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Rx Topical Corticosteroids

Rx Topical Corticosteroids

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Rx Topical Corticosteroids

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  1. Rx Topical Corticosteroids HPA Axis Suppression and Cutaneous Effects Denise Cook, M.D. Medical OfficerDivision of Dermatology and Dental Drug Products

  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

  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. 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

  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

  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

  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

  8. 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

  9. 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.

  10. Temovate Label - 1985 • TEMOVATETM (clobetasol cream and ointment), 0.05%, a Class I steroid • 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.

  11. Class Label Precautions Section

  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. 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. 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. Class Label Pediatric Use Section

  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. 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. Topical Corticosteroid DataHPA 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

  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

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

  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

  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

  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

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

  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

  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

  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

  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

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

  31. 2 out of 43 patients experienced adrenal suppression

  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

  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)

  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

  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

  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

  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

  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.

  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

  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

  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%)

  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

  43. Suppression by Age Group

  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

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

  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

  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

  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

  49. HPA Axis Suppression by Age

  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