1. OTC Dermatologic Topical Corticosteroids Michael L. Koenig, Ph.D. Interdisciplinary Scientist Division of Over-the-Counter Drug Products Center for Drug Evaluation and Research

2. 2 Joint DODAC/NDAC Meeting March 24, 2005 Overview 1.Regulation of OTC Drugs 2.Regulatory History of Hydrocortisone 3.Current Labeling of Hydrocortisone

3. 3 Joint DODAC/NDAC Meeting March 24, 2005 Regulation of OTC Drugs NDA (New Drug Application) –Drug product-specific –Confidential Monograph –Active ingredient-specific –Public

4. 4 Joint DODAC/NDAC Meeting March 24, 2005 OTC Monographs OTC Drug Review initiated in 1972 > 200,000 OTC drug products 700 active ingredients in 26 therapeutic categories

5. 5 Joint DODAC/NDAC Meeting March 24, 2005 OTC Monographs Category I: GRASE (Generally Recognized as Safe and Effective) Category II: not GRASE Category III: cannot determine if safe and effective Advisory Review Panel

6. 6 Joint DODAC/NDAC Meeting March 24, 2005 OTC Monographs Category I: GRASE Category II: not GRASE Category III: cannot determine if safe and effective ANPR

7. 7 Joint DODAC/NDAC Meeting March 24, 2005 OTC Monographs ANPR TFM Comments

8. 8 Joint DODAC/NDAC Meeting March 24, 2005 OTC Monographs TFM Comments Data FM

9. 9 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone

10. 10 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone Introduced as Rx drug (1952) Rx-to-OTC switch rejected (1957) –Failure to show safety for self-medication –More testing on absorption through the skin Included with other active ingredients in review of external analgesics (1973-1978)

11. 11 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone ANPR (1979) Lack of adverse local effects –Striae –Telangiectasia –Pustular eruptions and crusting

12. 12 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone ANPR (1979) Lack of systemic effects –Percutaneous absorption –Eosinophil count –Urinary levels of 17-hydroxysteroids and 17- ketosteroids –Blood glucose levels –Serum sodium –Plasma cortisol ↑ in response to insulin

13. 13 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone No HPA Axis Suppression Munro and Clift, Br. J. Dermatol., 1973 (TAB 5) –40 patients with eczema, psoriasis –Long term treatment (95% > 10 months) –Corticosteroid combinations 10 included 1% hydrocortisone acetate –10/10: normal insulin stress response

14. 14 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone Serious Adverse Events (1952-1973) 1960: Temporary growth retardation in 5.5 year old –1% hydrocortisone for 16 months 1962: Temporary growth retardation in infant –1% hydrocortisone twice daily for 6 months (total body) 1966: Rapid gain in body weight in 3-week old –0.25% hydrocortisone three times daily for 8.5 days –2100 mg/m 2 body surface area

15. 15 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone Panel Recommendations 0.25 – 0.5% hydrocortisone GRASE Recommended labeling: –Indication – temporary relief of minor skin irritations, itching, and rashes due to eczema, dermatitis… –Warnings Stop use if condition worsens or lasts > 7 days Do not use on children under 2 years of age –Directions – Apply to affected area not more than 3 to 4 times daily

16. 16 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone TFM (1983) FDA position –Agreed 0.25 – 0.5% hydrocortisone GRASE –Some labeling modifications Temporary relief of itching associated with minor skin irritations and rashes due to… Stop use if condition worsens or lasts > 7 days or if symptoms clear up and occur again within a few days

17. 17 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone Amended TFM (1990) Citizen Petition requested increase in dosage strength to 1% Data and literature review 0.25 – 1.0% hydrocortisone GRASE Additional labeling modifications –Do not use any other hydrocortisone product for the treatment of diaper rash

18. 18 Joint DODAC/NDAC Meeting March 24, 2005 Regulatory History of Hydrocortisone FM (20??) Pending Manufacturers generally comply with TFM and amended TFM Continuing review of data

