TCIs: Thinking Outside the Black Box
Friday, December 11, 2009
New classes of active topical medications are a rare occurrence
nowadays. In 2000 and 2001, the Food and Drug Administration (FDA),
followed shortly after by European countries and then by most of
the rest of the world, approved the drugs tacrolimus and
pimecrolimus. These medicines are topical calcineurin inhibitors
(TCIs) prescribed for the treatment of moderate-to-severe atopic
dermatitis (AD). In January 2006, however, a black box warning was
introduced by the FDA, indicating that the use of calcineurin
inhibitors (CIs) could induce a potential risk of
cancer1. Of note, the FDA was also concerned about the
fact that these treatments were prescribed sometimes, outside the
determined rules, to children under 2 years of age, which in my
opinion should never been done. Nevertheless, the European
Medicines Agency (EMEA) continued to consider that the balance of
benefits vs. risk of TCIs was favorable, but reminded the
physicians of the rules of short-term indications2.
Moreover, tacrolimus is effective in preventing recurrences of AD
and is approved by The Committee for Medicinal Products for Human
Use as preventive in the treatment of AD3.
Since the FDA warned physicians about the possible risks, the
EMEA has reminded physicians to restrict both the long-term
prescriptions and the time period that physicians are allowed to
prescribe tacrolimus as a preventive drug. This expert opinion will
focus on the safety of TCIs, which remains the cornerstone of the
precautions that were underlined by the regulatory authorities. To
evaluate this safety, we will briefly address the possible systemic
resorption of the molecules, the immune status of recipients
treated with TCIs and, finally, the data obtained from long-term
Are TCI True Topical Medications, or Is There Significant
When considering the potential oncogenic risks of TCI, a
preliminary question concerns the possible transcutaneous passage
of the molecules once applied to the skin. Such a process has now
been well studied.
Thirty-nine children between the ages of 6 and 12 years old were
given 0.1% tacrolimus ointment for the treatment of AD. After 2
weeks of treatment, concentrations in the blood were evaluated at
day 1 and at day 14. Ninety-two percent of all blood samples
collected contained tacrolimus concentrations <1 ng per mL,
whereas 17% of the blood samples were below 0.025 ng per mL, the
lower limit of quantification of the collection. There was a trend
for systemic exposure to tacrolimus to increase as the size of the
treated affected body surface area increased4. A similar
study was conducted in adults treated twice daily with 0.1%
tacrolimus for a 2-week period. Of all blood samples collected, 94%
contained tacrolimus concentrations <1 ng/mL, with 31% of
samples being below 0.025 ng/mL5. The highest
concentration measured at any time, in any patient, was 1.38 ng/mL,
whereas 5 to 20 ng/ml is the concentration used for
immunosuppression. Mean blood concentrations at 24 hours after the
first and last applications of tacrolimus were 0.13 ± 0.16 and 0.33
± 0.34 ng/mL, respectively5. Some diseases cause
alterations of skin barrier that could lead to enhanced systemic
resorption, as seen with Netherton syndrome treated with
pimecrolimus. Therefore, application of TCI is now strictly
contraindicated in this disease. Altogether, these data give a
precise evaluation of the absence of significant systemic exposure
to TCI if used in patients affected with AD.
Immune Status of Patients Treated with TCI
Another important point to address is the effect of TCI drugs on
systemic immunity. If these act locally, they should not affect the
immune responses of treated patients. The immune status of patients
treated with TCIs can be tested through several evaluations. One
such way is to evaluate, in vivo, the delayed
hypersensitivity reaction using an eight-pronged applicator
containing seven preloaded antigens and a vehicle control. A study
was performed in patients treated for 6 or 12 months with topical
tacrolimus6. The number of positive antigens was 1.3±1.2
at day 1, 1.5±1.3 at 6 months, and 1.8±1.4 at 12 months. No
changes in cellular immunity were detected even in
Another tool was employed to assess effects on immunization.
Twenty-three children were treated for 7 weeks with tacrolimus: 3
weeks before receiving the pneumococcal vaccine and 4 weeks after
receiving the vaccine. There were specific antibodies detectable in
all of these children7. Another study evaluated 132
children who received the meningococcal C vaccine during tacrolimus
treatment compared with 44 controls who were challenged without any
treatment. Specific antibodies were found in 97.5% in the
tacrolimus group vs. 99% of the control group8.
Therefore, the cellular and humoral immune responses do not seem to
be affected by TCI.
