Transcript Tacrolimus and Risk Of Malignancy

Elizabeth Gorevski
Kingsbrook Jewish Medical Center
Brooklyn, NY
Uses of Tacrolimus and Pimecrolimus
Tacrolimus
• Oral/injection:
• Potent
immunosuppressant
used in heart, kidney or
liver transplant
Pimecrolimus
• Topical:
• Mild to moderate
atopic dermatitis in
patient not responsive
to conventional
therapy
• Topical:
• moderate to severe
atopic dermatitis in
patients not responsive
to conventional therapy
Munzenberger P et al Pharmacotherapy 2007; 27(7)
Treating Atopic Dermatitis
International Consensus Conference on Atopic
Dermatitis II (ICCAD II) and American Academy
of Dermatology (AAD)
Pimecrolimus cream 1% - a second-line
therapy of mild – moderate atopic dermatitis
Tacrolimus ointment 0.03% - moderate –
severe atopic dermatitis that inadequately
responds to other topicals
In children 3-5 only use tacrolimus 0.03%
Munzenberger P et al Pharmacotherapy 2007; 27(7)
Mechanism of Action
Mirsland A. et al Euro J Derm 2002;12(6)
Boxed Warning of Tacrolimus and
Pimecrolimus
Lymphoma
• Increased susceptibility of infection and the
possible development of lymphoma may result
from immunosuppression
• Have been associated with rare cases of skin
malignancies, therefore it should be limited to
short and intermittent treatment using the
minimum amount necessary to control of
symptoms and only on areas involved
Casual relationship has not been
Skin Cancer
established
Administration
• Should be administered under the supervision of
a physician experienced in immunosuppressive
therapy in a facility appropriate for monitoring and
managing therapy
Why concerns?

Increased risk of malignancies with systemic
immunosuppression after long term-high dose
for graft rejection in transplant patients
 Oral tacrolimus associated with posttranslational
lymphoproliferative disease
 Occurs in first 8 months after stem cell transplant in
0.7% of population receiving related donor human
leukocyte antigen matched transplants

Animal studies show carcinogenicity
Yarosh D, et al J Invest Dermatol 2005; 125
Pharmacokinetic Data for Topical
Pimecrolimus and Tacrolimus
Pharmacokinetic studies with PO and IV tacrolimus
Concentrations achieved
PO : 82.7 ng/mL (0.075 mg/kg/12 hours)
IV : 3300 ng/mL (0.05 mg/kg/12 hours)
Sanchez-Perez J at al. Actas Derm 2007; 98
Agents Plasma Concentrations
•
Pimecrolimus
– Used twice daily led to blood concentrations
< 0.5 – 1 ng/mL
– Higher concentrations in patients with more
extensive disease  Netherton syndrome
•
In transplant patients the systemic
administrations has been increased rate of
lymphomas, nonmelanoma skin cancer
and melanomas in sun exposed areas
• Plasma concentrations are much lower
with topical application then systemic when
used in plasma patients
Arellano F. et al J Invest Derm 2007; 127
Lymphomas
•
•
No evidence of increased prevalence of lymphomas
associated with short term, intermittent topical application
According to clinical trials
– No observed lymphomas in close to 10,000 patients with
tacrolimus
– Only 2 cases of solid tumors in 25,000 patients treated with
pimecrolimus
•
Pharmacovigilance data
– Compared with general population following marketing no
increased risk of lymphoma in close to 7 million prescriptions of
pimecrolimus and 2 million prescriptions of topical tacrolimus
•
Systemic administration
– Posttransplant lymphoproliferative disease ranges from
2% - 60 % in patient and is most common with small intestant
transplant
– Lymphomas regress spontaneously upon discontinuation of
therapy in 30% - 50 % of cases
Arellano F. et al J Invest Derm 2007; 127
•
•
•
Skin Cancer
Clinical trials
– 13 cases of nonmalenoma skin cancer, 10 basal
cell epithelimas and 3 sqamous cell carcinomas
observed in 10,000 patients treated
FDA report in December 2004
– 10 cases of skin tumors in patients treated with
tacrolimus
– 6 cases of basla and sqamous cell carcinomas in
patients treated with pimecrolimus
– In subsequent publications number increased to
21 cases
Prospective study of 9813 patients with atopic
dermatitis for 208 days
– No increase was in nonmelanoma cancer was
observed when 0.1% and 0.003% tacrolimus
cream was used
Arellano F. et al J Invest Derm 2007; 127
A Cohort Analysis

