1. Ipecac Syrup: Regulatory History Nonprescription Drugs Advisory Committee Meeting Arlene Solbeck, M.S. Interdisciplinary Scientist, Division of OTC Drug Products Nonprescription Drugs Advisory Committee Meeting Arlene Solbeck, M.S. Interdisciplinary Scientist, Division of OTC Drug Products Center for Drug Evaluation and Research

2. Advisory Committee Meeting June 12, 2003 2 ContentContent The OTC Drug Monograph Process Regulatory History for Ipecac Syrup Highlights from the 1985 Tentative Final Monograph –Proposed Labeling Some Final Monograph Issues Summary The OTC Drug Monograph Process Regulatory History for Ipecac Syrup Highlights from the 1985 Tentative Final Monograph –Proposed Labeling Some Final Monograph Issues Summary

3. Advisory Committee Meeting June 12, 2003 3 OTC Drug Monograph Process (The OTC Drug Review) Established in 1972 Active ingredient based review ingredient: ipecac class: poison treatment Final Monograph states conditions for marketing and required labeling Ipecac syrup is regulated under the monograph process Established in 1972 Active ingredient based review ingredient: ipecac class: poison treatment Final Monograph states conditions for marketing and required labeling Ipecac syrup is regulated under the monograph process

4. Advisory Committee Meeting June 12, 2003 4 OTC Drug Monograph Process (3 Phases) Advance Notice of Proposed Rulemaking (ANPR) Advisory Review Panel Report Tentative Final Monograph (TFM) Final Monograph (FM) The rulemaking for ipecac syrup is in the Final Monograph phase Advance Notice of Proposed Rulemaking (ANPR) Advisory Review Panel Report Tentative Final Monograph (TFM) Final Monograph (FM) The rulemaking for ipecac syrup is in the Final Monograph phase

5. Advisory Committee Meeting June 12, 2003 5 FDA’s First Regulation for Ipecac Syrup Pre-OTC Drug Review In 1965, “Ipecac Syrup; warnings and directions for OTC sale” was added as a new regulation (now codified at 21 CFR 201.308). –immediate availability of ipecac syrup for use in poisoning emergencies necessitated quick and easy availability for consumers. –recommended by the Am. Acad. of Pediatrics, Am. Assoc. of Poison Control Centers, AMA, and the Medical Advisory Board of the FDA. –FDA Commissioner: “ipecac syrup in 1 fluid ounce containers should be permitted to be sold without prescription for emergency use to cause vomiting in poisoning”. In 1965, “Ipecac Syrup; warnings and directions for OTC sale” was added as a new regulation (now codified at 21 CFR 201.308). –immediate availability of ipecac syrup for use in poisoning emergencies necessitated quick and easy availability for consumers. –recommended by the Am. Acad. of Pediatrics, Am. Assoc. of Poison Control Centers, AMA, and the Medical Advisory Board of the FDA. –FDA Commissioner: “ipecac syrup in 1 fluid ounce containers should be permitted to be sold without prescription for emergency use to cause vomiting in poisoning”.

6. Advisory Committee Meeting June 12, 2003 6 FDA’s First Regulation for Ipecac Syrup Pre-OTC Drug Review Usual dosage: 15 mL in persons over 1 year of age Not to be used in unconscious persons Not to be administered after certain kinds of poisons strychnine corrosives petroleum distillates Before using, call physician, the Poison Control Center, or hospital emergency room immediately for advice Ipecac Syrup Principal Display Panel Labeling Principal Display Panel Labeling Warnings and Directions

7. Advisory Committee Meeting June 12, 2003 7 Regulatory History- Monograph Process Advance Notice of Proposed Rulemaking ANPR (1975) –Advisory Review Panel on OTC Laxative, Antidiarrheal, Emetic, and Antiemetic Drug Products (LAEA Panel) –LAEA Panel classified ipecac syrup as a Category I (safe and effective) emetic Tentative Final Monograph (1978) –FDA’s tentative conclusions on comments submitted in response to the 1975 Panel’s report infants under 1 year - 5 to 10 mL followed by 4-8 ounces liquid infants over 1 year, children, adults - 15mL followed by 8-16 ounces liquid do not administer milk or carbonated beverages with ipecac administer second dose after 20 min. if vomiting doesn’t occur do not administer in semiconscious or unconscious persons Drug Interaction Precaution Advance Notice of Proposed Rulemaking ANPR (1975) –Advisory Review Panel on OTC Laxative, Antidiarrheal, Emetic, and Antiemetic Drug Products (LAEA Panel) –LAEA Panel classified ipecac syrup as a Category I (safe and effective) emetic Tentative Final Monograph (1978) –FDA’s tentative conclusions on comments submitted in response to the 1975 Panel’s report infants under 1 year - 5 to 10 mL followed by 4-8 ounces liquid infants over 1 year, children, adults - 15mL followed by 8-16 ounces liquid do not administer milk or carbonated beverages with ipecac administer second dose after 20 min. if vomiting doesn’t occur do not administer in semiconscious or unconscious persons Drug Interaction Precaution

