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® Ointment in atopic dermatitis patients is approximately 0.5%. In adults with an average of 53% BSA treated, exposure (AUC) of tacrolimus from Protopic® Ointment 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.

Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression.

Based on the information above and the mechanism of action, there is a concern about potential risk with the use of topical calcineurin inhibitors, including Protopic® Ointment. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including Protopic® Ointment. Therefore:

• Protopic® Ointment should not be used in immunocompromised adults and children.
• If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed (see PRECAUTIONS: General).
• The safety of Protopic® Ointment has not been established beyond one year of non-continuous use.

(See CLINICAL PHARMACOLOGY, boxed WARNING, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

General

The use of Protopic® Ointment should be avoided on pre-malignant and malignant skin conditions. Some malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), may mimic atopic dermatitis.

The use of tacrolimus ointment is not recommended in patients having skin conditions with a skin barrier defect where there is the potential for increased systemic absorption of tacrolimus, including but not limited to, Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host Disease. Oral application is also not recommended. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.

The use of Protopic® Ointment may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of Protopic® Ointment application and typically improve as the lesions of atopic dermatitis resolve. With Protopic® Ointment 0.1%, 90% of the skin burning events had a duration between 2 minutes and 3 hours (median 15 minutes). 90% of the pruritus events had a duration between 3 minutes and 10 hours (median 20 minutes) (see ADVERSE REACTIONS).

Bacterial and Viral Skin Infections

Before commencing treatment with Protopic® Ointment, cutaneous bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of Protopic® Ointment in the treatment of clinically infected atopic dermatitis.

While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi’s varicelliform eruption), treatment with Protopic® Ointment may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum.

Patients with Lymphadenopathy

In clinical studies, 112/13494 (0.8%) cases of lymphadenopathy were reported and were usually related to infections (particularly of the skin) and noted to resolve upon appropriate antibiotic therapy. Of these 112 cases, the majority had either a clear etiology or were known to resolve. Transplant patients receiving immunosuppressive regimens (e.g., systemic tacrolimus) are at increased risk for developing lymphoma; therefore, patients who receive Protopic® Ointment and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, Protopic® Ointment should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Sun Exposure

During the course of treatment, patients should minimize or avoid natural or artificial sunlight exposure, even while Protopic® Ointment is not on the skin. It is not known whether Protopic®​ Ointment interferes with skin response to ultraviolet damage.

Immunocompromised Patients

The safety and efficacy of Protopic® Ointment in immunocompromised patients have not been studied.

Renal Insufficiency

Rare post-marketing cases of acute renal failure have been reported in patients treated with Protopic® Ointment. Systemic absorption is more likely to occur in patients with epidermal barrier defects especially when Protopic​® Ointment is applied to large body surface areas. Caution should also be exercised in patients predisposed to renal impairment.

Information for Patients

(See Medication Guide)

Patients using Protopic​® Ointment should receive and understand the information in the Medication Guide. Please refer to the Medication Guide for providing instruction and information to the patient.

What is the most important information patients should know about Protopic® Ointment?

The safety of using Protopic® Ointment for a long period of time is not known. A very small number of people who have used Protopic® Ointment have had cancer (for example, skin or lymphoma). However, a link with Protopic® Ointment has not been shown. Because of this concern, instruct patients:

• Do not use Protopic® Ointment continuously for a long time.
• Use Protopic® Ointment only on areas of skin that have eczema.
• Do not use Protopic®​ Ointment on a child under 2 years old.

Protopic® Ointment comes in two strengths:

• Only Protopic® Ointment 0.03% is for use on children aged 2 to 15 years.
• Either Protopic® Ointment 0.03% or 0.1% can be used by adults and children 16 years and older.

Advise patients to talk to their prescriber for more information.

How should Protopic® Ointment be used?

Advise patients to:

• Use Protopic® Ointment exactly as prescribed.
• Use Protopic® Ointment only on areas of skin that have eczema.
• Use Protopic® Ointment for short periods, and if needed, treatment may be repeated with breaks in between.
• Stop Protopic® Ointment when the signs and symptoms of eczema, such as itching, rash, and redness go away, or as directed.
• Follow their doctor’s advice if symptoms of eczema return after treatment with Protopic® Ointment.
• Call their doctor if:
  • Their symptoms get worse with Protopic® Ointment.
  • They get an infection on their skin.
  • Their symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema.

To apply Protopic® Ointment:

Advise patients:

• Wash their hands before applying Protopic® Ointment.
• Apply a thin layer of Protopic® Ointment twice daily to the areas of skin affected by eczema.
• Use the smallest amount of Protopic® Ointment needed to control the signs and symptoms of eczema.
• If they are a caregiver applying Protopic® Ointment to a patient, or if they are a patient who is not treating their hands, wash their hands with soap and water after applying Protopic® Ointment. This should remove any ointment left on the hands.
• Do not bathe, shower, or swim right after applying Protopic® Ointment. This could wash off the ointment.
• Moisturizers can be used with Protopic® Ointment. Make sure they check with their doctor first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If they use moisturizers, apply them after Protopic® Ointment.

