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The agent pimecrolimus (Elidel) is a topical
immunosuppressant calcineurin inhibitor and is currently being very
heavily marketed for use in children with eczema. It is more effective
than placebo, but there are no good studies comparing its efficacy and
safety with the previous standard treatment of weak topical
steroids.
There have been many concerns voiced regarding its potential for
unintended immunosuppression, and possible carcinogenicity. There
are good biological reasons to predict such effects and some animal &
human evidence to suggest the risks of both are not
insignificant.
In the last couple of months there have been 2 studies published
claiming evidence for safety and lack of effect on immune function (as
shown by immune response to vaccination). These studies are
small, short-term and uncontrolled. They must be interpreted with
caution.
Also, the Division of Pediatric Drug Development of the Federal Drug
Administration (FDA) has made recommendations that pimecrolimus
(Elidel) and tacrolimis (Protopic) carry a warning of these safety
concerns.
My view: these agents are probably effective in the treatment of mild
atopic eczema but there remain very significant concerns about safety
issues, which only very large, and long-term studies will resolve. With
the current level of knowledge, I might prescribe them for very
short-term use in older children but would not use them for widespread or
prolonged use in younger babies. I know some dermatologists hold
different views.
The RCH Drug Usage Committee has not approved these agents for use in our
hospital patients.
The studies mentioned, plus the FDA recommendation are detailed
below.
MIKE
Long-term control of atopic
dermatitis with pimecrolimus cream 1% in infants and young children: A
two-year study
J Am Acad Dermatol 2005;52:240-6Kim A. Papp,
MD, PhD, FRCP,a Thomas Werfel, MD,b Regina Fo¨lster-Holst, MD,c Jean-Paul
Ortonne, MD,d Paul C. Potter, MD,e Yves de Prost, MD,f Miles J. Davidson,
MD,g Nathalie Barbier, Hans-Peter Goertz, MPH,h and Carle Paul, MDh
Waterloo, Canada; Hannover and Kiel, Germany; Nice and Paris, France;
Cape Town, South Africa; Dronfield, United Kingdom; and Basel,
Switzerland
Objective and methods: The safety and efficacy of
treatment with pimecrolimus cream 1% was evaluated for up to 2 years in
infants and young children with atopic dermatitis. Ninety-one patients
participated in a 1-year, open-label extension to a 1-year double-blind
study. Of these, 76 received pimecrolimus 2 years. Pimecrolimus was
applied twice daily at the first signs or symptoms of the disease until
clearance. Outcome measures included the incidence of adverse events and
the Eczema Area and Severity Index (EASI).
Results: No patient discontinued because of adverse events. The
incidence of systemic and skin infections did not increase over time.
Over the 2-year period, 2 patients experienced an episode of clinically
diagnosed eczema herpeticum. In patients receiving pimecrolimus for 2
years, the mean decrease in EASI score from baseline was 68.7% at 3
months and 70.8% at 24 months.
Conclusion: Treatment with pimecrolimus cream 1% for up to 2 years
was well tolerated and resulted a marked and sustained improvement of
atopic dermatitis.
Long-term treatment of atopic dermatitis
with pimecrolimus cream 1% in infants does not interfere with the
development of protective antibodies after vaccination
J Am Acad Dermatol 2005;52:240-6
Objective We investigated whether treatment of atopic
dermatitis with pimecrolimus cream 1% in infants affects the development
of a normal antibody response to vaccinations.
Methods In all, 91 patients participated in a 1-year, open-label
extension to a 1-year double-blind study: 76 used pimecrolimus twice
daily at the first signs or symptoms of the disease until clearance for 2
years and 15 only in the second year. Serum concentrations of antibodies
against tetanus, diphtheria, measles, and rubella were measured at months
18 and 24.
Results The seropositivity rates of 93.6% for tetanus, 88.6% for
diphtheria, 88.5% for measles, and 84.4% for rubella were comparable with
those reported in literature. Seropositivity was not significantly
affected by the use of pimecrolimus at the time of vaccinations (± 28
days).
Conclusions Treatment of atopic dermatitis with pimecrolimus cream
1% in early childhood does not appear to interfere with the development
of a normal immune response to vaccinations.
