 patients on drugs known to cause seizures
• 8 with dechallenge, 1 possible rechallenge

43
POST-MARKETING

• Some signals arise in AERS database
• After careful review, each drug has some cases of
  cardiac events and seizures that cannot be
  otherwise explained
• All these events occur with some background rate
  in the general population

44
Epidemiology Assessment

• The epidemiology staff within OPDRA estimated
  reporting rates for these 3 drugs vs. expected
  background incidences
• Events examined
• serious cardiac events
• seizures
• hepatotoxicity for loratadine

45
Epidemiology Assessment

• Background incidence rates were estimated for
  comparison purposes
• Drug experience comes from a mixed-risk
  population
• Denominator for rates inferred from actual use
  data

46
Epidemiology Assessment

• Serious Cardiac Events
• estimated incidence of 44 per million
  person-years
• New Onset Solitary Seizures
• Estimated incidence of 90 per million
  person-years
• Hepatic Failure
• Estimated incidence of 1 to 2.3 per million
  person-years

47
Epidemiology Conclusions

• The calculated reporting rates for all three
  drugs were comparable for serious cardiac events
  and seizures
• Reporting rates are below background rate for all
  three drugs and all events
• Due to limitations of the data and these
  analyses, a safety problem for one or more of
  these drugs cannot be excluded

48
Overall Clinical/Regulatory Conclusions
49
Overall Conclusions

• Loratadine, fexofenadine, cetirizine have
  extensive, favorable marketing histories and
  safety profiles
• FDC Act sets criteria for when a drug should be
  Rx-only vs. OTC
• The US market has OTC antihistamines available to
  treat symptoms of allergic rhinitis

50
Overall Conclusions

• BC/BS petition requests FDA to initiate a switch
  of three Rx antihistamines to OTC status
• Available data for these drugs supports them
  being effective for allergic rhinitis
• Some low-frequency safety signals do arise from
  the post-marketing experience
• Weight of safety evidence is that all three drugs
  have a favorable safety profile

51
Advice Sought from NDAC/PADAC

• Given the current OTC status of certain
  antihistamines for the treatment for allergic
  rhinitis and the safety information discussed
  today
• Should each individual drug be available OTC?
• If not, what other safety studies or other
  information would be recommended?
• If yes, what modifications to the existing OTC
  antihistamine labeling would be recommend?