1. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 Rx Topical Corticosteroids HPA Axis Suppression and Cutaneous Effects Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products

2. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 2 OUTLINE Background Class Labeling for Topical Corticosteroids HPA Axis Suppression – The FDA Experience –Trial Data from Approved Drug Products –Resultant Labeling Changes –Postmarketing Summary Cutaneous Adverse Events from Topical Corticosteroid Use Background Class Labeling for Topical Corticosteroids HPA Axis Suppression – The FDA Experience –Trial Data from Approved Drug Products –Resultant Labeling Changes –Postmarketing Summary Cutaneous Adverse Events from Topical Corticosteroid Use

3. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 3 Topical Corticosteroid Classification Seven Classes –Class I – Superpotent –Class II – High Potency –Classes III, IV, V, VI – Midpotency –Class VII – Low Potency Vasoconstrictor Assay

4. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 4 Cosyntropin Stimulation Test Used to assess the function of the end organ - the adrenal gland - in the hypothalamic-pituitary- adrenal axis In the case of topical corticosteroids, assessing an exogenous unwanted treatment effect Cosyntropin 0.125 mg or 0.25 mg is administered IV at baseline and end of treatment Blood is drawn for serum cortisol values at 30 minutes and sometimes 60 minutes post stimulation Interpretation of the results determines a normal or abnormal response Used to assess the function of the end organ - the adrenal gland - in the hypothalamic-pituitary- adrenal axis In the case of topical corticosteroids, assessing an exogenous unwanted treatment effect Cosyntropin 0.125 mg or 0.25 mg is administered IV at baseline and end of treatment Blood is drawn for serum cortisol values at 30 minutes and sometimes 60 minutes post stimulation Interpretation of the results determines a normal or abnormal response

5. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 5 Evolution of Interpretation of Normal Function of the HPA Axis 1985 –am serum cortisol –Urinary corticoid concentrations 1996 – Cosyntropin Stimulation Test –30 minute post stimulation serum cortisol > 20 µg/dL –If prestimulation serum cortisol 20 µg/dL, then needed a 6ug/dL increment 1999 –30 minute post stimulation cortisol > 18 µg/dL 1985 –am serum cortisol –Urinary corticoid concentrations 1996 – Cosyntropin Stimulation Test –30 minute post stimulation serum cortisol > 20 µg/dL –If prestimulation serum cortisol 20 µg/dL, then needed a 6ug/dL increment 1999 –30 minute post stimulation cortisol > 18 µg/dL

6. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 6 Evolution of Interpretation of Normal Function of the HPA Axis 2001 - Cosyntropin Stimulation Test –Control plasma cortisol level should exceed 5 µg/100mL –30 minute level should show an increment of at least 7 µg/100mL –30 minute level should exceed 18 µg/100mL 2004 –30 minute level should exceed 18 µg/100mL 2001 - Cosyntropin Stimulation Test –Control plasma cortisol level should exceed 5 µg/100mL –30 minute level should show an increment of at least 7 µg/100mL –30 minute level should exceed 18 µg/100mL 2004 –30 minute level should exceed 18 µg/100mL

7. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 7 Class Labeling for Rx Topical Corticosteroids - 1990 Effects on the HPA Axis Effects on Glucose Metabolism Development of Cushing’s Syndrome Effects on Growth Effects on Intracranial Pressure Effects on the HPA Axis Effects on Glucose Metabolism Development of Cushing’s Syndrome Effects on Growth Effects on Intracranial Pressure

8. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 8 Two open-label trials with Temovate TM Ointment: Trial 1: 6 adult patients with psoriasis applied 7 grams/day to 30% BSA for 7 days ACTH stimulation was performed at baseline and 2 post-treatment A.M. cortisols 3/6 or 50% of patients exhibited decreases in cortisol production Trial 1: 6 adult patients with psoriasis applied 7 grams/day to 30% BSA for 7 days ACTH stimulation was performed at baseline and 2 post-treatment A.M. cortisols 3/6 or 50% of patients exhibited decreases in cortisol production

9. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 9 Two open-label trials with Temovate TM Ointment (cont’d): Trial 2: Objective - determine the largest dose over a 7 day period that would not cause significant suppression of the adrenal gland 3 doses were used - 7 grams/day, 3.5 grams/day, 2.0 grams/day Suppression was determined by A.M. plasma cortisol levels and urinary corticoid concentrations None of the psoriatic patients suppressed at 7.0 grams/day or 3.5 grams/day but doses as low as 2.0 grams/day caused marked suppression of cortisol secretion in patients with atopic dermatitis. Trial 2: Objective - determine the largest dose over a 7 day period that would not cause significant suppression of the adrenal gland 3 doses were used - 7 grams/day, 3.5 grams/day, 2.0 grams/day Suppression was determined by A.M. plasma cortisol levels and urinary corticoid concentrations None of the psoriatic patients suppressed at 7.0 grams/day or 3.5 grams/day but doses as low as 2.0 grams/day caused marked suppression of cortisol secretion in patients with atopic dermatitis.

10. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 10 Temovate Label - 1985 TEMOVATE TM (clobetasol cream and ointment), 0.05%, a Class I steroid PRECAUTIONS: General: TEMOVATE TM is a highly potent topical corticosteroid that has been shown to suppress the HPA axis at doses as low as 2 g per day. Pediatric Use: Use of TEMOVATE TM Cream and Ointment in children under 12 years of age is not recommended. TEMOVATE TM (clobetasol cream and ointment), 0.05%, a Class I steroid PRECAUTIONS: General: TEMOVATE TM is a highly potent topical corticosteroid that has been shown to suppress the HPA axis at doses as low as 2 g per day. Pediatric Use: Use of TEMOVATE TM Cream and Ointment in children under 12 years of age is not recommended.

11. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 11 Class Label Precautions Section

12. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 12 General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for gluco- corticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.

13. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 13 Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.

14. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 14 If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids.

15. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 15 Class Label Pediatric Use Section Class Label Pediatric Use Section

16. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 16 Safety and effectiveness in children and infants have not been established. Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment.

17. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 17 HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

18. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 18 Topical Corticosteroid Data HPA Axis Suppression 10 drug products –8 topical corticosteroid products –2 topical combination drug products 11 studies Ages 3 months – adult Open-label trials Cosyntropin stimulation test 10 drug products –8 topical corticosteroid products –2 topical combination drug products 11 studies Ages 3 months – adult Open-label trials Cosyntropin stimulation test

19. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 19 Topical Corticosteroid Drug Products Dermatop – a mid potency steroid Cutivate Cream – a mid potency steroid Diprolene AF Cream – a high potency steroid Diprosone Ointment – a high potency steroid Diprosone Cream – a mid potency steroid Diprosone Lotion – a mid potency steroid Clobex Lotion – a super potent steroid Temovate E Cream – a super potent steroid Dermatop – a mid potency steroid Cutivate Cream – a mid potency steroid Diprolene AF Cream – a high potency steroid Diprosone Ointment – a high potency steroid Diprosone Cream – a mid potency steroid Diprosone Lotion – a mid potency steroid Clobex Lotion – a super potent steroid Temovate E Cream – a super potent steroid

20. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 20 Dermatop (prednicarbate emollient cream), 0.1% a Class V steroid Approved May 1996 Pediatric Atopic Dermatitis Trial Dermatop (prednicarbate emollient cream), 0.1% a Class V steroid Approved May 1996 Pediatric Atopic Dermatitis Trial

21. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 21 59 pediatric patients enrolled 2 targeted populations - patients between 1 month and 2 years - patients between 2 and 12 years 10 patients were <2 years old 49 patients were ≥ 2 years old 59 pediatric patients enrolled 2 targeted populations - patients between 1 month and 2 years - patients between 2 and 12 years 10 patients were <2 years old 49 patients were ≥ 2 years old

22. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 22 Treatment Criteria >20% body surface area (BSA) involvement Twice daily for 21 consecutive days ACTH Stimulation Test Cosyntropin administered at baseline and day 22 – Patients ≥ 15 kg received 0.25 mg IV – Patients < 15 kg received 0.125 mg IV >20% body surface area (BSA) involvement Twice daily for 21 consecutive days ACTH Stimulation Test Cosyntropin administered at baseline and day 22 – Patients ≥ 15 kg received 0.25 mg IV – Patients < 15 kg received 0.125 mg IV

23. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 23 Criteria per protocol for a normal adrenal response to ACTH stimulation at 30 and 60 minutes: Post stimulation serum cortisol >20 µg/dL If pre-stimulation serum cortisol levels > 20 µg/dL, an incremental increase >6 µg/dL in serum cortisol Post stimulation serum cortisol >20 µg/dL If pre-stimulation serum cortisol levels > 20 µg/dL, an incremental increase >6 µg/dL in serum cortisol

24. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 24 Three patients according to the protocol criteria were suppressed: 2 patients, 1 an 18 month old, had a peak response of 5 µg/dL change from baseline. 1 patient had a post- stimulation cortisol value that decreased from baseline. At that time, the Agency agreed with an outside endocrinologist that since these 3 patients had a post- stimulation response that was greater than 20 µg/dL, although they didn't have the required incremental rise, they would not be considered suppressed. This led to the current label that reads that "none of the 59 patients showed evidence of HPA axis suppression."

25. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 25 Cutivate (fluticasone) Cream, 0.05% a Class V steroid Approved June 17, 1999 Pediatric Atopic Dermatitis and Psoriasis Trial

26. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 26 43 patients were evaluable ( all with moderate to severe atopic dermatitis) 29 patients – 3 months to 2 years old 14 patients – 3 years to 5 years old 43 patients were evaluable ( all with moderate to severe atopic dermatitis) 29 patients – 3 months to 2 years old 14 patients – 3 years to 5 years old

27. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 27 Treatment Criteria At least 35% BSA involvement Bid application for 3 - 4 weeks Patients up to 2 years limited to 120 grams/week Patients 3-5 years of age limited to 180 grams/week At least 35% BSA involvement Bid application for 3 - 4 weeks Patients up to 2 years limited to 120 grams/week Patients 3-5 years of age limited to 180 grams/week

28. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 28 BSA Improvement Over Time (N=46) 23 (50%) had a decrease of 50% by 2 weeks 9 (20%) had a decrease of 50% by 3 weeks 4 (9%) had a 50% decrease by 4 weeks 23 (50%) had a decrease of 50% by 2 weeks 9 (20%) had a decrease of 50% by 3 weeks 4 (9%) had a 50% decrease by 4 weeks

29. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 29 Cosyntropin Stimulation Test Test administered at baseline and end of treatment Younger age group given 0.125 mg cosyntropin IV Older age group given 0.25 mg cosyntropin IV Test administered at baseline and end of treatment Younger age group given 0.125 mg cosyntropin IV Older age group given 0.25 mg cosyntropin IV

30. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 30 Normal response Cosyntropin Stimulation Test A serum cortisol level >18 µg/dL at 30 minutes post-stimulation

31. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 31 2 out of 43 patients experienced adrenal suppression Serum Cortisol (  g/dL) BaselineEnd-TxFollow-up SubjectAge/Sex%BSASeverityDurationAmt. Used Pre- stim Post- stim Pre- stim Post- stim Pre- stim Post- stim B2015 yrs/M95 (95)22 (9)4 weeks561.0 grams 22.133.97.111.82.119.8 B2022 yrs/M35 (35)17 (7)5 weeks176.5 grams 10.828.62.19.4LTF

32. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 32 Label Change for Cutivate Cream Indication – Children as young as 3 months of age for up to 4 weeks of use Safety Update Information – Precautions: General and Pediatric Use Sections Indication – Children as young as 3 months of age for up to 4 weeks of use Safety Update Information – Precautions: General and Pediatric Use Sections

33. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 33 Betamethasone Propionate - Approved in 2001 Diprolene AF Cream, 0.05% - a Class II steroid Diprosone Ointment, 0.05% - a Class II steroid Diprosone Cream, 0.05% - a Class III steroid Diprosone Lotion, 0.05% - a Class V steroid Lotrisone Cream and Lotion (clotrimazole and betamethasone propionate) Diprolene AF Cream, 0.05% - a Class II steroid Diprosone Ointment, 0.05% - a Class II steroid Diprosone Cream, 0.05% - a Class III steroid Diprosone Lotion, 0.05% - a Class V steroid Lotrisone Cream and Lotion (clotrimazole and betamethasone propionate)

34. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 34 Criteria for a Normal HPA Axis Response Follow the Cortrosyn ® label Failure of any one of 3 criteria would indicate suppression of the HPA axis Stimulation should occur at baseline and end of treatment Follow the Cortrosyn ® label Failure of any one of 3 criteria would indicate suppression of the HPA axis Stimulation should occur at baseline and end of treatment

35. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 35 Criteria - 30 minute post-stimulation The control plasma cortisol level should exceed 5 µg/100 mL The 30-minute level should show an increment of at least 7 µg/100mL above the basal level The 30-minute level should exceed 18 µg/100mL The control plasma cortisol level should exceed 5 µg/100 mL The 30-minute level should show an increment of at least 7 µg/100mL above the basal level The 30-minute level should exceed 18 µg/100mL

36. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 36 Diprolene AF Cream, 0.05% 60 evaluable patients, ages 1-12 years with atopic dermatitis Mean BSA involvement - 58% (range: 35% - 95%) Used study drug bid for 2 - 3 weeks –Limited to 45 grams/week 60 evaluable patients, ages 1-12 years with atopic dermatitis Mean BSA involvement - 58% (range: 35% - 95%) Used study drug bid for 2 - 3 weeks –Limited to 45 grams/week

37. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 37 Diprolene AF Cream, 0.05% (cont’d) 19/60 or 32% of these patients showed evidence of HPA axis suppression 11/19 (58%) had a post-stimulation plasma cortisol value < 18 µg/dL 6/19 (32%) failed to have an incremental change of at least 7 µg/dL 2/19 (11%) had a pre-stimulation cortisol < 5 µg/dL 19/60 or 32% of these patients showed evidence of HPA axis suppression 11/19 (58%) had a post-stimulation plasma cortisol value < 18 µg/dL 6/19 (32%) failed to have an incremental change of at least 7 µg/dL 2/19 (11%) had a pre-stimulation cortisol < 5 µg/dL

38. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 38 Suppression by Age Group Recovery of normal HPA axis function 4 patients were retested 2 weeks post- treatment and 3 of the 4 recovered normal function of the HPA axis. Recovery of normal HPA axis function 4 patients were retested 2 weeks post- treatment and 3 of the 4 recovered normal function of the HPA axis. Age Group3mo-1 yr n=4 2yr-5yr n=16 6yr-8yr n=28 9yr-12yr n=12 # suppressed2692 %50383217

39. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 39 Statistical Analysis in the Development of HPA Axis Suppression No correlation between amount of drug used, body weight, age or sex and the incidence of adrenal gland suppression Statistical relationship did exist between BSA and risk of HPA axis suppression “for an increase of 1% BSA involved, risk of HPA axis suppression increased 4.4%” p ≤ 0.01 No correlation between amount of drug used, body weight, age or sex and the incidence of adrenal gland suppression Statistical relationship did exist between BSA and risk of HPA axis suppression “for an increase of 1% BSA involved, risk of HPA axis suppression increased 4.4%” p ≤ 0.01

40. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 40 Label Change for Diprolene AF Cream, 0.05% Indication - added an age restriction to 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections Indication - added an age restriction to 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections

41. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 41 Diprosone Ointment, 0.05% 53 evaluable subjects with atopic dermatitis Age Range - 6 months to 12 years old Medication applied bid for 2 to 3 weeks Mean BSA Involvement - 58% (range: 35% - 99%) 53 evaluable subjects with atopic dermatitis Age Range - 6 months to 12 years old Medication applied bid for 2 to 3 weeks Mean BSA Involvement - 58% (range: 35% - 99%)

42. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 42 Diprosone Ointment, 0.05% (cont’d) 15/53 or 28% of patients showed evidence of HPA axis suppression 8/15 or 53% had a post-stimulation plasma cortisol value < 18 µg/dL 7/15 or 47% failed to have an incremental change of at least 7 µg/dL 15/53 or 28% of patients showed evidence of HPA axis suppression 8/15 or 53% had a post-stimulation plasma cortisol value < 18 µg/dL 7/15 or 47% failed to have an incremental change of at least 7 µg/dL

43. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 43 Suppression by Age Group Age Group3mo-1 yr n=11 2yr-5yr n=21 6yr-8yr n=15 9yr-12yr n=6 # suppressed4641 %36292717

44. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 44 Statistical Analysis in the Development of HPA Axis Suppression No statistically significant effect for – Drug usage – % BSA – Weight – Age Higher proportion of males than females (p=0.006) who developed HPA axis suppression No statistically significant effect for – Drug usage – % BSA – Weight – Age Higher proportion of males than females (p=0.006) who developed HPA axis suppression

45. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 45 Recovery of HPA Axis Function Diprosone Ointment 2/15 patients were retested 100% recovery at 2 weeks 2/15 patients were retested 100% recovery at 2 weeks

46. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 46 Label Change Diprosone Ointment, 0.05% Indication - added an age restriction to 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections Indication - added an age restriction to 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections

47. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 47 Diprosone Cream, 0.05% 43 evaluable patients with atopic dermatitis Age Range - 1 year to 12 years old Mean BSA Involvement - 40% (range: 35% - 90%) Medication applied bid for 2-3 weeks 43 evaluable patients with atopic dermatitis Age Range - 1 year to 12 years old Mean BSA Involvement - 40% (range: 35% - 90%) Medication applied bid for 2-3 weeks

48. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 48 Diprosone Cream, 0.05% (cont’d) 10/43 or 23% of patients showed evidence of adrenal suppression 5/10 or 50% had a post-stimulation plasma cortisol value < 18 µg/dL 3/10 or 30% failed to have an incremental change of at least 7 µg/dL 2/10 or 20% had a pre-stimulation cortisol < 5 µg/dL 10/43 or 23% of patients showed evidence of adrenal suppression 5/10 or 50% had a post-stimulation plasma cortisol value < 18 µg/dL 3/10 or 30% failed to have an incremental change of at least 7 µg/dL 2/10 or 20% had a pre-stimulation cortisol < 5 µg/dL

49. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 49 HPA Axis Suppression by Age Age Group 3mo-1yr n=3 2yr-5yr n=20 6yr-8yr n=13 9yr-12yr n=7 # suppressed 0631 %0302314

50. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 50 Statistical Analysis in the Development of HPA Axis Suppression No statistically significant effect for – Number of days treated – Weight – Age Statistical significance found for mean amount of drug used - 81 grams vs. 37 grams (p<0.001) There was a numerically higher %BSA involvement Numerically, more males developed suppression No statistically significant effect for – Number of days treated – Weight – Age Statistical significance found for mean amount of drug used - 81 grams vs. 37 grams (p<0.001) There was a numerically higher %BSA involvement Numerically, more males developed suppression

51. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 51 Recovery of HPA Axis Function Diprosone Cream 2/10 patients were retested 1/2 (50%) recovered HPA axis function at 2 weeks 2/10 patients were retested 1/2 (50%) recovered HPA axis function at 2 weeks

52. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 52 Label Change Diprosone Cream, 0.05% Indication - added an age restriction to 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections Indication - added an age restriction to 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections

53. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 53 Diprosone Lotion, 0.05% 15 evaluable patients with atopic dermatitis Age Range - 6 to 12 years old Mean BSA Involvement - 45% (range: 35% - 72%) Medication applied bid for 2-3 weeks 15 evaluable patients with atopic dermatitis Age Range - 6 to 12 years old Mean BSA Involvement - 45% (range: 35% - 72%) Medication applied bid for 2-3 weeks

54. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 54 Diprosone Lotion, 0.05% (cont’d) 11/15 or 73% of patients showed evidence of HPA axis suppression 10/11 or 91% had a post-stimulation plasma cortisol value < 18 µg/dL 1/11 or 9% failed to have an incremental change of at least 7 µg/dL 11/15 or 73% of patients showed evidence of HPA axis suppression 10/11 or 91% had a post-stimulation plasma cortisol value < 18 µg/dL 1/11 or 9% failed to have an incremental change of at least 7 µg/dL

55. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 55 Suppression by Age Group Age Group3mo-1 yr n=0 2yr-5yr n=0 6yr-8yr n=10 9yr-12yr n=5 # suppressedNone enrolled 74 %--7080

56. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 56 Statistical Analysis in the Development of HPA Axis Suppression Numerical analysis – Subjects exhibiting HPA axis suppression Larger mean amount of drug used (92.8 g vs. 69.4 g) Slightly higher %BSA involved (45.8% vs. 41.8%) Lower mean weights at visit 1 (65 lbs. vs. 81 lbs.) Lower mean weights at visit 4 (65 lbs. vs. 80 lbs.) Differences with respect to age and days of treatment were miniscule Numerical analysis – Subjects exhibiting HPA axis suppression Larger mean amount of drug used (92.8 g vs. 69.4 g) Slightly higher %BSA involved (45.8% vs. 41.8%) Lower mean weights at visit 1 (65 lbs. vs. 81 lbs.) Lower mean weights at visit 4 (65 lbs. vs. 80 lbs.) Differences with respect to age and days of treatment were miniscule

57. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 57 Recovery of HPA Axis Function Diprosone Lotion 6/11 patients were retested 4/6 (67%) recovered HPA axis function at 2 weeks 6/11 patients were retested 4/6 (67%) recovered HPA axis function at 2 weeks

58. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 58 Label Change Diprosone Lotion, 0.05% Indication – added an age restriction to 13 years and older Clinical Safety Information – Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections Indication – added an age restriction to 13 years and older Clinical Safety Information – Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections

59. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 59 Comparison of HPA Axis Criteria Betamethasone Dipropionate

60. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 60 Lotrisone Cream Tinea Pedis Study Tinea Cruris Study Both studies were in the adolescent population ages 12 – 16 years Medication was applied twice daily Study duration –4 weeks for tinea pedis –2 weeks for tinea cruris Tinea Pedis Study Tinea Cruris Study Both studies were in the adolescent population ages 12 – 16 years Medication was applied twice daily Study duration –4 weeks for tinea pedis –2 weeks for tinea cruris

61. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 61 Lotrisone Cream (cont’d) 17/43 (39.5%) demonstrated adrenal suppression in the tinea pedis study 8/17 (47.1%) demonstrated adrenal suppression in the tinea cruris study 17/43 (39.5%) demonstrated adrenal suppression in the tinea pedis study 8/17 (47.1%) demonstrated adrenal suppression in the tinea cruris study

62. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 62 Label Change Lotrisone Cream and Lotion An Expanded Indications Section –Added an age restriction – patients 17 years and older –Recommended that effective treatment may be obtained without the use of a corticosteroid for noninflammatory tinea infections Updated Safety Information – Precautions: General, Pediatric Use, Geriatric Use and Dosage and Administration Sections An Expanded Indications Section –Added an age restriction – patients 17 years and older –Recommended that effective treatment may be obtained without the use of a corticosteroid for noninflammatory tinea infections Updated Safety Information – Precautions: General, Pediatric Use, Geriatric Use and Dosage and Administration Sections

63. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 63 Clobex (clobetasol propionate), Lotion 0.05% a Class I steroid Approved July 24, 2003 Atopic Dermatitis and Psoriasis Trials Clobex (clobetasol propionate), Lotion 0.05% a Class I steroid Approved July 24, 2003 Atopic Dermatitis and Psoriasis Trials

64. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 64 Clobex Lotion 3 studies –2 adult studies – one in psoriasis and one in atopic dermatitis –1 pediatric study (ages 12 – 17 years) in atopic dermatitis Comparator drug – Temovate E Cream –Class I steroid –Same chemical moiety, clobetasol propionate –Different vehicle, an emollient cream 3 studies –2 adult studies – one in psoriasis and one in atopic dermatitis –1 pediatric study (ages 12 – 17 years) in atopic dermatitis Comparator drug – Temovate E Cream –Class I steroid –Same chemical moiety, clobetasol propionate –Different vehicle, an emollient cream

65. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 65 Construct of HPA Axis Evaluation The control plasma cortisol level should exceed 5 micrograms/100 mL The 30 minute level should show an increment of at least 7 micrograms/100 mL above basal level The 30 minute level should exceed 18 micrograms/100 mL Exceptions: –plasma cortisol levels were drawn at 60 minutes post-stimulation. –In adult studies, subjects were stimulated with cosyntropin weekly. The control plasma cortisol level should exceed 5 micrograms/100 mL The 30 minute level should show an increment of at least 7 micrograms/100 mL above basal level The 30 minute level should exceed 18 micrograms/100 mL Exceptions: –plasma cortisol levels were drawn at 60 minutes post-stimulation. –In adult studies, subjects were stimulated with cosyntropin weekly.

66. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 66 Adolescent study 24 evaluable patients – 14 treated with Clobex Lotion and 10 treated with Temovate E Cream Moderate to severe atopic dermatitis BSA treated – at least 20% Medication applied BID for 2 weeks 50 grams/week limit 24 evaluable patients – 14 treated with Clobex Lotion and 10 treated with Temovate E Cream Moderate to severe atopic dermatitis BSA treated – at least 20% Medication applied BID for 2 weeks 50 grams/week limit

67. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 67 HPA axis suppression 9/14 (64%) of subjects treated with Clobex Lotion suppressed 2/10 (20%) of subjects treated with Temovate E Cream suppressed 9/14 (64%) of subjects treated with Clobex Lotion suppressed 2/10 (20%) of subjects treated with Temovate E Cream suppressed

68. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 68 Statistical Analysis Mean %BSA treated was higher for patients with adrenal suppression 32.8% vs. 27.7% for Clobex Lotion 35% vs. 25.3% for Temovate E Cream Mean %BSA treated was higher for patients with adrenal suppression 32.8% vs. 27.7% for Clobex Lotion 35% vs. 25.3% for Temovate E Cream

69. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 69 Recovery of HPA Axis Function 1/4 of patients treated with Clobex Lotion remained suppressed after 2 weeks 1/1 patient retested after treatment with Temovate E Cream recovered 1/4 of patients treated with Clobex Lotion remained suppressed after 2 weeks 1/1 patient retested after treatment with Temovate E Cream recovered

70. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 70 Adult Study 18 evaluable patients – 9 treated with Clobex Lotion and 9 treated with Temovate E Cream Moderate to Severe Atopic Dermatitis Mean BSA treated – 19.3 % for Clobex Lotion and 19.4% for Temovate E Cream Medication applied BID for 2 weeks 50 gram/week limit 18 evaluable patients – 9 treated with Clobex Lotion and 9 treated with Temovate E Cream Moderate to Severe Atopic Dermatitis Mean BSA treated – 19.3 % for Clobex Lotion and 19.4% for Temovate E Cream Medication applied BID for 2 weeks 50 gram/week limit

71. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 71 HPA Axis Suppression 5 / 9 (56%) of subjects treated with Clobex Lotion suppressed 4 / 9 (44%) of subjects treated with Temovate E Cream suppressed 5 / 9 (56%) of subjects treated with Clobex Lotion suppressed 4 / 9 (44%) of subjects treated with Temovate E Cream suppressed

72. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 72 Recovery of HPA Axis Function 1 / 3 patients on Clobex Lotion failed to recover function 7 days post treatment 2 /2 patients on Temovate E Cream recovered function 7 days post treatment 1 / 3 patients on Clobex Lotion failed to recover function 7 days post treatment 2 /2 patients on Temovate E Cream recovered function 7 days post treatment

73. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 73 Adult Study 20 evaluable patients – 10 treated with Clobex lotion and 10 treated with Temovate E Cream Moderate to Severe Plaque Psoriasis Mean BSA treated – 16.2 % for Clobex Lotion and 17.9 % for Temovate E Cream Medication applied BID for 4 weeks 50 gram/week limit 20 evaluable patients – 10 treated with Clobex lotion and 10 treated with Temovate E Cream Moderate to Severe Plaque Psoriasis Mean BSA treated – 16.2 % for Clobex Lotion and 17.9 % for Temovate E Cream Medication applied BID for 4 weeks 50 gram/week limit

74. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 74 HPA Axis Function 8 / 10 (80%) of subjects treated with Clobex Lotion suppressed 3 / 10 (30%) of subjects with Temovate E Cream suppressed 1 / 2 subjects with Clobex Lotion retested remained suppressed after 8 days 0 / 3 subjects on Temovate E Cream were retested 8 / 10 (80%) of subjects treated with Clobex Lotion suppressed 3 / 10 (30%) of subjects with Temovate E Cream suppressed 1 / 2 subjects with Clobex Lotion retested remained suppressed after 8 days 0 / 3 subjects on Temovate E Cream were retested

75. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 75 Label for Clobex Lotion Indication – restricted to patients 18 years or older 2 consecutive weeks not to exceed 50 grams (50 mL or 1.75 fl. Oz) per week Moderate or severe psoriasis, for localized lesions < 10% BSA can be treated an additional 2 weeks Updated Safety Information – Indications and Usage, Precautions: General and Pediatric Use, and Dosage and Administration Sections Indication – restricted to patients 18 years or older 2 consecutive weeks not to exceed 50 grams (50 mL or 1.75 fl. Oz) per week Moderate or severe psoriasis, for localized lesions < 10% BSA can be treated an additional 2 weeks Updated Safety Information – Indications and Usage, Precautions: General and Pediatric Use, and Dosage and Administration Sections

76. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 76 Postmarketing Summary HPA Axis Suppression Sources AERS Database Medical Literature Case Reports Postmarketing Summary HPA Axis Suppression Sources AERS Database Medical Literature Case Reports

77. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 77 Adverse Event Reporting System (AERS) Spontaneous, voluntary surveillance system –Voluntary reporting by health care professionals and consumers –Mandatory reporting by manufacturers Approximately 3 million reports in database Database origin 1969 Contains human drug and “therapeutic” biologic reports; exception = vaccines (VAERS) Quality of a report is variable and often incomplete Subject to under-reporting (true numerator not known) Duplicate reporting occurs Spontaneous, voluntary surveillance system –Voluntary reporting by health care professionals and consumers –Mandatory reporting by manufacturers Approximately 3 million reports in database Database origin 1969 Contains human drug and “therapeutic” biologic reports; exception = vaccines (VAERS) Quality of a report is variable and often incomplete Subject to under-reporting (true numerator not known) Duplicate reporting occurs

78. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 78 Postmarketing Summary HPA Axis Suppression 94 cases spanning 3 decades –65 adult cases –29 pediatric cases Manifestations –Adrenal insufficiency –Cushing’s Syndrome –Growth Retardation 94 cases spanning 3 decades –65 adult cases –29 pediatric cases Manifestations –Adrenal insufficiency –Cushing’s Syndrome –Growth Retardation

79. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 79 Postmarketing Reports Pediatric Cases 29 pediatric patients –11 with adrenal insufficiency –17 with Cushing’s Syndrome –13 with Growth Retardation Characteristics –Age range 6 weeks – 15 years; mean age 5.0 years –duration of use 22 days – 7.5 years; mean use 20.8 months –16 (55%) received medication for 3 months or longer –Varied indications but 34% used topical steroids for diaper rash –Betamethasone containing, clobetasol, and mometasone products implicated most often, with 34% using high potency topical steroids –Resulted in 14 hospitalizations and 2 deaths, the latter from Cushing’s Syndrome 29 pediatric patients –11 with adrenal insufficiency –17 with Cushing’s Syndrome –13 with Growth Retardation Characteristics –Age range 6 weeks – 15 years; mean age 5.0 years –duration of use 22 days – 7.5 years; mean use 20.8 months –16 (55%) received medication for 3 months or longer –Varied indications but 34% used topical steroids for diaper rash –Betamethasone containing, clobetasol, and mometasone products implicated most often, with 34% using high potency topical steroids –Resulted in 14 hospitalizations and 2 deaths, the latter from Cushing’s Syndrome

80. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 80 Postmarketing Reports Adult Cases 65 adult cases –46 with adrenal insufficiency/suppression –32 with Cushing’s Syndrome Characteristics –Age range 19 years – 74 years; mean age 47.4 years –duration of use 7 days – 12.0 years; mean use 35.6 months –30 (46%) received medication for 3 months or longer –Varied indications but 51% used topical steroids for psoriasis –Betamethasone containing and clobetasol products implicated most often, with 61% using high potency topical corticosteroids –Resulted in 34 hospitalizations and 2 deaths –Deaths attributed in part to the adrenal event 65 adult cases –46 with adrenal insufficiency/suppression –32 with Cushing’s Syndrome Characteristics –Age range 19 years – 74 years; mean age 47.4 years –duration of use 7 days – 12.0 years; mean use 35.6 months –30 (46%) received medication for 3 months or longer –Varied indications but 51% used topical steroids for psoriasis –Betamethasone containing and clobetasol products implicated most often, with 61% using high potency topical corticosteroids –Resulted in 34 hospitalizations and 2 deaths –Deaths attributed in part to the adrenal event

81. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 81 Postmarketing Reports Common Factors in Adverse Events Most AEs occurred in the setting of one or more of the following: –Prolonged use of topical corticosteroid –Use of a super potent topical corticosteroid –Use of multiple topical corticosteroid products or concomitant use with other corticosteroid formulations –Use of an excessive amount or possible inappropriate use of the topical corticosteroid product Most AEs occurred in the setting of one or more of the following: –Prolonged use of topical corticosteroid –Use of a super potent topical corticosteroid –Use of multiple topical corticosteroid products or concomitant use with other corticosteroid formulations –Use of an excessive amount or possible inappropriate use of the topical corticosteroid product

82. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 82 Summary – HPA Axis Suppression HPA axis suppression does occur with the use of topical corticosteroids The adrenal suppression is not limited to the super potent class of topical corticosteroids High BSA involvement and amount of drug used appear to be risk factors for HPA axis suppression HPA axis suppression does occur with the use of topical corticosteroids The adrenal suppression is not limited to the super potent class of topical corticosteroids High BSA involvement and amount of drug used appear to be risk factors for HPA axis suppression

83. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 83 Summary – HPA Axis Suppression The type of vehicle may contribute to the extent of absorption of the active chemical moiety The suppression appears, in most cases, to be reversible upon cessation of drug usage Long-term use of topical corticosteroids, particularly high potency ones, can lead to serious morbidity and even death The type of vehicle may contribute to the extent of absorption of the active chemical moiety The suppression appears, in most cases, to be reversible upon cessation of drug usage Long-term use of topical corticosteroids, particularly high potency ones, can lead to serious morbidity and even death

84. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 84 Cutaneous Safety Known cutaneous adverse events Question of cutaneous malignancy Known cutaneous adverse events Question of cutaneous malignancy

85. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 85 Cutaneous Safety Adverse Events associated with topical corticosteroid use –Atrophy of the skin –Telangiectasia –Striae –Erythema of the face –Steroid Rosacea –Hypopigmentation –Infection –Retarded Wound Healing Adverse Events associated with topical corticosteroid use –Atrophy of the skin –Telangiectasia –Striae –Erythema of the face –Steroid Rosacea –Hypopigmentation –Infection –Retarded Wound Healing

86. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 86 Pictorial Presentation from University of Erlangen Website and Bolognia Textbook of Dermatology

87. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 87 Atrophy

88. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 88 Telangiectasia

89. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 89 Striae

90. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 90 Striae

91. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 91 Facial Erythema

92. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 92 Facial Erythema

93. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 93 Steroid Rosacea

94. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 94 Hypopigmentation

95. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 95 Other Adverse Effects Topical corticosteroids placed on certain infections, e.g. tinea infections, may exacerbate them Topical corticosteroids placed on open or surgical wounds will retard healing Use of topical corticosteroids in the periorbital area may cause an increase in intraocular pressure Topical corticosteroids placed on certain infections, e.g. tinea infections, may exacerbate them Topical corticosteroids placed on open or surgical wounds will retard healing Use of topical corticosteroids in the periorbital area may cause an increase in intraocular pressure

96. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 96 Cutaneous Malignancy Postmarketing Reports 2 reports in AERS database as of February 5, 2005; US Cases –A 7 month old male with a history of mastocytoma was diagnosed with skin cancer several months after discontinuation of clobetasol –A female of unknown age used betametasone cream for psoriasis and reported “what started as psoriasis became cancer” AERS data do not suggest a compelling safety signal for malignancy formation with the use of topical corticosteroids 2 reports in AERS database as of February 5, 2005; US Cases –A 7 month old male with a history of mastocytoma was diagnosed with skin cancer several months after discontinuation of clobetasol –A female of unknown age used betametasone cream for psoriasis and reported “what started as psoriasis became cancer” AERS data do not suggest a compelling safety signal for malignancy formation with the use of topical corticosteroids

97. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 97 Cutaneous Adverse Events Corticosteroid induced AEs –Can be an early or late event –Depends on potency of drug and duration of use –Depends on site of application –Occlusion at the site may increase risk Corticosteroid induced AE –May resolve slowly –May not resolve Corticosteroid induced AEs –Can be an early or late event –Depends on potency of drug and duration of use –Depends on site of application –Occlusion at the site may increase risk Corticosteroid induced AE –May resolve slowly –May not resolve

98. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 98 Conclusion HPA Axis Suppression Can occur with short term use of topical corticosteroids Can occur with even mid-potency topical steroids Can occur as early as two continuous weeks of therapy Can occur with short term use of topical corticosteroids Can occur with even mid-potency topical steroids Can occur as early as two continuous weeks of therapy

99. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 99 Conclusion HPA Axis Suppression Is usually reversible The interrelationship between BSA, amount of drug used, and potency of medication is complex Long term use and/or misuse of topical corticosteroids, particularly those of high potency, can lead to serious medical complications and death Is usually reversible The interrelationship between BSA, amount of drug used, and potency of medication is complex Long term use and/or misuse of topical corticosteroids, particularly those of high potency, can lead to serious medical complications and death

100. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 100 Conclusion Cutaneous Adverse Events Can be related to both duration of use and potency of topical corticosteroid Can occur with short-term or long-term use Resolution is possible with some but not all of these cutaneous events There is no firm evidence to date to link cutaneous malignancy with use of topical corticosteroids Can be related to both duration of use and potency of topical corticosteroid Can occur with short-term or long-term use Resolution is possible with some but not all of these cutaneous events There is no firm evidence to date to link cutaneous malignancy with use of topical corticosteroids

101. Nonprescription Drugs Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee March 24, 2005 101 Rx Topical Corticosteroids HPA Axis Suppression and Cutaneous Effects