8. Advisory Committee Meeting June 12, 2003 8 Regulatory History- Monograph Process (con’t) Advance Notice of Proposed Rulemaking ANPR (1982) –Advisory Review Panel on OTC Miscellaneous Internal Drugs (MI Panel) reviewed kit containing ipecac and activated charcoal –MI Panel classified ipecac syrup and activated charcoal as Category 1 (safe and effective) to treat acute toxic ingestion Tentative Final Monograph (1985) –Based on the recommendations of both the LAEA and MI Panels and comments on those reports –Contains FDA’s tentative conclusions and proposed labeling on OTC poison treatment drugs Advance Notice of Proposed Rulemaking ANPR (1982) –Advisory Review Panel on OTC Miscellaneous Internal Drugs (MI Panel) reviewed kit containing ipecac and activated charcoal –MI Panel classified ipecac syrup and activated charcoal as Category 1 (safe and effective) to treat acute toxic ingestion Tentative Final Monograph (1985) –Based on the recommendations of both the LAEA and MI Panels and comments on those reports –Contains FDA’s tentative conclusions and proposed labeling on OTC poison treatment drugs

9. Advisory Committee Meeting June 12, 2003 9 1985 Tentative Final Monograph Principal Display Panel Labeling If possible call a Poison Control Center, emergency medical facility, or health professional for help before using this product. If help cannot be reached quickly, follow the directions. Read the warnings and directions as soon as you buy this product. Insert emergency phone numbers in space provided on the label. 30 mL Ipecac Syrup

10. Advisory Committee Meeting June 12, 2003 10 1985 Tentative Final Monograph - Directions Proposed Dosages –adults and children 12 years and older: 30 mL followed by 8-16 ounces liquid –children 1-under 12 years: 15 mL followed by 8-16 ounces liquid –children 6 mo. to under 1 year: 5 mL followed by 4-8 ounces liquid –children under 6 months: not recommended Proposed Directions –water or other clear liquids to be administered following ipecac; milk should not be given –repeat dosage if vomiting does not occur within 30 min. –keep patients active and moving Proposed Dosages –adults and children 12 years and older: 30 mL followed by 8-16 ounces liquid –children 1-under 12 years: 15 mL followed by 8-16 ounces liquid –children 6 mo. to under 1 year: 5 mL followed by 4-8 ounces liquid –children under 6 months: not recommended Proposed Directions –water or other clear liquids to be administered following ipecac; milk should not be given –repeat dosage if vomiting does not occur within 30 min. –keep patients active and moving

11. Advisory Committee Meeting June 12, 2003 11 1985 Tentative Final Monograph - Warnings Proposed Warnings –do not use in persons who are not fully conscious –do not use this product if turpentine, corrosives (such as alkalies (lye) and strong acids), or petroleum distillates (such as kerosene, gasoline, paint thinner or furniture polish) have been ingested. –do not administer milk Poison Treatment Kit –Drug Interaction Precaution: Do not give activated charcoal until after the patient has vomited, unless directed by a health professional. Proposed Warnings –do not use in persons who are not fully conscious –do not use this product if turpentine, corrosives (such as alkalies (lye) and strong acids), or petroleum distillates (such as kerosene, gasoline, paint thinner or furniture polish) have been ingested. –do not administer milk Poison Treatment Kit –Drug Interaction Precaution: Do not give activated charcoal until after the patient has vomited, unless directed by a health professional.

