Clinical Perspective on Citizen Petition NDAC/PADAC Joint Meeting Robert J. Meyer, MD Director, DPADP CDER/FDA May eleventh, 2001Slide 2
Clinical Perspective Important Considerations for OTC Switch : The capacity of the customer to self-analyze as well as self-oversee Safety and adequacy for medication utilized as a part of OTC setting (i.e., without an "educated middle person")Slide 3
Clinical Perspective These critical contemplations are frequently tended to by : OTC genuine utilize ponder; as well as Label cognizance concentrate onSlide 4
Clinical Perspective Allegra, Claritin and Zyrtec are all antihistamines, all affirmed to treat unfavorably susceptible rhinitis FDA acknowledges hypersensitive rhinitis as a proper OTC sign, and FDA acknowledges antihistamines as suitable for OTC utilize FDA has built up fitting OTC naming for antihistamine itemsSlide 5
Clinical Perspective Neither a real utilize think about nor a naming understanding study is fundamental for the OTC switch proposed FDA is not looking for guidance on : Allergic rhinitis as an OTC sign On the viability of Claritin, Zyrtec or Allegra in OTC settingSlide 6
Clinical Perspective Focus of FDA clinical presentation is on security and how the wellbeing encounters bear on the choice for OTC accessibility FDA performed full security survey NDA information Post-promoting information (AERS) Other sourcesSlide 7
Safety Presentation Elements of security presentation : NDA information Standard security information, cardiovascular wellbeing assessment, tranquilize collaborations Post-showcasing background Case Review, Epidemiology Focus for NDA on single fixing mixes AERS reports for incorporate all plansSlide 8
Safety Presentation - Caveats Safety audit is not expected to be similar of the three specialists Safety audit won\'t endeavor to thoroughly contrast with OTC antihistamines Safety survey will characterize the wellbeing knowledge with these operators separatelySlide 9
Safety Presentation - Caveats Most authoritative wellbeing information are from NDA Post-advertising information offers less conclusive data about item security The utilization of the study of disease transmission assessments of AERS information can put post-promoting information in context, however is not completeSlide 10
NDA Data Introduction Claritin (loratadine) endorsed for promoting April 12, 1993 Zyrtec (cetirizine) affirmed for promoting Dec. 8, 1995 Allegra (fexofenadine) endorsed for advertising July 25, 1996Slide 11
NDA Safety Data Numbers of Patients Exposed Safety Experience in Clinical Trials Cardiac Safety (in vitro, creatures, human) Drug InteractionsSlide 12
NDA Safety Data Introduction Why the emphasis on cardiovascular security and medication tranquilize collaborations? Issues for Seldane (terfenadine): ECG/repolarization impacts (QT interim) Cases of threatening arrhythmias (TdP) Problem was clinically show because of medication collaborations Similar issues with HismanalSlide 13
NDA Safety Data Introduction Cardiac Investigation of this potential for another medication may incorporate : In vitro investigations of particle (K + ) stations and repolarization in separated cardiovascular muscle In vivo creature thinks about Clinical information e.g., high measurement and medication cooperation ponders, clinical observing in clinical trialsSlide 14
Claritin NDA Database In the NDA database for loratadine more than 90,000 patients uncovered Adverse occasion profile was reliable for an antihistamine given for unfavorably susceptible rhinitis No huge clinical wellbeing signals in unique NDASlide 15
Claritin NDA DatabaseSlide 16
Claritin NDA Database Somnolence was dosage related, with reporting of 10% with 20 mg QD, 12% with 40 mg QD Pediatric studies (6 - 11 years) demonstrated comparable AE profile Nervousness, hyperkinesia, wheezing and stomach torment likewise reported No huge security worries at the season of endorsementSlide 17
Claritin Cardiac Safety In vitro testing (particle station, myocardial cells) was negative No QT or repolarization impacts recorded in creatures No noteworthy heart AE\'s seen in clinical trials (up to 160 mg) No clinically significant impact on QTc archived in clinical studiesSlide 18
Claritin Metabolic Considerations Loratadine metabolized by CYP3A4, 2D6 Drug connection examines with erythromycin, cimetidine and ketoconazole demonstrated some expansion in loratadine and desloratadine AUCs No clinically huge effect Renal and hepatic deficiency diminish freedomSlide 19
Zyrtec NDA Database An Active metabolite of hydroxyzine Over 3900 patients were dealt with in clinical trials with Zyrtec Adverse occasion profile predictable with an antihistamine given for hypersensitive rhinitisSlide 20
Zyrtec NDA DatabaseSlide 21
Zyrtec NDA Database Somnolence was dosage related Other AEs reported in kids at a rate higher than fake treatment in both doses: stomach torment, the runs, heaving sleepiness in youngsters 1.9% with 5 mg, 4.2% with 10 mg, fake treatment = 1.3% No huge security signals from unique NDASlide 22
Zyrtec Cardiac Safety In vitro testing (myocytes, particle stations) uncovered no impacts at applicable fixations No critical QT or repolarization impacts found in entire creatures No huge cardiovascular AE\'s seen in clinical trials, including 6 times the suggested measurement 1 of 4 security presentation concentrates on demonstrated an impact on the ECG 9.1 msec increment in QTC utilizing Bazett\'s remedySlide 23
Zyrtec Metabolic Considerations Renal discharge, the larger part unaltered No huge medication communications Renal weakness causes direct decline in leeway Hepatic impedance causes little impact on freedomSlide 24
