Joint NDAC/DODAC Advisory Committee Meeting

March 24, 2005

 

 

Executive SummaryExecutive SummaryBibliography

 

 

          The focus of this advisory committee is to discuss the safety considerations data needed for arelated to the  switch of dermatologic topical corticosteroids from prescription to over-the-counter (OTC) use.  The focus of the discussion will be center on the effect of corticosteroids to induce hypothalamic-pituitary-adrenal (HPA) axis suppression and other effectssafety issues (e.g. growth suppression, local skin effects) associated with the use of corticosteroids.pre-switch assessments of safety regarding both local and systemic adverse events.

 

BACKGROUND

                    Currently, Tthe only topical dermatologic corticosteroid currently marketed for OTC use is hydrocortisone acetate (hydrocortisone acetate).  .  ThisIt Hydrocortisone was originally introduced into the marketed as a prescription drug sincein 1952.  FDA received aA 1956 petition in 1956 to switch hydrocortisone from prescription to OTC status.  FDAWe initially rejected this petition was rejected in 1957 for two reasons:  (1) consumers’ ability to safely self-medicate had not been demonstrated and (2) more testing was needed on percutaneous absorption.  However, FDAwe later reconsidered and allowed 0.25% to 0.5% hHydrocortisone to be marketed OTC was included as an anti-pruritic beginning under the OTC Drug Review begun in 1972, and in 1979 under an OTC drug monograph for external analgesic products (see Tab 2Ref. 1). This was based on consideration of several studies evaluating potential systemic effects of dermatologically applied hydrocortisone and concluding that the clinical data did not preclude topical hydrocortisone from being safely marketed.  For example, one study indicated that hydrocortisone, applied topically for prolonged periods of time, did not cause HPA axis suppression (evaluated by insulin stress testing) in patients with chronic skin disease (i.e., eczema or psoriasis) (see Tab 5).  However, this study was not conducted using current standards for HPA axis suppression (i.e., cosyntropin/cortrosyn stimulation test).    In 1990, FDAwe amended the external analgesic monograph to allow 0.25% to 1.0% hydrocortisone use as an anti-pruritic (see Ref. 2Tab 4).  ThusCurrently, under the external analgesic monograph, any manufacturer currently can market a product containing 0.25% to 1.0% hydrocortisone as an anti-pruritic without pre-approval by FDA.the Advisory Review Panel on Topical Analgesic, Antirheumatic, Otic, Burn, and Sunburn Drug Products recommended that hydrocortisone be generally recognized as safe and effective (GRASE).  In 1983, FDA agreed with the Panel’s recommendation in 1983 and classified 0.25% to -0.5% hydrocortisone as generally recognized as safe and effective (GRASE.) in the OTC drug monograph for external analgesics.  This In response to a 1987 citizen petition requesting that hydrocortisone be made available OTC at concentrations up to 1 percent, FDA amended was later amendedthe rule in 1990 to includedesignate hydrocortisone at 0.25%concentrations greater than 0.5 up to 1.0% hydrocortisoneas GRASE.

 

          Because FDA does not pre-approval is not requirede for OTC products marketed under the external analgesic monograph, The FDA requires that such products must to contain certainspecific labeling’s current.  First, rule regarding the OTC products containing use of hydrocortisone must be monograph allows OTC hydrocortisone to be marketed and labeled with the following indicationas anti-pruritic: “for the temporary relief of itching associated with minor skin irritations, inflammation, and rashes..  Optionally, this may be followed by:  “due to eczema, psoriasis, seborrheic dermatitis, insect bites, poison ivy, poison oak, or poison sumac, soaps, detergents, cosmetics, jewelry, and/or external genital, feminine, and anal itching.”

