Inhaled and intranasal corticosteroids (ICS and INS) are guidelinerecommended, first-line therapies for asthma and allergic rhinitis, respectively.(1,
2) There are significant risks in adults and children as well, summarized in a
previous position statement of the Joint Task Force of the American Academy of
Allergy, Asthma & Immunology and American College of Allergy, Asthma &
Immunology.(3) Since its publication in 2006, additional new evidence has
emerged from studies in children that further strengthen the arguments put forth
in the position paper.
Via a combination of absorption from the respiratory and gastrointestinal tracts,
corticosteroids can be detected in the blood after ICS and INS use and have
been clearly linked to growth suppression in children.(4, 5) There is evidence of
dose-relatedness and variation in sensitivity and risk across individuals.
Most of the earlier studies were designed primarily to detect efficacy, with growth
as a secondary outcome. However, the FDA also required manufacturers to
conduct Phase IV studies with growth as the primary outcome. Most of those
early Phase IV trials were poorly designed and flawed, but many produced
positive results (growth suppression of about 1 cm/year). Much evidence for
growth suppression accrued, prompting the FDA to conduct a meeting in 1998 to
review all growth data collected in trials of ICS and INS. The result was a classlabeling change for all ICS and INS stating they all can affect growth;
summarized; it states the potential growth effects of prolonged treatment should
be weighed against clinical benefits obtained and the availability of safe and
effective non-corticosteroid treatment alternatives, a recommendation for
monitoring of growth routinely using stadiometry, and the publication of a
guidance on the proper conduct of future growth studies. (6) In order to eliminate
design flaws present in earlier studies, the guidance issued specific
1
recommendations about the study population (age, disease severity), study
design (baseline period, 52-week blinded treatment period, and a follow-period),
and analysis.
In studies not designed according to the FDA guidance, there was evidence of a
growth effect of all ICS used for asthma. In contrast, there was evidence of
growth suppression for only one INS, beclomethasone,(4) and not for FP, MF
and BUD.(7-9) Subsequently, there were three ICS studies (10-12) and two INS
studies conducted fully or largely in accordance with the FDA guidance. Two of
the three ICS studies were negative (no growth effect). However, rather than
concluding that one of the ICS (ciclesonide) had no growth effect (10) the FDA
concluded that conclusions could not be drawn from this study because
compliance could not be assured.(13) Compliance in this trial was assessed
using standard methods (diary and canister weights) and was similar to that in
previously-published growth studies. Of the two INS studies, both yielded a
positive result .(TAA and FF) (14) (15) Collectively, these results suggest that all
INS, which previously produced no growth effect in less-optimally-designed
studies, should be required to undergo testing for growth effects using the same
rigorous design recommended in the FDA guidance.
Prior to the availability of the results of the TAA and FF INS studies, INS were
assumed to have no effect on growth based on the use of an excessive dose in
the positive BDP study, high oral bioavailability of BDP relative to other INS, (16)
and negative studies for the INS FP, MF and BUD. However, based on the
position FDA took on the negative ciclesonide ICS study, conclusions should not
be drawn from these three negative INS studies because compliance could not
be assured. It has become clear that when better science is applied in studies
designed with growth as a primary outcome, growth suppression can be
detected. Even this effect was deemed insignificant until recently, since
evidence of “catch-up” growth after ICS discontinuation was observed in some of
the studies. (17) This was supported by an earlier study that suggested that
there was no effect of long-term ICS treatment in children on final adult height.
2
(18) In contrast, in a study with better study design, long-term follow-up of a large
number of 5-12 year old children treated for 4-6 years with low-dose ICS in the
Childhood Asthma Management Program showed a small, but significant effect
on final adult height. (5)
On a clinical basis, INS and ICS must be used in a supervised, controlled
environment. It is essential that nasal steroids are prescribed by a clinicians, so
that they may continually engage in discussions of potential benefits and risks,
and assure the parents that he/she will make every effort to use the lowest ICS
dose possible long-term. In addition, clinicians can work closely with parents to
ensure that risks are miminized through monitoring, and develop a partnership
for long-term, routine monitoring of growth using stadiometry.(19)
What about children with asthma, who are already using ICS, and whose parents
place them on OTC INS for allergic rhinitis symptoms? To date, no studies have
adequately evaluated the effect of combined INS and ICS treatment on growth.
