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Rx Only
Prescribing Information
See boxed WARNINGS
concerning long-term safety of topical calcineurin inhibitors
DESCRIPTION
PROTOPIC (tacrolimus) Ointment contains tacrolimus, a macrolide
immunosuppressant produced by Streptomyces
tsukubaensis. It is for topical dermatologic use only. Chemically,
tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,
12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]
oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,monohydrate. It has the following
structural formula:
Tacrolimus has an empirical formula of C44H69NO12•H2O and a
formula weight of 822.03. Each gram of PROTOPIC Ointment contains (w/w) either
0.03% or 0.1% of tacrolimus in a base of mineral oil, paraffin,
propylene carbonate, white petrolatum and white wax.
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CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of tacrolimus in atopic dermatitis is not
known. While the following have been observed, the clinical significance of
these observations in atopic dermatitis is not known. It has been demonstrated
that tacrolimus inhibits T-lymphocyte activation by first binding to an
intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium,
calmodulin, and calcineurin is then formed and the phosphatase activity of
calcineurin is inhibited. This effect has been shown to prevent the
dephosphorylation and translocation of nuclear factor of activated T-cells
(NF-AT), a nuclear component thought to initiate gene transcription for the
formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus
also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF,
and TNF-α, all of which are involved in the early stages of T-cell activation.
Additionally, tacrolimus has been shown to inhibit the release of pre-formed
mediators from skin mast cells and basophils, and to down regulate the
expression of FcεRI on Langerhans cells.
Pharmacokinetics
Absorption
The pooled results from three pharmacokinetic studies in 88 adult
atopic dermatitis patients indicate that tacrolimus is minimally absorbed after
the topical application of PROTOPIC Ointment. Peak tacrolimus blood
concentrations ranged from undetectable to 20 ng/mL after single or multiple
doses of 0.03% and 0.1% PROTOPIC Ointment, with 85% (75/88) of the patients
having peak blood concentrations less than 2 ng/mL. In general as treatment
continued, systemic exposure declined as the skin returned to normal. In
clinical studies with periodic blood sampling, a similar distribution of
tacrolimus blood levels was also observed in adult patients, with 90%
(1253/1391) of patients having a blood concentration less than 2 ng/mL.
The absolute bioavailability of tacrolimus from PROTOPIC in atopic dermatitis
patients is approximately 0.5%. In adults with an average of 53% BSA treated,
exposure (AUC) of tacrolimus from PROTOPIC is approximately 30-fold less than
that seen with oral immunosuppressive doses in kidney and liver transplant
patients.
Mean peak tacrolimus blood concentrations following oral administration (0.3
mg/kg/day) in adult kidney transplant (n=26) and liver transplant (n=17)
patients are 24.2±15.8 ng/mL and 68.5±30.0 ng/mL, respectively. The lowest
tacrolimus blood level at which systemic effects (e.g., immunosuppression) can
be observed is not known.
Systemic levels of tacrolimus have also been measured in pediatric patients
(see
Special Populations: Pediatrics
).
Distribution
The plasma protein binding of tacrolimus is approximately 99% and
is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound
mainly to albumin and alpha-1-acid glycoprotein, and has a high level of
association with erythrocytes. The distribution of tacrolimus between whole
blood and plasma depends on several factors, such as hematocrit, temperature at
the time of plasma separation, drug concentration, and plasma protein
concentration. In a US study, the ratio of whole blood concentration to plasma
concentration averaged 35 (range 12 to 67).
There was no evidence based on blood concentrations that tacrolimus
accumulates systemically upon intermittent topical application for periods of up
to 1 year. As with other topical calcineurin inhibitors, it is not known whether
tacrolimus is distributed into the lymphatic system.
Metabolism
Tacrolimus is extensively metabolized by the mixed-function
oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic
pathway leading to the formation of 8 possible metabolites has been proposed.
Demethylation and hydroxylation were identified as the primary mechanisms of
biotransformation in vitro. The major metabolite identified in incubations with
human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a
31-demethyl metabolite has been reported to have the same activity as
tacrolimus.
Excretion
The mean clearance following IV administration of tacrolimus is
0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant
patients and adult liver transplant patients, respectively. In man, less than 1%
of the dose administered is excreted unchanged in urine.
In a mass balance study of IV administered radiolabeled tacrolimus to 6
healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal
elimination accounted for 92.4 ± 1.0% and the elimination half-life based on
radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on
tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015
L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg.
When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%.
Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for
2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5
hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The
mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of
tacrolimus 0.172 ± 0.088 L/hr/kg.
Special Populations
Pediatrics
In a pharmacokinetic study of 14 pediatric atopic dermatitis
patients, between the ages of 2-5 years, peak blood concentrations of tacrolimus
ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03%
PROTOPIC Ointment, with 86% (12/14) of patients having peak blood concentrations
below 2 ng/mL throughout the study.
The highest peak concentration was observed in one patient with 82% BSA
involvement on day 1 following application of 0.03% PROTOPIC Ointment. The peak
concentrations for this subject were 14.8 ng/mL on day 1 and 4.1 ng/mL on day
14. Mean peak tacrolimus blood concentrations following oral administration in
pediatric liver transplant patients (n = 9) were 48.4± 27.9 ng/mL.
In a similar pharmacokinetic study with 61 enrolled pediatric patients (ages
6 -12 years) with atopic dermatitis, peak tacrolimus blood concentrations ranged
from undetectable to 5.3 ng/mL after single or multiple doses of 0.1% PROTOPIC
Ointment, with 91% (52/57) of evaluable patients having peak blood
concentrations below 2 ng/mL throughout the study period. When detected,
systemic exposure generally declined as treatment continued.