 

          Additional required labeling includes a warning that consumers using OTC external analgesic products containing hydrocortisone must stop use and ask a doctor if conditions worsen, last longer than seven days, or clear up and occur again within a few days.  Finally, Second, directions on a hHydrocortisone-containing OTC product must specify that instruct adults and children over 2 years of ageconsumers are not to can be used the product more than 3 to- 4 times daily for adults and children over 2 years of age and to not use the product is not to be used on children under 2 years of age.  Lastly, with regard to warnings, OTC external analgesic products containing Like all other OTC external analgesics, hydrocortisone must direct labeling includes warnings directing consumers to stop applying the product use if symptoms get worse , or l symptomsor last longer than seven days, and not to use the product onfor children under two years of age.

 

          The dataset upon which FDA based its  GRASE findingdecision to allowed OTC marketing of for hydrocortisone after considering several studies evaluating potential systemic effects of dermatologically applied hydrocortisone.  FDA did not believe that any of the clinical data precluded topical hydrocortisone from being safely marketed OTC.  For example, for OTC use includes a clinicalone study indicating indicated that hydrocortisone, applied topically for prolonged periods of time, diddid not cause HPA axis suppression in patients with chronic skin disease (i.e., eczema or, psoriasis) (Ref. 3).  However, Tthis study was not doneconducted using current standards for HPA axis suppression (i.e., cosyntropin/cortrosyn stimulation test). as  Instead, tthane primary endpoint was alteration in plasma or urinary steroidsinsulin stress test was used to determine HPA axis suppression..  Please see 1990 amendment to OTC monograph for reference.  FDA was not aware of anyNo clinical studies onf hydrocortisone-induced growth suppression and, therefore, has not reviewed such studies were submitted or reviewed reviewed at the time.

 

          Recently, FDAwe  hashave met with sponsors to discussionsrequesting  RxRx-to-OTC switches for  hashave been directed towards considerationing OTC whetherto allowto allow marketing of  additional topicaldermatologicdermatologic corticosteroids that are more potent than hydrocortisone tocould to be marketed OTCover-the-counter.  FDA would like to provide the sponsors with guidance on the safety database requiredAn Advisory Committee meeting discussion is needed as to the safety database for a dermatologictopical corticosteroid to be considered for OTC use and the minimum requirements for safety needed for such a product to be marketed OTC.  More specifically, FDA would like to identify theWe are convening this advisory committee to seek guidance on potential safety data necessary for the switch of more potent corticosteroids.  These data needed concerningcould include, but are not limited to, HPA axis suppression, growth suppression, and as well as local  adverse events for a potential OTC dermatologic corticosteroid.An Advisory Committee discussion is needed regarding the safety database needed for a product to be considered for OTC use and the minimum requirements for safety needed for such a product to be marketed OTC.

 

 

Potential effects from glucocorticoids (including topical)SYSTEMIC EFFECTS

 

HPA axis suppression

          The hypothalamic-pituitary-adrenal axis is sensitive to exogenous topical or systemic corticosteroid administration and may be suppressed with topical or systemic exposure.  Even relatively short-term therapy (e.g. 4 weeks) with exogenous corticosteroids can suppress the HPA axis to the point where normal stress-related increase in plasma or serum cortisol levels fails to occur.  Failure to increase cortisol secretion in these situations can result in acute adrenal insufficiency, which in some circumstances can be life threatening (see Tab 7).   

 

HPA axis suppression from use of topical corticosteroids has been demonstrated in studies using ACTH1-24 (cosyntropin) stimulation testing.  These studies have been reviewed by the FDA.  Increased The relationship between HPA axis suppression and efficacy has not been established.  However, increased risk for HPA axis suppression may result from prolonged use or application to an increased body surface area leading to greater systemic exposureof exposure (i.e., increased bioavailability) and prolonged use.  The risk for HPA axis suppression may be greater in pediatric patients due to increased body surface area to mass ratio.

