1. NDAC/PADAC Joint Meeting May 11, 2001 Cazemiro R. Martin Regulatory Review Chemist FDA, Division of OTC Drug Products

2. Prescription Availability Durham-Humphrey Amendment to the Federal FD&C Act (1951)

3. Durham-Humphrey Amendment n 503(b)(1)(A) : Because of toxicity or potentially harmful effects (not safe unless used under supervision) or…. or…. n 503(b)(1)(B) : Limited by approved application to use under supervision

4. OTC Availability n New Drug Application Process (NDA) – Prescription (Rx)-to-OTC Switch process – Marketed directly OTC n OTC Drug Monograph Process – Established conditions under which OTC drug products are generally recognized as safe and products are generally recognized as safe and effective (GRAS/E) effective (GRAS/E)

5. NDA Process Rx-to-OTC Considerations: n Can the condition be adequately self-recognized? self-recognized? n Can the condition be successfully self-treated? self-treated? n Is the self-treatment product safe and effective during consumer use? and effective during consumer use?

6. NDA Process Rx-to-OTC Switch Candidate: n Acceptable margin of safety based on prior prescription marketing experience prescription marketing experience n OTC dosages/indications are relatively safe - low misuse potential - low misuse potential - minimal abuse potential - minimal abuse potential - reasonable therapeutic window of safety - reasonable therapeutic window of safety

7. NDA Process Rx-to-OTC Switch Candidate (cont.) n Self-treatment and self-monitoring with minimal physician supervision with minimal physician supervision n Adequately labeled to allow safe and effective use of the OTC drug and effective use of the OTC drug n Benefits from the OTC switch clearly outweigh the risks outweigh the risks

8. OTC Drug Monograph Process n Advisory Review Panel n Advance Notice of Proposed Rulemaking - advisory panel report Rulemaking - advisory panel report n Tentative Final Monograph n Final Monograph

9. Advisory Review Panel OTC Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products

10. Advanced Notice of Proposed Rulemaking - 1976 Panel’s Antihistamine Review Panel’s Antihistamine Review n Effective in suppressing symptoms of allergic rhinitis (such as hay fever) rhinitis (such as hay fever) n Low order of acute and chronic toxicity

11. Advisory Panel Report (Antihistamine Review - cont.) n Common side effects - rarely serious » CNS depression: drowsiness » Anticholinergic: dryness of the mouth; urinary retention; reduced bronchial urinary retention; reduced bronchial secretions secretions n Rarely occurring side effects » Cardiovascular, gastrointestinal, hematological

12. Advisory Panel Report (Antihistamine Review - cont.) n Labeling recommendations: Uses: temporary relief of symptoms associated with allergic rhinitis with allergic rhinitis Warnings: » may cause drowsiness » avoid driving or operating machinery » avoid alcoholic drinks » consult a physician before use if you have difficulty in urination or difficulty breathing difficulty in urination or difficulty breathing

13. Tentative Final Monograph January 15, 1985

14. Final Monograph - 1992 (OTC Antihistamines) 21 CFR 341 n 13 antihistamine active ingredients marketed under the OTC drug monograph system under the OTC drug monograph system n Final rule addresses “allergy” indications only n Labeling of OTC antihistamine drug products

15. OTC Monograph Antihistamines 21 CFR 341.12 n Brompheniramine maleate n Chlorcyclizine HCl n Chlorpheniramine maleate n Dexbrompheniramine maleate n Dexchlorpheniramine maleate n Diphenhydramine citrate n Diphenhydramine HCl n Doxylamine succinate n Phenindamine tartrate n Pheniramine maleate n Pyrilamine maleate n Thonzylamine HCl n Triprolidine HCl

16. OTC NDA/ANDA Antihistamines Extended Release: Extended Release:  Brompheniramine maleate  Chlorpheniramine maleate  Dexbrompheniramine maleate  Triprolidine HCl Immediate Release:  Clemastine fumarate

17. Nonmonograph Ingredients n Methapyrilene fumarate n Methapyrilene HCl n Phenyltoloxamine dihydrogen citrate dihydrogen citrate n Promethazine HCl n Thenyldiamine HCl n Tripelennamine HCl - potential carcinogen - inadequate efficacy data - tardive dyskinesia: causal role - single ingredient: no long-term use - inadequate efficacy data - safe/effective:no data submitted

18. OTC Antihistamines Drug Facts Labeling Drug Facts Labeling 21 CFR 201.66 Format and Content Requirements for OTC Drug Product Labeling

20. Summary n OTC Drug Products: – acceptable margin of safety (minimal toxicity) – low potential for harmful effects – low misuse/minimal abuse potential – reasonable therapeutic window of safety n Self-treatment and self-monitoring n Adequately labeled to allow safe and effective use n Benefits outweigh risks