Federal Drug Administration - Division of
Pediatric Drug Development. Recommendations for Tacrolimus and
Pimecrolimus
The Division of Pediatric Drug Development (DPDD) recommends a boxed
warning for both Protopic and Elidel. This recommendation is based on the
totality of scientific information available thus far which includes
animal carcinogenicity signal both in mice and monkeys, post-marketing
tumor-related adverse event reports coupled with the increased absorption
in atopic dermatitis resulting in greater systemic exposure. The evidence
raises serious safety concerns in children regarding the potential for
carcinogenicity in humans treated with these agents. These products are
being widely used to treat atopic dermatitis, a non-life threatening
disease, and heavily advertised for use in young children without
appreciation by parents and physicians regarding the potential for
carcinogenic risk. We believe regulatory action is needed at this time
since a definitive answer to the carcinogenic risk of these products will
not be known for years and the difficulty of designing a clinical study
that will provide a definitive answer to this question
For background, Protopic Ointment (tacrolimus) and Elidel Cream
(pimecrolimus) are indicated for the short-term and intermittent
long-term treatment of atopic dermatitis in patients >2 years of age
who are either unresponsive or intolerant of alternative, conventional
therapies or in whom the use of these therapies is deemed inadvisable due
to potential risks. Protopic and Elidel are calcineurin inhibitors and
immunosuppressants. Although their exact mechanism of action is not
known, they exert direct immunosuppressive effects as evidenced by
inhibition of T cell activation and inhibition of various interleukins
and interferon gamma.
Although these products are applied topically, they may be systemically
absorbed. Detectable drug levels in the blood are more frequently
observed in children than in adults. This higher systemic drug exposure
in children may be related to their greater body surface area to mass
ratio.
Scientific evidence for systemic immunosuppression from topical
application of these products is available in both humans and
animals.
In animals, the carcinogenicity signal is strong, consistent, and
dependent on dose and treatment duration. In mice, lymphoma formation was
reported with application of Protopic and with Elidel dissolved in
ethanol, at 26x and 47x MRHD (maximum recommended human dose) based on
AUC comparisons, respectively. In addition, the median time to skin tumor
formation was decreased in hairless mice following chronic Protopic
administration with concurrent exposure to UV irradiation. Furthermore,
the latency time to lymphoma formation was shortened to 8 weeks after
administration of Elidel in ethanol to mice at a dose of 179-217x MRHD
based on AUC comparisons.
In humans, post-marketing tumor-related adverse events related to
these products continues to be reported. Since marketing approval
(12/08/00 for Protopic and 12/13/01 for Elidel), 7 cases of lymphoma have
been reported, four with Protopic and three with Elidel. Five of these 7
cases occurred in adults; one, in a 2 year old child; and one in a
patient of unreported age. Duration of use is known in 5/7 cases (several
weeks, 5 months, 6 months in 2 and 1 ½ years in another); occurrence was
reported at the site of drug application in one. In addition, there is
one case of cutaneous Kaposis sarcoma which developed at the site of
Protopic application and that became metastatic in an HIV positive adult.
To date, 6 cases of skin cancer (of which three were recurrences) have
been reported in adults, five with Protopic and one with Elidel. In 4/6
cases, the latency time to skin cancer was reported: 1-2 weeks, 3-4
weeks, 8 weeks and 3 months. Of these 6 cases, there was a history of
atrophic lichen sclerosis in two cases and occurrence at the site of drug
application in 2 different cases. Of note, the incidence of skin
papillomas, a risk factor for precancerous lesions and cancer, was
reported pre-marketing in children treated with Elidel (in the Adverse
Reactions section of the Elidel package insert, the incidence of skin
papillomas in the 6-week pediatric study was 0.4% (1/267) with Elidel and
0 (0/136) with vehicle control; in the 1-year safety study, it was 3.3%
(9/272) with Elidel and <1% of 75 patients treated with vehicle
control ). Post-marketing, 2 cases of papilloma have been reported with
Elidel, one in a child and one in an adult. Additional post-marketing
tumor-related cases in children include one case each of facial tumor,
type unspecified, with Elidel cream, Sezarys syndrome after three years
of Protopic use, hepatoblastoma after one year of Protopic use and one
case of sudden increase in size of metastatic angiosarcoma after three
months of Protopic use.