19. 19 Joint DODAC/NDAC Meeting March 24, 2005 Hydrocortisone Does Not Suppress HPA Axis Published StudynHydrocortisone (%) Duration of Treatment Munro, 19799 1*14 days Marten et al., 198010128 days Patel et al., 19951413 - 10 years Lucky et al., 19978 2.528 days Ellison et al., 2000710.5 – 17.7 years * Hydrocortisone acetate

20. 20 Joint DODAC/NDAC Meeting March 24, 2005 Current Labeling of Hydrocortisone

21. 21 Joint DODAC/NDAC Meeting March 24, 2005 Monograph Labeling: Hydrocortisone Drug Facts Active ingredient Purpose Hydrocortisone (1%)…………………………………………....Anti-itch Uses ■ temporarily relieves itching associated with minor skin irritations, inflammation, and rashes due to: ■ eczema ■ poison ivy, oak, sumac ■ insect bites ■ soaps ■ detergents ■ cosmetics ■ jewelry ■ seborrheic dermatitis ■ psoriasis ■ and for external genital or anal itching ■ other uses of this product should be only under the advice and supervision of a doctor Warnings External use only Do not use ■ for the treatment of diaper rash. Consult a doctor. ■ in the genital area if you have a vaginal discharge. Consult a doctor. Drug Facts (continued) When using this product ■ avoid contact with the eyes ■ do not exceed the recommended daily dosage unless directed by a doctor ■ do not cover treated skin ■ do not use any other hydrocortisone product ■ do not put directly in rectum using fingers or any mechanical device Stop use and ask a doctor if ■ condition worsens ■ symptoms persist for more than 7 days or clear up and occur again within a few days ■ rectal bleeding occurs Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions ■ adults and children 2 years of age and older: apply to affected area not more than 3 to 4 times daily. ■ children under 2 years of age: Do not use. Consult a doctor.

22. 22 Joint DODAC/NDAC Meeting March 24, 2005 Monograph Labeling: Hydrocortisone Drug Facts Active ingredient Purpose Hydrocortisone (1%)…………………………………………....Anti-itch Uses ■ temporarily relieves itching associated with minor skin irritations, inflammation, and rashes due to: ■ eczema ■ poison ivy, oak, sumac ■ insect bites ■ soaps ■ detergents ■ cosmetics ■ jewelry ■ seborrheic dermatitis ■ psoriasis ■ and for external genital or anal itching ■ other uses of this product should be only under the advice and supervision of a doctor Warnings External use only Do not use ■ for the treatment of diaper rash. Consult a doctor. ■ in the genital area if you have a vaginal discharge. Consult a doctor. Drug Facts (continued) When using this product ■ avoid contact with the eyes ■ do not exceed the recommended daily dosage unless directed by a doctor ■ do not cover treated skin ■ do not use any other hydrocortisone product ■ do not put directly in rectum using fingers or any mechanical device Stop use and ask a doctor if ■ condition worsens ■ symptoms persist for more than 7 days or clear up and occur again within a few days ■ rectal bleeding occurs Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions ■ adults and children 2 years of age and older: apply to affected area not more than 3 to 4 times daily. ■ children under 2 years of age: Do not use. Consult a doctor. temporarily relieves itching associated with minor skin irritations, inflammation and rashes due to: ■ eczema■ poison ivy, oak, sumac ■ insect bites■ soaps ■ detergents■ cosmetics ■ jewelry■ seborrheic dermatitis ■ psoriasis■ and for external genital or anal itching Stop use and ask a doctor if ■ symptoms persist for more than 7 days or clear up and occur again within a few days ■ apply to affected area not more than 3 to 4 times daily. ■ children under 2 years of age: Do not use. Consult a doctor.

23. 23 Joint DODAC/NDAC Meeting March 24, 2005 temporarily relieves itching of minor skin irritations, inflammation and rashes… symptoms persist for more than 7 days or clear up and occur again within a few days ■ apply to affected area not more than 3 to 4 times daily ■ children under 2 years of age: do not use, ask a doctor