However, effects possibly larger than those seen in INS or ICS studies would be
expected.
If INS are made available OTC, long-term and appropriate monitoring of dose
and height by a trained professional will not be possible and will undoubtedly and
unnecessarily cause growth suppression in a large number of children.
Analyzing data from INS and ICS, we learn that some adults and children are
more sensitive to the adverse effects. Therefore analyses of mean data cannot
be reassuring. One must consider the consequences of over-the-counter use of
steroids when extrapolated to the general population. Many allergic individuals
have concomitant asthma and atopic dermatitis; thus, they may be exposed to
cumulative dosages of inhaled, intranasal, and dermatological steroids. Further,
the adverse effects of corticosteroids, including on bone resorption and growth,
may not present themselves for years. Although short-term data may be
reassuring, there is a paucity of long-term data. Unmonitored and potentially
greater use of INS has excessive risk.
3
Ocular side effects are concerning as topical corticosteroids may elevate
intraocular pressure and be associated with cataract formation. In the crosssectional, population-based Blue Mountain Eye Study, there was an association
between ICS use and glaucoma or elevated intraocular pressure in people with a
family history of glaucoma (OR 2.5, 95% CI 1.2-5.8).(20) Older individuals may
be at particular risk of cataract development. The Quebec Universal Health
Insurance Program for the Elderly evaluated 3,677 elders who underwent
cataract removal compared with 21,868 randomly-matched controls.(21) The use
of ICS for 3 or more years was associated with a 3.06-fold increase of cataract
extraction (95% CI, 1.53-6.13). Similar findings occurred in the General Practice
Research Database in the United Kingdom when studying intranasal steroids.
(22)There was a dose-dependent relationship with both larger corticosteroid
doses and increased numbers of prescriptions increasing the risk of cataract.
The odds ratio was 1.33 for those receiving intranasal steroids with insufficient
power to detect differences between the types of steroids used. These larger,
population-based studies demonstrate that topical corticosteroids can be a risk
factor for posterior subcapsular cataracts.
Use of INS can also increase the risk of osteoporosis. According to a World
Health Organization review paper, “… all considered inhaled
corticosteroids…appear to affect bone metabolism in adults and, as a
consequence, markers of bone mineral density…Triamcinolone acetonide led to
the most deleterious effect.” (23) A review of studies published between 1966
and January 2004 was conducted to evaluate the effects of INS on bone health.
(24) The review noted that several of the larger studies showed that inhaled
corticosteroids cause a dose-related reduction in bone mineral density. In
addition, three-cross sectional studies found a dose-related increase in fractures
in people taking an inhaled corticosteroid compared with controls. The review
concluded that “it is not clear whether there is a threshold dose for adverse
4
events…..Strategies are needed to reduce the systemic effects of inhaled
corticosteroids.”(24)
In adults, nasal steroids could adversely affect bone metabolism. Studies of
adults taking inhaled corticosteroids found a reduction of osteocalcin, a marker of
bone formation that correlates with a lower growth hormone peak response. (25)
Due to the paucity of data of intranasal corticosteroids on bone and ocular
complications, we cannot state this route of administration is safe in an
unmonitored setting.
The adverse local effects of INS are well-known and could present particular
concern to patients and families. These include epistaxis, nasal irritation,
changes in taste and smell, Candida infection, contact dermatitis, and septal
perforation. (3) A medical professional is necessary to perform nasal
examinations to evaluate if damage is occurring. Also, a Healthcare Provider is
best positioned to advise their patients properly on appropriate usage techniques
and treatment of these known and expected complications.
The correct monitoring and management of local and systemic adverse effects
can only be done in a healthcare setting. With these considerations, we
recommend that INS NOT be approved for over-the-counter usage.
References
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