Allegra NDA Database Acid metabolite (dynamic) of terfenadine Over 2,353 patients presented to Allegra AE profile was of course given Allegra\'s medication class and signs contemplatedSlide 25
Allegra NDA DatabaseSlide 26
Allegra NDA Database Reporting of drowsiness not measurements related AE profile in Children furthermore appeared: migraines, incidental wounds, hack, fever, torment, otitis media and URIs No huge wellbeing signals in unique NDASlide 27
Allegra Cardiac Safety In vitro testing (particle stations, detached myocytes) demonstrated no confirmation of repolarization impacts No entire creature impacts even at high exposures No huge cardiovascular occasions reported in clinical trials No clinical ECG interim impacts seen, even at dosages up to 690 mg BIDSlide 28
Allegra Metabolic Considerations Fexofenadine negligibly metabolized Drug association contemplates indicated little increment in AUC No proof of vital changes in digestion system in exceptional populacesSlide 29
NDA synopsis All three medications with adequate wellbeing in NDAs Work-up for heart impacts consoling Claritin with some medication tranquilize connections, however no evident clinical outcomesSlide 30
POST-MARKETING Duration of showcasing will influence add up to quantities of reports Extent of utilization will influence add up to number of reports Heightened sensitivities may influence number of reportsSlide 31
POST-MARKETING Databases first broadly questioned up to 4/2000, upgraded for genuine occasions Overall, this evaluation demonstrates every one of the 3 medications to have a decent post-advertising security profile, however a couple signals seen No issues found in audit that would warrant reevaluation of endorsementSlide 32
POST-MARKETING - OTC antihistamines Review of writing, AERS database additionally performed OTC antihistamines have satisfactory security profile CNS and anticholinergic AEs normal Rare instances of seizures, liver disappointment, genuine heart antagonistic occasions and other uncommon occasions have been notedSlide 33
POST-MARKETING – Claritin 4081 Spontaneous AEs for all loratadine items Most regularly reported occasions were: Drug incapable Tachycardia Drug cooperation Insomnia Headache Sedation Palpitations Dermatitis Dizziness NervousnessSlide 34
POST-MARKETING – Claritin Serious Cardiac occasions: 86 cases were checked on top to bottom Patient ages went from 2 to 87 years 38% of reports were for patients under 50 years of age Large greater part of cases happened in setting of frustrating variablesSlide 35
POST-MARKETING – Claritin Some hepatic terms are incorporated into posting of in Claritin naming 5 instances of hepatic disappointment in AERS database 3 of 5 had bewildering elements 2 of 5 not generally clarified, without clear causalitySlide 36
POST-MARKETING – Zyrtec 3096 Spontaneous AEs in database for cetirizine Most ordinarily reported occasions were: Drug inadequate Pruritus Sedation Drug Interaction Thrombocytopenia Asthenia Urticaria Headache Dermatitis HypersensitivitySlide 37
POST-MARKETING – Zyrtec Thrombocytopenia (low blood platelets): 1 case in NDA database 170 cases in the AERS database All yet 11 cases were not conceivably connected to cetirizine utilize Review of the 11 cases don\'t give a reasonable connection to the medicationSlide 38
POST-MARKETING – Zyrtec Seizures - 64 cases 26 cases reduced as unrealistically connected 38 cases were looked into top to bottom, 5 were not seizure occasions Ages ran from 3 to 79 years 21 new onset/12 previous seizureSlide 39
POST-MARKETING – Zyrtec Serious cardiovascular occasions 37 cases were inspected top to bottom Patient ages extended from 3 to 80 years More than half under 50 years Majority of cases with jumbling highlightsSlide 40
POST-MARKETING – Allegra 1768 Spontaneous AEs for fexofenadine items Most usually reported occasions were: Drug ineffectual Sedation Nausea Insomnia Dizziness Palpitations Dermatitis Diarrhea Headache DyspnoeaSlide 41
POST-MARKETING – Allegra Serious heart occasions 39 cases assessed Age go from 15 to 81 years Of the most genuine cases, the lion\'s share had an earlier heart history or potentially accompanying medicationsSlide 42
POST-MARKETING – Allegra Seizures 17 of 30 cases were surveyed top to bottom ages ran from 22 to 80years old 9 patients with no past history 10 patients on medications known to bring about seizures 8 with dechallenge
Translational Examination - A Fundamental Science Point of view Translational exploration: makes ...
2.2 Waterfall Model as Overview. Understanding necessities ... Waterfall model. stays one of the ...
Untamed life Management District #6. T 8 R 3 WELS. DWA# Acres. 120102 297 ... Untamed life Manag ...
Untamed life Conservation as a Science (Leopold composed
Gatherings hold level headed discussions between competitors. Applicants are dispensed with ... ...
2)Each school is instruction establishment that can raise reserves from the general public ... s ...
Established in 1978 as the World Computing Services Industry Association ... Netherlands. Nether ...
PRESIDENTIAL REQUIREMENTS. Common BORN CITIZENMust be conceived in the United States or destined ...
10/8/2011. 2. Citizen\'s Advisory Committee Environmental Design. Charge: Explore
Welcome!. Mini-CFSR Training Presented by the Department of Family Services & Wyoming Cit ...
Restoring the Whole Person With Nutritional and Botanical Detoxification: A Clinical Perspecti ...
Introduction. Value Engineering workshop for Senior Citizen Bathroom . AGENDA. Introduc ...
Overview of Exposures of Concern: A Clinical Perspective- What We Have Seen in the Literature ...
Foundation. USDC Involvement Began in 1997GRAS Petition (1998)USDC Inspection Policy (1998)FDA I ...
2. Involvement with majority rule government . . .. Government where everyone\'s assessment tall ...