 

The recommendede most appropriate testing for HPA axis suppression with the use of corticosteroids is the cosyntropin stimulation test.  The currently used criterion for indicating suppression is a serum or plasma cortisol level post-cosyntropin stimulation of less than or equal to 18 micrograms per deciliter 30 minutes after stimulation.  The currently recommended dose of cosyntropin for these tests (as discussed in the label for cosyntropin) is 250 micrograms or 125 micrograms for pediatric patients age 2 years or younger, administered as an intravenous bolus in the morning.

 

Inclusion of sufficient numbers of pediatric patients in any assessment forof HPA axis suppression is recommended.  FFurther, for safety reasons, FDAwe recommends for the more potent topical corticosteroids be tested sequentially testing starting with consenting adults, followed by progressively younger subsets of pediatric patients, is recommended for the more potent topical corticosteroids. recommended.

 

 

A lack of patients suppressed in a given HPA axis study only assures, at a given level of confidence, that such suppression is unlikely for the general population.  .The greater the number of patients studienrolled in a study resulting in no findings of HPA axis suppression, the greater level of confidence that a safety concern to this regard is unlikely (see Tab 8).  The level of confidence and the rate of HPA axis suppression which would beconsidered safe acceptable for OTC topicaldermatologic corticosteroids will be addressed by the Committee.  In addition, tThe Committee should also consider whether labeling that limits duration of use (e.g. to seven days) can effectively reduce safety concerns about HPA axis suppression effects. that consumers may use OTC dermatologic corticosteroids for longer times than the seven days specified on the label.  Depending on the numbers of patients studied, a result with no patients in a study with HPA axis suppression suggest a certain degree of confidence that there is a lack of this systemic adverse effect.

 

 

 

 

Growth suppression

          Long-term systemic exposure to corticosteroids has been studied with regard to growth suppression.  It is plausible that topical administration of exogenous corticosteroids may result in growth suppression as a result of systemic exposure.  However, growth studies may be difficult to perform with topical corticosteroids used for dermatologic conditions.  Continuous corticosteroid use at the same potency and dose throughout the long study period required for growth studies is not likely for dermatologic conditions in the pediatric age group.

Systemic adverse effects other than HPA axis suppressionGrowth suppression

          Mineralocorticoid effectsSodium retention

            Corticosteroids have the potential to cause sodium retention, (i.e., mineralocorticoid effect).  Of the corticosteroids used topically, hydrocortisone has relatively greater mineralocorticoid potency than triamcinolone or betamethasone.  The effect may be minimal with topical administration due to relatively low acute systemic exposure combined with much lower mineralocorticoid potency compared to glucocorticoid potency.

 

          Glucose intolerance

Corticosteroids have the potential to cause glucose intolerance, especially in more sensitive patients (e.g. diabetics).  This effect was explored for 1.0% hydrocortisone as discussed in the OTC drug monograph amendment (see Tab 4) for the higher concentration (1.0%) hydrocortisone.  Studies reviewed at that time disclosed “no significant systemic effect (, i.e., changes in blood glucose levels).

 

Osteoporosis

          Effects on bone -          Long-term systemic exposure to corticosteroids has been studied with regard to potential for bone loss (, e.g., osteoporosis).  It would be difficult to establish that topical corticosteroid use would result in bone loss.  (sSee Effects on growth (below).Growth suppression above).

 

Sodium retention

          Corticosteroids have the potential to cause sodium retention (i.e., mineralocorticoid effect).  Of the corticosteroids used topically, hydrocortisone has relatively greater mineralocorticoid potency than triamcinolone or betamethasone.  The effect may be minimal with topical administration due to relatively low acute systemic exposure combined with much lower mineralocorticoid potency compared to glucocorticoid potency.

 

Effects on Ggrowth suppression

          - Long-term systemic exposure to corticosteroids has been studied with regard to growth suppression.  It is plausible that topical aAdministration of exogenous corticosteroids may result in growth suppression as a result of systemic exposure.  However, growth studies may be difficult to perform, particularly with topical corticosteroids as used for dermatologic conditions.  The need forContinuous corticosteroid continuouslyuse at the same potency and dose throughout the long study period required for growth studies is not likely for dermatologic conditions in the pediatric age group.  Difficulties may be due to compliance, surface area of use, and progression of the dermatitis (improvement or worsening may lead to changes in therapy).