293, 253 patients
 58.6% < 20 years old
 Almost 60% female
 20% met criteria for severe atopic dermatitis

Topical agents at follow up







40% used topical steroids
7.4% pimecrolimus
13.7% tacrolimus
0.9% to pimecrolimus and tacrolimus
Almost half of patients did not use medications
Most patients were enrolled in database from 2001
onward
Atopic dermatitis was diagnosed by family physician,
pediatrician or dermatologist
Arellano F. et al J Invest Derm 2007; 127
Exposure to Medication and Risk of Lymphoma
Medication
Cases
Controls OR
Non-use
131
603
1
Top corticosteroids (high
potency)
72
195
1.23
0.83 – 1.84
Top corticosteroids (low
potency)
61
263
1.06
0.72 – 1.57
Pimecrolimus
14
65
0.82
0.42 – 1.61
Pimecrolimus with TS
9
27
1.09
0.45 – 2.64
Pimecrolimus without TS
5
38
0.60
0.21 – 1.69
Tacrolimus
11
41
0.79
0.37 – 1.71
Tacrolumus with TS
9
28
0.93
0.39 – 2.22
Tacrolimus without TS
2
13
0.5
0.10 – 2.53
Pimecrolimus +Tacrolimus
with TS
4
9
1.01
0.25 – 4.12
Pimecrolimus +Tacrolimus
without TS
1
0
INF
INF
Arellano F. et al J Invest Derm 2007; 127
95% CI
Risk of Lymphoma According to Age
Age
Cases
Controls
OR
0–2
24
181
1.00
3–5
17
142
0.94
0.48 – 1.82
6 – 10
10
161
0.48
0.22 – 1.03
11 – 20
30
197
1.18
0.66 – 2.11
21 – 30
11
85
0.99
0.46 – 2.13
31 – 40
31
134
1.67
0.93 – 2.99
41 – 50
65
135
3.67
2.17 – 6.23
51 – 60
74
118
4.75
2.79 – 8.10
> 61
32
23
9.67
4.74 – 19.72
Arellano F. et al J Invest Derm 2007; 127
95 % CI
International Consensus
European
Academy of
Dermatology
No casual
relationship
between use of
topical
calcineurin
inhibitors and
cancer in
humans
Spanish
Academy of
Dermatology and
Venereology
American
Academy of
Dermatology
Rare cases of
cancer have not
been associated
with the use of
these medications
Published
declaration
against the FDA’s
proposal for boxed
warning
Number of cases
reported with use
of calcineurin
inhibitors are
lower than the
incidence in
general population
Data demonstrating
danger of topical
calcienurin inhibitors
is unavailable and
may cause concern
among patients
Conclusions






Pharmacokinetics data do not suggest that TCI affect the
systemic immune system, as their oral counterparts
There is no data associated with an increased risk of
lymphoproliferative disease with topical tacrolimus and
pimecrolimus
Short term efficacy and safety data was demonstrated in
clinical trials and post-surveillance in approximately 11
million patients
Several professional and patient organization are
supporting safety, with close monitoring
Box warning itself states no casual link between TCI and
malignancy
Post marketing surveillance for at least 8 – 10 years is
required to ensure safety
Application to Pharmacists
• Is patient > 2
years?
History of
Therapy
• Have they
tried 1st line
agents?
Age
• Do not use
with occlusive
dressing
• Have signs
and symptoms
improved
within 6
weeks?
Monitor/Administration
Medication
Guide
• Always dispense
medication guide
to patients who
have a
prescription for
TCI