Clinical Perspective on Citizen Petition .


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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
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Clinical Perspective on Citizen Petition NDAC/PADAC Joint Meeting Robert J. Meyer, MD Director, DPADP CDER/FDA May eleventh, 2001

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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")

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Clinical Perspective These critical contemplations are frequently tended to by : OTC genuine utilize ponder; as well as Label cognizance concentrate on

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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 items

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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 setting

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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 sources

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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 plans

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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 separately

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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 complete

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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, 1996

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NDA Safety Data Numbers of Patients Exposed Safety Experience in Clinical Trials Cardiac Safety (in vitro, creatures, human) Drug Interactions

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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 Hismanal

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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 trials

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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 NDA

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Claritin NDA Database

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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 endorsement

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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 studies

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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 freedom

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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 rhinitis

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Zyrtec NDA Database

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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 NDA

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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 remedy

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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 freedom

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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 contemplated

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Allegra NDA Database

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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 NDA

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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 BID

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Allegra Metabolic Considerations Fexofenadine negligibly metabolized Drug association contemplates indicated little increment in AUC No proof of vital changes in digestion system in exceptional populaces

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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 outcomes

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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 reports

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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 endorsement

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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 noted

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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 Nervousness

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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 variables

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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 causality

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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 Hypersensitivity

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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 medication

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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 seizure

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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 highlights

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POST-MARKETING – Allegra 1768 Spontaneous AEs for fexofenadine items Most usually reported occasions were: Drug ineffectual Sedation Nausea Insomnia Dizziness Palpitations Dermatitis Diarrhea Headache Dyspnoea

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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 medications

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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

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