 

 

LOCAL Local sSsKINkin aADVERSEdverse effects EFFECTS

          Additional safety considerations for topical corticosteroids include local safety concerns, such as cutaneous atrophy, striae, erythema of the face, telangiectasia, hypopigmentation and retarded wound healing.  The unwanted local application site effects of topical steroids may be related to their potencies and the duration and site of application (surface area of application????)..  In addition, these effects may be worse with use under occlusion.

 

 

SAFETY DATABASE NEEDS

Primary, regarding considerations for OTC use of topical corticosteroids, is theWhen considering the safety of these products for OTC use, a key consideration is the safety of the product when used by the lay consumer without an learned intermediary.  Post-marketing adverse event rReports related toof the insidious condition of HPA axis suppression are rare with topical corticosteroid use,.  hHowever, consumers not associate the association between signs and symptoms of HPA axis suppression and with a topical drug product may not be easily made.  Thus, the Agencywe are considering whether HPA axis suppression should proposes that this serious condition  be the primary safety concern for OTC marketing.  Additional systemic effects, such as mineralocorticoid effects, glucose intolerance, growth suppression in children, and bone density changes in adults are also a concern, but measuring the effect of topical corticosteroids on these parameters is difficult at best.  Local skin effects need to be considered, but may be greatly minimizedcircumvented by limiting the potency of corticosteroids available, the amount available in unit packaging, and limiting the duration of therapy through labeling.

 


A regulatory decision tree has been devised by the AgencyFDA for the Committee to review and to stimulate discussion.  This decision tree lists options for regulatory oversight based on the results of HPA axis suppression testing, growth suppression testing, and local effects.  The decision tree places a hierarchy on the clinical importance of the various side effects (HPA axis suppression followed by other systemic effects, in turn followed by local effects):

 

HPA Suppression Test

 

 
 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


Severe or Irreversible

 

Mild or Reversible

 

None

 
                                    

 

 

 

 

 

 

 

 

 

 

 

 


Draft Discussion Questions for the Advisory Committee:

0.            Does the potential for suppression of the HPA axis with the use of a by a dermatologic topicaldermatologic cortico steroid preclude OTC marketing?

0.             

 

0.            The number of subjects evaluated provides for the confidence in ruling out HPA axis suppression at a desired upper limit.  With a 95% confidence limit, what is the greatest rate of HPA axis suppression to be ruled out (e.g., 0.5%, 1%, 5%, or 10%)?

 

2.0.BeyondIn the absence of HPA axis suppression, are there other safety concerns that would disallownot permit OTC marketing of topical corticosteroid?

 

3.0.Willould labeling for the systemic effects other than HPA axis suppression be an acceptable regulatory path in lieu of asking for growth suppression studies (or other tests of systemic effect, e.g. glucose intolerance testing, tests for bone density)?

0.             

4.0.What impact will this have on the development of other Rx to OTC steroid products (where growth suppression studies have been required)? ???

0.             

5.0.Is Does labeling for OTC topical corticosteroid formulations to adequately warn about local dermatologic safety concernsadverse effects resulting withfrom a certain durations of exposure and dosingextent of use sufficient (this could potentially result in shorter maximum use for corticosteroids with worse safety profiles)?

 

6.0.With regard to dermatologic local effects, at what level of severity do risks outweigh the benefits???  At what level of local adverse events would concern for local safety disallow outweigh the benefit of OTC use of topical corticosteroids use in OTC setting?


REFERENCES

 

 

1.  External Analgesic Drug Products for Over-the-Counter Human Use; Advance Notice of Proposed Rulemaking (44 FR 69768) 1979.

