NDAC/DODAC Advisory Committee Meeting
The focus of this advisory committee
is to discuss the safety data needed for a switch of topical corticosteroids from
prescription to over-the-counter (OTC) use.
The focus of the discussion will be on the effect of corticosteroids to induce hypothalamic-pituitary-adrenal (HPA) axis
suppression and other ef fects (e.g. growth suppression, local skin effects) .
Currently, t he only topical corticosteroid currently
marketed for OTC use is hydrocortisone acetate (hydrocortisone ) . This was originally market ed as a
prescription drug since
1952. In 1983, FDA classified
0.25% - 0.5%
hydrocortisone as generally recognized as safe
and effective ( GRASE ) in the OTC drug monograph for external analgesic s . This was later amended in 1990 to include 0.25% to 1.0% hydrocortisone .
The monograph allows OTC hydrocortisone
to be marketed and labeled as anti-prur itic : “for the
temporary relief of itching associated with minor skin irritations,
inflammation, and rashes ” .
H ydrocortisone can be use d 3 - 4 times
daily for adults and children over 2
years of age . Like all other OTC
external analge sics, hydrocortisone labeling
includes warnings directing consumers to stop use if symptoms get worse or l ast longer than seven days and not to
use the product on children
under two years of age .
dataset upon which FDA based its GRASE
finding for hydrocortisone include s a clinical study indicating that hydrocortisone, applied
topically for prolonged periods of time, did not cause HPA axis suppression
in patients with chronic skin disease ( eczema , psoriasis) . No clinical studies o f growth suppression were reviewed at the time .
Recent discuss ion has been directed
towards consider ation to all ow additional topical
corticosteroids to be marketed OTC . 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.
axis is sensitive to exogenous corticosteroid administration and may be suppressed with topical or systemic exposure . Even relatively short-term
therapy with exogenous corticosteroids can suppress the
HPA axis to the point where normal stress-related increase in plasma or serum cortisol 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 .
suppression from use of topical corticosteroids has been demonstrated in
studies using ACTH 1-24 (cosyntropin) stimulation
testing. These studies have been reviewed by the FDA. The relationship between HPA axis suppression and efficacy has not been established. However, increased risk for HPA axis
suppression may result from increased body surface area of
exposure (i.e., increased
and prolonged use . The risk for HPA axis
suppression may be greater in pediatric patients due to increased body surface area to mass ratio.
Th e most appropriate testing for HPA axis
suppression with 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.
of sufficient numbers of pediatric patients in any assessment for HPA axis suppression is
recommended. Further, f or safety reasons, sequential testing starting with consenting adults followed by progressively
younger subsets of pediatric patients is recommended for the more potent topical
Depending on the number s o f patients studied, a result
with no patients in a study with HPA axis suppression suggest a c ertain degree of confidence
that there is a lack of this systemic adverse effect.
A dministration of exogenous corticosteroids may
result in growth suppression . However,
growth studies may be difficult to perform ,
particularly with topical corticosteroids as used for dermatologic conditions. 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 s KIN 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 effects of topical steroids
may be related to their potencies and the duration of application .
considerations for OTC use of topical corticosteroids, is the safety of these products when used by the lay
consumer without an learned intermediary. R eports of the insidious condition of HPA axis suppression are
rare with topical use , h owever, the association between symptoms of HPA axis
suppression and a topical drug product may not be easily made . Thus, the Agency proposes that this serious condition be the primary concern . Additional systemic effects, such as 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 circumvented by limiting the potency of
corticosteroids available, the amount available in unit packaging, and limiting the duration of therapy
regulatory decision tree has been devised by the Agency for Committee review and 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) :
Questions for the Advisory
Does the potential for
suppression of the HPA axis by a dermatologic topical steroid preclude OTC
In the absence of HPA axis suppression, are
there other safety concerns that would disallow OTC marketing ?
W ill labeling for the systemic
effects 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)?
What impact will this have on
the development of other Rx to OTC steroid products (where growth
suppression studies have been required)?
Is labeling for OTC topical corticosteroid
formulations to warn about local safety concerns with a certain extent
sufficient (this could potentially result in shorter maximum
use for corticosteroids with worse safety profiles)?
At what level would concern for local safety disallow OTC use of topical corticosteroid s ?