Tacrolimus (topical)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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Black Box Warning
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Title
See full prescribing information for complete Boxed Warning.
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Overview
Tacrolimus (topical) is an immunosuppressive agent that is FDA approved for the treatment of moderate to severe atopic dermatitis, prophylaxis of cardiac transplant rejection, liver transplant rejection, renal transplant rejection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema, alopecia, persistent erythema of skin, persistent erythema of skin, pruritus, rash, constipation, diarrhea, nausea, vomiting, anemia, leukocytosis, thrombocytopenia, headache, insomnia, paresthesia, tremor.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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- Dosing Information
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- Dosing Information
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- Dosing Information
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Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (topical) in adult patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tacrolimus (topical) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Tacrolimus (topical) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
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Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (topical) in pediatric patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tacrolimus (topical) in pediatric patients.
Contraindications
- PROTOPIC (tacrolimus) Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.
Warnings
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Title
See full prescribing information for complete Boxed Warning.
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- Description
Precautions
- Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Tacrolimus (topical) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tacrolimus (topical) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Drug Interactions
- Drug
- Description
Use in Specific Populations
Pregnancy
- Pregnancy Category
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tacrolimus (topical) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Tacrolimus (topical) during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Tacrolimus (topical) with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Tacrolimus (topical) with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Tacrolimus (topical) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Tacrolimus (topical) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Tacrolimus (topical) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Tacrolimus (topical) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Tacrolimus (topical) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tacrolimus (topical) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Tacrolimus (topical) in patients who are immunocompromised.
Administration and Monitoring
Administration
- Oral
- Intravenous
Monitoring
There is limited information regarding Monitoring of Tacrolimus (topical) in the drug label.
- Description
IV Compatibility
There is limited information regarding IV Compatibility of Tacrolimus (topical) in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
- Description
Management
- Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Tacrolimus (topical) in the drug label.
Pharmacology
There is limited information regarding Tacrolimus (topical) Pharmacology in the drug label.
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.
Structure
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.
Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tacrolimus (topical) in the drug label.
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.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Tacrolimus (topical) in the drug label.
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 < 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 < 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.
A statistically significant difference in the percentage of adult patients with ≥ 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 ≥ 90% improvement was achieved by week 2 for those treated with PROTOPIC Ointment 0.03%.
In adult patients who had achieved ≥ 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 ≥ 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 < 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.
The following two graphs depict the time course of improvement in erythema in adult and in pediatric patients as a result of treatment.
The time course of improvement in the remaining secondary efficacy variables was similar to that of erythema, with improvement in lichenification slightly slower.
How Supplied
Storage
There is limited information regarding Tacrolimus (topical) Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tacrolimus (topical) in the drug label.
Precautions with Alcohol
- Alcohol-Tacrolimus (topical) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- ®[1]
Look-Alike Drug Names
- A® — B®[2]
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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