2.  External Analgesic Drug Products for Over-the-Counter Human Use; Amendment of Tentative Final Monograph (55 FR 6932), 1990.

3.  Munro, D.D. and D.C. Clift, “Pituitary adrenal function after prolonged use of topical corticosteroids,” British Journal of Dermatology, 88:381-385, 1973.

4.  Munro, D.D.,

5.  Cooper, M.S., and P.M. Stewart, “Corticosteroid insufficiency in acutely ill patients, New England Journal of Medicine, :727-734, 2003.

 

 

 

Appendix

 

 

TAB 1                  From Valencia, E.C. and F.A. Kerdel, “Topical Glucocorticoids,” in                                         Freedberg, I.M., A.Z Eisen, K. Wolff, K.F. Austen, L.A. Goldsmith, and                                              S.I. Katz, eds., “Fitzpatrick’s Dermatology in General Medicine, Volume                                      II,” p. 2325, 2003.

                                                Potency Ranking Of Some Commonly Used Brand-Name                                                        Glucocorticoids,

 

TAB 2        Recommendations Regarding the Safety and Effectiveness of Hydrocortisone, Advance Notice of Proposed Rulemaking (44 FR 69768 at 69813 - 69824) 1979.

                        The Advisory Review Panel on OTC Topical Analgesic, Antirheumatic, Otic, Burn, and Sunburn Prevention and Treatment Drug Products (the Topical Analgesics Panel) met from 1972 to 1978 to evaluate the safety and effectiveness of active ingredients in OTC external analgesic drug products.  One of the active ingredients reviewed was hydrocortisone (hydrocortisone acetate).  Attached is the Topical Analgesics Panel’s review of hydrocortisone (published in volume 44 of the Federal Register, December 1979).  The panel recommended that hydrocortisone be generally recognized as safe and effective as an OTC antipruritic active ingredient.

           

TAB 3        FDA Concurrence with the Recommendation of the Topical Analgesics Panel, Tentative Final Monograph (48 FR 5852 at 5865 - 5869), 1983.

                        FDA agreed with the Topical Analgesics (Advisory Review) Panel recommendation that hydrocortisone and hydrocortisone acetate be considered safe and effective as OTC antipruritic active ingredients.  Both the panel and FDA classified hydrocortisone and hydrocortisone acetate as Category I (safe and effective) active ingredients.  Attached is an excerpt from volume 48 of the Federal Register which summarizes FDA’s position with respect to the Topical Analgesics Panel’s recommendations.  The excerpt includes Part 348 of the Code of Federal Regulations listing hydrocortisone and hydrocortisone acetate, 0.25 to 0.5 percent, as active ingredients (21 CFR 348.10(d)(1) and (d)(2)) and defining appropriate labeling (21 CFR 348.50).

 

TAB  4       FDA Recognition that Hydrocortisone is Safe and Effective as an OTC Antipruritic Active Ingredient at Concentrations up to 1.0 Percent, Amendment of Tentative Final Monograph (55 FR 6932), 1990.

                        In response to a citizen petition, FDA agreed that hydrocortisone can be considered safe an effective as an OTC antipruritic active ingredient at concentrations greater than 0.5 percent up to a maximum of 1.0 percent.  FDA’s reasoning and conclusions were published in volume 55 of the Federal Register.  This publication dealt exclusively with the safety and effectiveness of hydrocortisone and is attached in its entirety.

 

TAB 5                  Munro, D.D. and D.C. Clift, “Pituitary adrenal function after prolonged                                      use of topical corticosteroids,” British Journal of Dermatology, 88:381-                                           385, 1973.

                        Clinical study referred to by Advisory Review Panel in considering the safety of hydrocortisone as an antipruritic.  40 patients with chronic skin disease (eczema, psoriasis) were treated with topically applied corticosteroids including 1.0 percent hydrocortisone for periods ranging from less than 10 to over 100 months.  Hypothalamic-pituitary-adrenal axis function was measured by evaluating response to insulin stress.