Safety Data on Carcinogenic Risks of CI
The initial warning from the FDA relied on post-market data that
included ten cases of neoplasia in pimecrolimus recipients; four
children and six adults, with a total of four lymphomas. There were
19 cancers in the tacrolimus-treated patients; three children and
16 adults, with a total of nine lymphomas. In addition,
further studies have shown few single reports of neoplasia,
essentially cases that develop in lichen-sclerosus-treated
patients, and one melanoma in a vitiligo-treated patient. However,
a careful analysis of the FDA reported cases by Ormerod and
colleagues found that many of these solid tumors had either
powerful oncogenic stimuli, such as smoking, systemic cyclosporine
or ultraviolet light (UV), which were able to induce the reported
neoplasia9. Furthermore, the same study noted that the
features of the reported lymphoma did not correspond to the
features observed after immunosuppressive drugs9. It
should be noted that lymphomas due to the TCI should have been B
cell lymphomas, but these were not seen . Finally, four cohort
analyses, including three case-control studies, have been
performed10-13. None of these show any over-risk
of malignancy. The largest study has been reported by Fonacier
et al. in the USA10. It showed that the
incidence of lymphoma was 0.65/100,000 in tacrolimus-treated cases
vs. 22/ 100,000 in the general population. The incidence of
non-melanoma skin cancer was 0.93/100,000 in tacrolimus-treated
cases vs. 533/ 100,000 in the general
population10. Therefore, the incidence of lymphomas and
cutaneous malignancies is lower in patients receiving TCI's
compared with the general population.
Another study analyzed 293,253 patients, from 73 sites in the
USA , who have had AD for at least 6 months. Within this study, 294
lymphoma cases were found. These were compared with a population of
AD cases without apparent lymphoma12. The adjusted odds
ratio for drug exposure was 0.79 for tacrolimus and 0.82 for
pimecrolimus12. Of note, the only risk factor for
lymphoma in these cases was the severity of AD .
After initial and reasonable precautions, TCI drugs appear to be
reasonably safe as long as they are used according to their
- Protopic and Elidel presentation for regulatory briefing on
January 14, 2005. Available at:
- European Medicines Agency. Last accessed October 2009.
Available at: www.emea.europa.eu
- European Public Assessment Report (EPAR), Protopic: EPAR
Summary for the Public. Last accessed October 2009. Available
- Harper J, Smith C, Rubins A, et al. A multicenter
study of the pharmacokinetics of tacrolimus ointment after first
and repeated application to children with atopic dermatitis. J
Invest Dermatol. 2005;124(4):695-699.
- Undre NA, Moloney FJ, Ahmadi S, Stevenson P, Murphy GM. Skin
and systemic pharmacokinetics of tacrolimus following topical
application of tacrolimus ointment in adults with moderate to
severe atopic dermatitis. Br J Dermatol.
- Reitamo S, Wollenberg A, Schöpf E, et al. Safety and
efficacy of 1 year of tacrolimus ointment monotherapy in adults
with atopic dermatitis. The European Tacrolimus Ointment Study
Group. Arch Dermatol. 2000;136(8):999-1006.
- Stiehm ER, Roberts RL, Kaplan MS, et al. Pneumococcal
seroconversion after vaccination for children with atopic
dermatitis treated with tacrolimus ointment. J Am Acad
Dermatol. 2005;53(2 Suppl 2):S206-13.
- Hofman T, Cranswick N, Kuna P, et al; International
Tacrolimus Ointment Study Group. Tacrolimus ointment does not
affect the immediate response to vaccination, the generation of
immune memory, or humoral and cell-mediated immunity in children.
Arch Dis Child. 2006;91(11):905-910.
- Ormerod AD. Topical tacrolimus and pimecrolimus and the risk of
cancer: how much cause for concern? Br J Dermatol.
- Fonacier L, Spergel J, Charlesworth EN, et al.
American College of Allergy, Asthma and Immunology; American
Academy of Allergy, Asthma and Immunology. Report of the Topical
Calcineurin Inhibitor Task Force of the American College of
Allergy, Asthma and Immunology and the American Academy of Allergy,
Asthma and Immunology. J Allergy Clin Immunol.
- Margolis DJ, Hoffstad O, Bilker W. Lack of association between
exposure to topical calcineurin inhibitors and skin cancer in
adults. Dermatology. 2007;214(4):289-295.
- Arellano FM, Wentworth CE, Arana A, Fernández C, Paul CF. Risk
of lymphoma following exposure to calcineurin inhibitors and
topical steroids in patients with atopic dermatitis. J Invest
- Naylor M, Elmets C, Jaracz E, Rico JM. Non-melanoma skin cancer
in patients with atopic dermatitis treated with topical tacrolimus.
J Dermatolog Treat. 2005;16(3):149-153.