What should patients avoid while using Protopic® Ointment?

Advise patients:

• Do not use ultraviolet light therapy, sun lamps, or tanning beds during treatment with Protopic® Ointment.
• Limit sun exposure during treatment with Protopic® Ointment even when the medicine is not on their skin. If patients need to be outdoors after applying Protopic® Ointment, wear loose fitting clothing that protects the treated area from the sun. Doctors should advise what other types of protection from the sun patients should use.
• Do not cover the skin being treated with bandages, dressings or wraps. Patients can wear normal clothing.
• Avoid getting Protopic® Ointment in the eyes or mouth. Do not swallow Protopic® Ointment. Patients should call their doctor if they swallow Protopic® Ointment.

Drug Interactions

Formal topical drug interaction studies with Protopic®Ointment have not been conducted. Based on its extent of absorption, interactions of Protopic® Ointment with systemically administered drugs are unlikely to occur but cannot be ruled out (see CLINICAL PHARMACOLOGY). The concomitant administration of known CYP3A4 inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice. Tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Oral (feed) carcinogenicity studies have been carried out with systemically administered tacrolimus in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found at daily doses up to 3 mg/kg [9X the Maximum Recommended Human Dose (MRHD) based on AUC comparisons] and 5 mg/kg (3X the MRHD based on AUC comparisons), respectively.

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment) (26X MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment) (10X MRHD based on AUC comparisons).

In a 52-week photocarcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with tacrolimus ointment at ≥0.1% tacrolimus.

Reproductive toxicology studies were not performed with topical tacrolimus. In studies of oral tacrolimus no impairment of fertility was seen in male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.12X MRHD based on body surface area [BSA]) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (0.43X MRHD based on BSA), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Pregnancy

Pediatric Use

Protopic® Ointment is not indicated for children less than 2 years of age.

Only the lower concentration, 0.03%, of Protopic® Ointment is recommended for use as a second-line therapy for short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised children 2 to 15 years of age who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.

The long-term safety and effects of Protopic®​ Ointment on the developing immune system are unknown (see boxed WARNING, WARNINGS and INDICATIONS AND USAGE).

Four studies were conducted involving a total of about 4,400 patients 2-15 years of age: one 12-week randomized vehicle-controlled study and three open-label safety studies of one to three years duration. About 2,500 of these patients were 2 to 6 years of age.

The most common adverse events from these studies associated with Protopic® Ointment application in pediatric patients were skin burning and pruritus (see ADVERSE REACTIONS). In addition to skin burning and pruritus, the less common events (<5%) of varicella zoster (mostly chicken pox), and vesiculobullous rash were more frequent in patients treated with Protopic® Ointment 0.03% compared to vehicle. In the open-label safety studies, the incidence of adverse events, including infections, did not increase with increased duration of study drug exposure or amount of ointment used. In about 4,400 pediatric patients treated with Protopic® Ointment, 24 (0.5%) were reported with eczema herpeticum. Since the safety and efficacy of Protopic® Ointment have not been established in pediatric patients below 2 years of age, its use in this age group is not recommended.

In an open-label study, immune response to a 23-valent pneumococcal polysaccharide vaccine was assessed in 23 children 2 to 12 years old with moderate to severe atopic dermatitis treated with Protopic® Ointment 0.03%. Protective antibody titers developed in all patients. Similarly, in a seven-month, double-blind trial, the vaccination response to meningococcal serogroup C was equivalent in children 2 to 11 years old with moderate to severe atopic dermatitis treated with Protopic® Ointment 0.03% (n=121), a hydrocortisone ointment regimen (n=111), or normal children (n=44).

Geriatric Use

Four hundred and four (404) patients ≥ 65 years old received Protopic® Ointment in phase 3 studies. The adverse event profile for these patients was consistent with that for other adult patients.

Post-Marketing Events 

The following adverse reactions have been identified during postapproval use of Protopic® Ointment. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CNS

Seizures

Neoplasms

Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma

Infections

Bullous impetigo, osteomyelitis, septicemia

Renal

Acute renal failure in patients with or without Netherton’s syndrome, renal impairment

Skin

Rosacea, application site edema

OVERDOSAGE

Protopic® Ointment is not for oral use. Oral ingestion of Protopic® Ointment may lead to adverse effects associated with systemic administration of tacrolimus. If oral ingestion occurs, medical advice should be sought.

ADULT

Protopic® Ointment 0.03% and 0.1%

• Apply a thin layer of Protopic® Ointment to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve.
• If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis.
• Continuous long-term use of topical calcineurin inhibitors, including Protopic® Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of Protopic® Ointment under occlusion, which may promote systemic exposure, has not been evaluated. Protopic® Ointment should not be used with occlusive dressings.

PEDIATRIC – FOR CHILDREN 2-15 YEARS

Protopic® Ointment 0.03%

• Apply a thin layer of Protopic® Ointment, 0.03% to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve.
• If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis.
• Continuous long-term use of topical calcineurin inhibitors, including Protopic® Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of Protopic® Ointment under occlusion, which may promote systemic exposure, has not been evaluated. Protopic® Ointment should not be used with occlusive dressings.