# Presentation: 896412

## Clinical Perspective on Citizen Petition

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

## 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”)**

## Clinical Perspective

_***These important considerations are often addressed by***_**:**
**OTC actual-use study; and/or**
**Label comprehension study**

**Notes:**
The OTC use study is to examine the ability of consumers to self-diagnose and effectively and safety self-treat

Label comprehension studies are done to assess the ability of consumers to understand the necessary conditions of use for their disease and for the drug proposed for a switch.

## 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**

**Notes:**
These products are all antihistamines, approved for seasonal allergic rhinits.  FDA already accepts allergic rhinits as an appropriate OTC indication (for OTC antihistamines, decongestants, cromolyn) and that antihistamines can be used effectively and safety in that setting.  Further, FDA has standard OTC labeling for antihistamines that we find reasonable in terms of conveying the necessary conditions of use. 

## 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**
**    **

**Notes:**
FDA does not believe that an in-use study nor a labeling comprehension study would be  necessary for the switch of any of these agents to the OTC setting.

Therefore, today, we are not seeking advice from the committee on allergic rhinitis as an OTC indication nor on the effectiveness of these drugs used in that setting.

## 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**

**Notes:**
Rather, FDA will focus on the safety history both pre-approval and subsequent to marketing with these agents.  How these safety data should inform any decision to take any one of these drugs over the counter is the focus of our presentation and the advice we seek from the committees.

## 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**

## 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**

**Notes:**
On the next few slides are  some important caveats I would like to make before turning to the substantive part  of the presentation

## 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**

**Notes:**
In a heirarchy of the data reviewed, the NDA database - through the non-human testing and primarily theControlled Clinical Trials, offers the most definitive safety data.  However, the safety evaluations in NDAs cannot not reliably detect rare or unusually occurring adverse vents.
Post-marketing data from A> E> R> S  - after thousands or millions of patients receive the drug offers the possibility of  detecting rarer adverse events.  However, due to reporting biases, non-reporting, lack of information in cases and a lack of a true denominator, it does not allow quantitation of occurrences.  For reports of events that otherwise occur with some regularity in the population, then, it is often hard to sort out reports as to likely causality.  That is, it is often hard to determine if the drug caused the event.
Epidemiologic approaches to the data can help with this to a degree, but short of controlled data, it still may be hard to accurately assess whether a certain number of reports represents a true signal of concern.

## 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**

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

**Safety Experience in Clinical Trials**
**Cardiac Safety (in vitro, animals, human)**
**Drug Interactions**

**NDA Safety Data**

## 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**

## 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**

## 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**

## Claritin NDA Database

## 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**

## Claritin Cardiac Safety

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

## 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**

## 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**

## Zyrtec NDA Database

## 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**

## 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 AE’s 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 Bazett’s correction**

## 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**

## Allegra NDA Database

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

## Allegra NDA Database

## 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**

## 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**

## Allegra Metabolic Considerations

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

## 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**

## 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**

## 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**

## 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 **

## 4081 Spontaneous AEs for all loratadine products

Most commonly reported events were:
		Drug ineffective 		 Tachycardia
		Drug interaction 		 Insomnia 	
		Headache 			 Sedation
		Palpitations 			 Dermatitis
		Dizziness 			 Nervousness

**Most commonly reported events were:**
**	****	****Drug ineffective ****	****	**** Tachycardia**
**	****	****Drug interaction ****	****	**** Insomnia ****	**
**	****	****Headache ****	****	****	**** Sedation**
**	****	****Palpitations ****	****	****	**** Dermatitis**
**	****	****Dizziness ****	****	****	**** Nervousness**

**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

**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**

**POST-MARKETING – Claritin**

## 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**

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

**	****Most commonly reported events were:**
** ****	****	****Drug ineffective ****	****	****	****Pruritus**
**	****	****Sedation ****	****	****	****	****Drug Interaction**
**	****	****Thrombocytopenia ****	****	****	****Asthenia**
**	****	****Urticaria ****	****	****	****	****Headache**
**	****	****Dermatitis ****	****	****	****	****Hypersensitivity**** **
**	****	****	****	**

**POST-MARKETING – Zyrtec**

## 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**

## 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**

## 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**

## 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 **
**	****	****	**
**	****	**
**	****	**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## Overall Clinical/Regulatory Conclusions

## Overall Conclusions

**Loratadine, fexofenadine, cetirizine have extensive, favorable marketing histories and safety profiles**
**FD&C 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**

## 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 **

## 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?**