 

TAB 6        Munro, D.D., “The effect of percutaneously absorbed steroids on hypothalamic pituitary-adrenal  function after intensive use in in-patients” British Journel of Dermatology 94:67-76:1976

 

                    This is a study in HPA axis suppression in adults and children comparing betamethasone valerate, 0.1% ointment and hydrocortisone acetate, 1% ointment.

 

TAB 7        Cooper, M.S. and P.M. Stewart, “Corticosteroid Insufficiency In Acutely Ill Patients,” New England Journal of Medicine, :727-734, 2003.

                        Review article describing activity of the hypothalamic-pituitary-adrenal (HPA) axis operating normally and when suppressed (as may occur in acute illness).

 

TAB 8        Hanley, J.A., and A. Lippman-Hand, “If  Nothing Goes Wrong, Is Everything All Right? Interpreting Zero Numerators,Journal of American Medical Association, 249:1743-1745, 1983.

         

TAB 9        Ellison ,J.A., L. Patel, D.W. Ray, and P.E. Clayton, “Hypothalamic-Pituitary-Adrenal Function and Glucocorticoid Sensitivity in Atopic Dermatitis,” Pediatrics 105:794-799, 2000.

                        Study of hypothalamic-pituitary-adrenal axis function in 35 pediatric patients with atopic dermatitis.  Seven patients were treated with mildly potent dermatologic corticosteroids; 17 patients were treated with moderately potent corticosteroids, and 4 were treated with potent/very potent corticosteroids.

 

TAB 10                Seth, A. and A. Aggarwal, “Monitoring Adverse Reactions to Steroid                                       Therapy in Children,” Indian Pediatrics 41:349-357, 2004.

                        Review article describing the adverse consequences of long term steroid use in children.

 

TAB 11      Dorin, R.I., C.R. Qualls, and L.M. Crape, “Diagnosis of Adrenal Insufficiency,” Annals of Internal Medicine 139:194-206, 2003.

                        A discussion about cosyntropin stimulation testing for evaluation of adrenal insufficiency

 

TAB  12       Table:  Relative Glucocorticoid And Mineralocorticoid Potency Of Natural Corticosteroids And Some Synthetic Analogs In Clinical Use, from: Berne, R.M. and M.N. Levy (eds.), “Physiology,” The C.V. Mosby Company, St. Louis, p. 1046, 1983.

                        This table shows the relative glucocorticoid and mineralocorticoid potencies of some commonly used corticosteroids.

 

TAB 13        Table:  Relative Potencies and Equivalent Doses of Representative Corticosteroids, from: Hardman, J.G., A.G. Gilman, and L.E. Limbird (eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, New York, p. 1466, 1996.

                        This table shows that anti-inflammatory and sodium retention potencies do not necessarily correlate for different commonly used corticosteroids.

 

TAB 14A Abma, E.M., R. Blanken, and L.J. DeHeide, “Cushing’s syndrome caused by topical steroid therapy for psoriasis,” PubMed ID: 12164372, www.ncbi.nlm.nih.gov

            Abstracts of case studies - long term treatment with topical corticosteroids

TAB 14B Cook, L.J., R.K. Freinkel, C. Zugerman, D.L. Levin, and R. Radtke, “Iatrogenic hyperadrenocorticism during topical steroid therapy: assessment of systemic effects by metabolic criteria,” PubMed ID: 7047591, www.ncbi.nlm.nih.gov


 

TAB 14C

Weber, S.L., “Cushing’s syndrome attributable to topical use of lotrisone,” PubMed ID: 15251475, www.ncbi.nlm.nih.gov

 

 

TAB 15        Picado, C. and M. Luengo, “Corticosteroid-Induced Bone Loss.  Prevention and Management,Drug Safety 15:347-359, 1996.

                        A review article discussing osteoporosis as an adverse effect of long term treatment with corticosteroids.