In clinical studies with periodic blood sampling, a similar distribution of
tacrolimus blood levels was also observed, with 98% (509/522) of pediatric
patients having a blood concentration below 2 ng/mL.
Renal Insufficiency
The effect of renal insufficiency on the pharmacokinetics of
topically administered tacrolimus has not been evaluated. The mean clearance of
IV administered tacrolimus in patients with renal dysfunction was similar to
that of normal volunteers. On the basis of this information dose-adjustment is
not expected to be needed.
Hepatic Insufficiency
The effect of hepatic insufficiency on the pharmacokinetics of
topically administered tacrolimus has not been evaluated but dose-adjustment is
not expected to be needed.
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CLINICAL STUDIES
Three randomized, double-blind, vehicle-controlled, multi-center,
phase 3 studies were conducted to evaluate PROTOPIC Ointment for the treatment
of patients with moderate to severe atopic dermatitis. One (Pediatric) study
included 351 patients 2-15 years of age, and the other two (Adult) studies
included a total of 632 patients 15-79 years of age. Fifty-five percent (55%) of
the patients were women and 27% were black. At baseline, 58% of the patients had
severe disease and the mean body surface area (BSA) affected was 46%. Over 80%
of patients had atopic dermatitis affecting the face and/or neck region. In
these studies, patients applied either PROTOPIC Ointment 0.03%, PROTOPIC
Ointment 0.1%, or vehicle ointment twice daily to 10% - 100% of their BSA for up
to 12 weeks.
In the pediatric study, a significantly greater (p less than 0.001) percentage of
patients achieved at least 90% improvement based on the physician’s global
evaluation of clinical response (the pre-defined primary efficacy endpoint) in
the PROTOPIC Ointment 0.03% treatment group compared to the vehicle treatment
group, but there was insufficient evidence that PROTOPIC Ointment 0.1% provided
more efficacy than PROTOPIC Ointment 0.03%.
In both adult studies, a significantly greater (p less than 0.001) percentage of
patients achieved at least 90% improvement based on the physician’s global
evaluation of clinical response in the PROTOPIC Ointment 0.03% and PROTOPIC
Ointment 0.1% treatment groups compared to the vehicle treatment group. There
was evidence that PROTOPIC Ointment 0.1% may provide more efficacy than PROTOPIC
Ointment 0.03%. The difference in efficacy between PROTOPIC Ointment 0.1% and
0.03% was particularly evident in adult patients with severe disease at
baseline, adults with extensive BSA involvement, and black adults. Response
rates for each treatment group are shown below by age groups. Because the two
adult studies were identically designed, the results from these studies were
pooled in this table.
Global Improvement over Baseline at the End-Of-Treatment in Three Phase
3 Studies
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Physician’s Global Evaluation of Clinical
Response
(% Improvement)
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Pediatric Study (2-15
Years of Age)
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Adult
Studies
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Vehicle
Ointment
N = 116
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PROTOPIC Ointment
0.03%
N = 117
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Vehicle Ointment
N =
212
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PROTOPIC Ointment
0.03%
N = 211
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PROTOPIC Ointment
0.1%
N = 209
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100% |
4 (3%) |
14 (12%) |
2 (1%) |
21 (10%) |
20 (10%) |
≥ 90% |
8 (7%) |
42 (36%) |
14 (7%) |
58 (28%) |
77 (37%) |
≥ 75% |
18 (16%) |
65 (56%) |
30 (14%) |
97 (46%) |
117 (56%) |
≥ 50% |
31 (27%) |
85 (73%) |
42 (20%) |
130 (62%) |
152 (73%) |
A statistically significant difference in the percentage of adult patients
with greater than or equal to 90% improvement was achieved by week 1 for those treated with PROTOPIC
Ointment 0.1%, and by week 3 for those treated with PROTOPIC Ointment 0.03%. A
statistically significant difference in the percentage of pediatric patients
with greater than or equal to 90% improvement was achieved by week 2 for those treated with PROTOPIC
Ointment 0.03%.
In adult patients who had achieved greater than or equal to 90% improvement at the end of treatment,
35% of those treated with PROTOPIC Ointment 0.03% and 41% of those treated with
PROTOPIC Ointment 0.1%, regressed from this state of improvement at 2 weeks
after end-of-treatment. In pediatric patients who had achieved greater than or equal to 90%
improvement, 54% of those treated with PROTOPIC Ointment 0.03% regressed from
this state of improvement at 2 weeks after end-of-treatment. Because patients
were not followed for longer than 2 weeks after end-of-treatment, it is not
known how many additional patients regressed at periods longer than 2 weeks
after cessation of therapy.
In both PROTOPIC Ointment treatment groups in adults and in the PROTOPIC
Ointment 0.03% treatment group in pediatric patients, a significantly greater
improvement compared to vehicle (p less than 0.001) was observed in the secondary
efficacy endpoints of percent body surface area involved, patient evaluation of
pruritus, erythema, edema, excoriation, oozing, scaling, and lichenification.
The following two graphs depict the time course of improvement in the percent
body surface area affected in adult and in pediatric patients as a result of
treatment.
Figure 2 – Pediatric Patients Body Surface Area Over
Time
The following two graphs depict the time course of improvement in erythema in
adult and in pediatric patients as a result of treatment.
Figure 3 - Adult Patients Mean Erythema Over Time
Figure 4 - Pediatric Patients Mean Erythema Over
Time
The time course of improvement in the remaining secondary efficacy variables
was similar to that of erythema, with improvement in lichenification slightly
slower.
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