Joint
NDAC/DODAC Advisory Committee Meeting
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.
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,”
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
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.