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. Overview

Regulation of OTC Drugs

Regulatory History of Hydrocortisone

Current Labeling of Hydrocortisone

3. Regulation of OTC Drugs

NDA (New Drug Application)

• Drug product-specific

• Confidential

Monograph

• Active ingredient-specific

• Public

4. OTC Monographs

OTC Drug Review initiated in 1972

> 200,000 OTC drug products

700 active ingredients in 26 therapeutic categories

5. 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. OTC Monographs

Category I: GRASE

Category II: not GRASE

Category III: cannot determine if safe and effective

ANPR 7. OTC Monographs Comments ANPR TFM 8. OTC Monographs Comments Data TFM FM 9. Regulatory History of Hydrocortisone 10. 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. Regulatory History ofHydrocortisone

ANPR (1979)

Lack of adverse local effects

• Striae

• Telangiectasia

• Pustular eruptions and crusting

12. Regulatory History ofHydrocortisone

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. 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. Regulatory History ofHydrocortisone

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 2body surface area

15. 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. Regulatory History ofHydrocortisone

TFM (1983)

FDA position

• Agreed 0.25 0.5% hydrocortisone GRASE

• Some labeling modifications

• • Temporary relief of itchingassociated with minor skin irritations and rashes due to

• • Stop use if condition worsens or lasts > 7 daysor if symptoms clear up and occur again within a few days

17. Regulatory History of Hydrocortisone

Amended TFM (1990)

Citizen Petition requestedincrease in dosage strength to1%

Data and literature review

0.25 1.0% hydrocortisone GRASE

Additional labeling modifications

• Do not use

• • any other hydrocortisone product

• • for the treatment ofdiaper rash

18. Regulatory History of Hydrocortisone

FM (20??)

Pending

Manufacturers generally comply with TFM and amended TFM

Continuing review of data

19. Hydrocortisone Does Not Suppress HPA Axis * Hydrocortisone acetate 7 8 14 10 9 n Ellison et al., 2000 Lucky et al., 1997 Patel et al., 1995 Marten et al., 1980 Munro, 1979 Published Study 0.5 17.7 years 1 28 days 2.5 3 - 10 years 1 28 days 1 14 days 1* Duration of Treatment Hydrocortisone (%) 20. Current Labeling of Hydrocortisone 21. Monograph Labeling:Hydrocortisone 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 adoctor.

Uses

temporarily relieves itching associated with minor skin

irritations, inflammation, and rashes due to :

• eczemapoison ivy, oak, sumac

• insect bitessoaps

• detergentscosmetics

• jewelryseborrheic dermatitis

• psoriasis and forexternal genital or anal

• itching

other uses of this product should be only under the advice and

supervision of a doctor

Active ingredientPurpose Hydrocortisone (1%)....Anti-itch Drug Facts Drug Facts(continued) When using this product avoid contact with the eyes do not exceed the recommended daily dosage unless directed bya doctor do not cover treated skin do not use any other hydrocortisone product do not put directly in rectum using fingers or any mechanicaldevice Directions adults and children 2 years of age and older:a pply to affectedarea not more than 3 to 4 times daily. children under 2 years of age:Do not use.Consult a doctor. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Stop use and ask a doctor if condition worsens symptoms persist for more than 7 days or clear up and occuragain within a few days rectal bleeding occurs 22. Monograph Labeling:Hydrocortisone 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. 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 adoctor.

Uses

temporarily relieves itching associated with minor skin

irritations, inflammation, and rashes due to :

• eczemapoison ivy, oak, sumac

• insect bitessoaps

• detergentscosmetics

• jewelryseborrheic dermatitis

• psoriasis and forexternal genital or anal

• itching

other uses of this product should be only under the advice and

supervision of a doctor

Active ingredientPurpose Hydrocortisone (1%)....Anti-itch Drug Facts Drug Facts(continued) When using this product avoid contact with the eyes do not exceed the recommended daily dosage unless directed bya doctor do not cover treated skin do not use any other hydrocortisone product do not put directly in rectum using fingers or any mechanicaldevice Directions adults and children 2 years of age and older:a pply to affectedarea not more than 3 to 4 times daily. children under 2 years of age:Do not use.Consult a doctor. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Stop use and ask a doctor if condition worsens symptoms persist for more than 7 days or clear up and occuragain within a few days rectal bleeding occurs 23. temporarily relieves itching of minor skin irritations, inflammation and rashes symptoms persist for more than 7 days or clear up andoccur 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