Additional supportive evidence of immunosuppression in pediatric patients
includes the increased incidence of specific infections that occurred
with these products compared to vehicle alone in the pediatric clinical
trials conducted pre-marketing. These results are reported in the
Pediatric Use and Adverse Reactions sections of the Package Inserts. Of
the cases of infections reported post marketing in pediatric patients,
the most significant case was that of an 8-month old male who developed
eczema herpeticum with pseudomonas sepsis and subsequent cardiac arrest.
Protopic ointment was applied over his entire body for 6 months. Of note,
the serum tacrolimus level was 3.5 ng/ml two weeks after Protopic had
been discontinued. The patient survived.
It is known that oral or parenteral administration of immunosuppressant
drugs is associated with an increased incidence of infection and cancer,
particularly lymphoma. Tacrolimus injection (Prograf), cyclosporine and
azathioprine, all of which include an indication for prevention of organ
transplant rejection, contain a boxed warning. Although a systemic
preparation of tacrolimus, Prograf, is available, there currently is no
marketed systemic preparation of Elidel. Of note, a recent non-human
primate study conducted with an oral formulation of Elidel which is under
development, demonstrated the occurrence of lymphoma in all dose groups
studied, including the lowest dose which represented 30x MRHD for the
topical product. Therefore, a NOEL for lymphoma was not established in
this study. Of further concern, lymphoma was reported in one of four
recovery animals despite discontinuation of treatment. In this study,
lymphoma was associated with a latent infection by an Epstein Barr
related virus which is the same mechanism described in immunosuppressed
humans following transplantation. In addition, three of nine monkeys
developed concurrent leukemia.
The immunosuppressive effects of these topical products in animals,
manifested primarily as lymphoma formation, are strong, consistent and
compelling. The biological relevance of these animal findings to humans
exposed to these drugs cannot be excluded. In addition, immunosuppression
is the proposed mechanism of action of Protopic and Elidel.
These products are indicated for the intermittent but chronic treatment
of a non life-threatening condition, atopic dermatitis. The abraded skin
characteristic of atopic dermatitis increases systemic absorption of
these drugs and, as noted above, children have higher systemic blood
levels of these drugs compared to adults, and, thus, greater systemic
drug exposure. Given that these topical products may be applied
chronically in a young child over an extensive surface area of abraded
skin, there is potential for significant cumulative drug exposure. As
demonstrated in the animal carcinogenicity studies, the development of
lymphoma was dependent on cumulative drug exposure, being a function of
dose and treatment duration. The increasing number of post-marketing
tumor-related adverse events is concerning because they too, like the
animal carcinogenicity findings and the known carcinogenicity potential
with systemic administration of these drugs to humans, relate to the
mechanism of action of this drug class, i.e., immunosuppression.
CFR 201.57 provides the Agency with the legal and regulatory authority to
require a boxed warning based on serious animal toxicity in the absence
of clinical data. FDA has previously exercised this authority. Such was
the case for Forteo (teriparatide injection) and Flagyl (metronidazole
tablets). Therefore, there is precedent. A boxed warning is the most
effective labeling tool FDA has to convey a potential safety signal or
risk. It is also recommended that the PPI for these products inform
patients/parents/caregivers of the potential cancer risk based on the
animal carcinogenicity findings and the post-marketing adverse
events.
The use of these products continues to increase, including use in the
very young, although they are not approved in patients less than 2 years
of age. For example, from June, 2003-May, 2004, the number of
prescriptions dispensed for Protopic, increased by 16% and for Elidel, by
46%, compared to the previous year. In this same time period, patients
aged 1-2 years, accounted for 8% and 13% of Protopic and Elidel
prescriptions, respectively.
The increasing use may be related to aggressive and inappropriate
advertising with portrayal of these products as safer than steroids and
the implication that they can be used as first-line therapy and for
unlimited periods of time.
A presentation entitled: ELIDEL Redefining Successful Therapy& A
Blockbuster in the Making!was delivered by Kurt Graves, Chief Marketing
Officer, Novartis, on their 2003 R&D day. Included in this
presentation were plans to develop the drug for flare prevention among
other indications (e.g., chronic hand dermatitis) and to expand usage to
infants with atopic dermatitis.
In conclusion, based on the scientific information available to date
which raises serious safety concerns regarding the potential for
carcinogenicity of these agents in humans, the Division of Pediatric Drug
Development recommends that a boxed warning be included in the Package
Inserts for Protopic and Elidel.
Mike
A/Prof Mike South,
Royal Children's Hospital, Parkville, Victoria 3052, Australia
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