12. Advisory Committee Meeting June 12, 2003 12 XXXXX IPECAC SYRUP USP EMETIC ALCOHOL 1.75% If possible, call a Poison Control Center, emergency facility or health professional for help before using this product. If help cannot be reached quickly, follow the directions on this label. Read the warnings and directions as soon as you buy this product. Insert emergency phone number(s) in space provided on the label_____________________________ Contents 1 FL.OZ. (30 mL) POISON FIRST AID DIRECTIONS: Adults and children 12 years of age and over: oral dosage is 2 tablespoonfuls (30 milliliters or 1 bottle) followed by 1-2 glasses (8-16 ozs.) of water or other clear liquid as directed by a health professional. Children 1 to under 12 years of age: oral dosage is 1 tablespoonful (15 milliliters or 1/2 bottle) followed by 1 to 2 glasses or water or other clear liquid or as directed by a health professional. Children 6 months to under 1 year of age: oral dosage is 1 teaspoonful (5 milliliters) followed by 1/2 to 1 glass (4-8 ozs.) of water or other clear liquid or as directed by a health professional. Children under 6 months of age: Do not administer unless directed by a health professional. If vomiting does not occur within 30 minutes, repeat the dose. If previous attempts to contact a poison control center, emergency medical facility, or health professional were unsuccessful, continue trying. Keep patient active and moving. Save the container of poison. ACTIVE INGREDIENTS; Ipecac F.E. ALSO CONTAINS: Glycerin, Sodium Benzoate, Sucrose, Purified Water. WARNING: Do not use if shrink band around cap imprinted “Sealed For Your Protection” is broken or missing. INDICATIONS: For emergency use to cause vomiting of swallowed poisons. WARNING: Do not use in persons who are not fully conscious. Do not use this product, unless directed by a health professional, if turpentine, corrosives, such as alkalies (lye) and strong acids, or petroleum distillates, such as kerosene, gasoline, paint thinner, cleaning fluid, or furniture polish, have been ingested. Do not administer milk with this product. INTERACTION PRECAUTION: Activated charcoal will absorb ipecac syrup. Do not give activated charcoal until after the patient has vomited, unless directed by a health professional. SAFETY SEALED Sample Label

13. Advisory Committee Meeting June 12, 2003 13 Comments After the 1985 Tentative Final Monograph Published FDA received comments from –6 poison control centers –6 hospitals –7 medical schools –3 trade associations –5 manufacturers –3 law firms –14 individuals Comments for OTC availability –OTC availability of ipecac syrup for treating accidental poisonings in the public interest medically and financially FDA received comments from –6 poison control centers –6 hospitals –7 medical schools –3 trade associations –5 manufacturers –3 law firms –14 individuals Comments for OTC availability –OTC availability of ipecac syrup for treating accidental poisonings in the public interest medically and financially

14. Advisory Committee Meeting June 12, 2003 14 Comments (con’t) Comments about safety aspects of using ipecac –concern for proper management of poisoning –children under 1 year of age may have an increased risk for aspiration and dehydration –potential risks of ipecac syrup induced vomiting in the elderly –concern that ipecac syrup not be misused or abused Comments about safety aspects of using ipecac –concern for proper management of poisoning –children under 1 year of age may have an increased risk for aspiration and dehydration –potential risks of ipecac syrup induced vomiting in the elderly –concern that ipecac syrup not be misused or abused

15. Advisory Committee Meeting June 12, 2003 15 Recent Developments Post - 1985 Tentative Final Monograph Medical literature and some poison control and clinical toxicology societies indicate the safety and efficacy of ipecac syrup should be reevaluated Clinical studies question benefit of ipecac Medical literature and some poison control and clinical toxicology societies indicate the safety and efficacy of ipecac syrup should be reevaluated Clinical studies question benefit of ipecac

16. Advisory Committee Meeting June 12, 2003 16 Recent Developments (con’t) Recommends reevaluation of ipecac’s benefit –American Academy of Clinical Toxicology - 1997 position statement – European Association of Poison Centers & Clinical Toxicologists - 1997 position statement –American Board of Applied Toxicology (endorses 1997 statement) – Canadian Association of Poison Control Centers (endorses 1997 statement) Recommends ipecac for accidental poisonings –American College of Emergency Physicians – American Medical Association Recommends reevaluation of ipecac’s benefit –American Academy of Clinical Toxicology - 1997 position statement – European Association of Poison Centers & Clinical Toxicologists - 1997 position statement –American Board of Applied Toxicology (endorses 1997 statement) – Canadian Association of Poison Control Centers (endorses 1997 statement) Recommends ipecac for accidental poisonings –American College of Emergency Physicians – American Medical Association

17. Advisory Committee Meeting June 12, 2003 17 SummarySummary Poison Treatment rulemaking is in the Final Monograph stage. Ipecac syrup and activated charcoal are the only two ingredients classified as Category I (safe and effective) for OTC poison treatment. Should ipecac syrup remain OTC? Poison Treatment rulemaking is in the Final Monograph stage. Ipecac syrup and activated charcoal are the only two ingredients classified as Category I (safe and effective) for OTC poison treatment. Should ipecac syrup remain OTC?