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  1. FDA Experience: Topical Corticosteroids and HPA Axis Suppression Denise Cook, M.D. Medical OfficerDivision of Dermatology and Dental Drug Products FDA

  2. OUTLINE • History of Labels • Regulations and Legislation • Specific Drug Product Data

  3. Seven Classes Class I – Superpotent Class II – High Potency Classes III, IV, V, VI – Midpotency Class VII – Low Potency Vasoconstrictor Assay Topical Corticosteroid Classification

  4. History of Labels

  5. Labels - 1970's • Lidex (fluocinonide) Gel, 0.05% - Class II steroid • Precaution Section: If extensive areas are treated, the possibility exists of increased systemic absorption and suitable precautions should be taken.

  6. Labels - 1980's • TEMOVATETM (clobetasol cream and ointment), 0.05%, a Class I steroid - Approved in 1985 • PRECAUTIONS: General: TEMOVATETM 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 TEMOVATETM Cream and Ointment in children under 12 years of age is not recommended.

  7. Two open-label trials withTemovateTM 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

  8. Two open-label trials with TemovateTM 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.

  9. Class Labeling for Topical Corticosteroids 1990 Precautions Section Pediatric Use Section

  10. Precautions Section

  11. 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.

  12. 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.

  13. 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.

  14. Pediatric Use Section

  15. 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.

  16. 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.

  17. Regulation and Legislation

  18. 1994 - Pediatric Rule 1997 - Section 111 of FDAMA 2002 – Best Pharmaceuticals for Children Act

  19. Pediatric Rule • allowed for extrapolation of adult efficacy data to pediatric patients when appropriate, plus • additional safety, pk, and/or dose ranging studies in the targeted pediatric population

  20. Section 111 of FDAMA Written Request Sponsors are offered 6 months of exclusivity for their chemical moiety if they fairly respond to the Agency’s request for pediatric studies.

  21. Best Pharmaceuticals for Children Act • Establishes additional mechanisms for the study of both on-patent and off-patent drugs • Pediatric Supplements are now Priority Reviews

  22. Specific Drug Product Data • 10 drug products • 8 topical corticosteroid products • 2 combination drug products • 11 studies • Ages 3 months – adult • Open-label trials • Cosyntropin stimulation test

  23. Dermatop (prednicarbate emollient cream), 0.1% a Class V steroid Approved May 1996 Pediatric Atopic Dermatitis Trial

  24. 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

  25. 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

  26. 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

  27. 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."

  28. Cutivate (fluticasone) Cream, 0.05% a Class V steroid Approved June 17, 1999 Pediatric Atopic Dermatitis and Psoriasis Trial

  29. 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

  30. 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

  31. 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

  32. 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

  33. Normal responseCosyntropin Stimulation Test A serum cortisol level >18 µg/dL at 30 minutes post-stimulation

  34. 2 out of 43 patients experienced adrenal suppression

  35. 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

  36. 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)

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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.

  42. 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

  43. Label Change for Diprolene AF Cream, 0.05% • Indication - added an age restriction of 13 years and older • Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections

  44. 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%)

  45. 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

  46. Suppression by Age Group

  47. 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

  48. Recovery of HPA Axis FunctionDiprosone Ointment • 2/15 patients were retested • 100% recovery at 2 weeks

  49. Label Change Diprosone Ointment, 0.05% • Indication - added an age restriction of 13 years and older • Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections

  50. 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