Tacrolimus Prescribing Information
Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment.
Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.
- Tacrolimus ointment is not indicated for use in children less than 2 years of age. Only 0.03% tacrolimus ointment is indicated for use in children 2 to 15 years of age.
Tacrolimus ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2 to 15 years, is indicated as
Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment.
Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.
- Tacrolimus ointment is not indicated for use in children less than 2 years of age. Only 0.03% tacrolimus ointment is indicated for use in children 2 to 15 years of age.
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 tacrolimus 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 tacrolimus ointment. Therefore:
- Tacrolimus 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 tacrolimus ointment has not been established beyond one year of non-continuous use.
(See
Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment.
Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.
- Tacrolimus ointment is not indicated for use in children less than 2 years of age. Only 0.03% tacrolimus ointment is indicated for use in children 2 to 15 years of age.
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 tacrolimus 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 tacrolimus ointment. Therefore:
- Tacrolimus 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 tacrolimus ointment has not been established beyond one year of non-continuous use.
(See
The use of tacrolimus 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 tacrolimus 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 tacrolimus ointment application and typically improve as the lesions of atopic dermatitis resolve. With tacrolimus 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
Before commencing treatment with tacrolimus ointment, cutaneous bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of tacrolimus 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 tacrolimus 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.
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 tacrolimus 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, tacrolimus ointment should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
During the course of treatment, patients should minimize or avoid natural or artificial sunlight exposure, even while tacrolimus ointment is not on the skin. It is not known whether tacrolimus ointment interferes with skin response to ultraviolet damage.
The safety and efficacy of tacrolimus ointment in immunocompromised patients have not been studied.
Rare post-marketing cases of acute renal failure have been reported in patients treated with tacrolimus ointment. Systemic absorption is more likely to occur in patients with epidermal barrier defects especially when tacrolimus ointment is applied to large body surface areas. Caution should also be exercised in patients predisposed to renal impairment.
Patients using tacrolimus 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.
The safety of using tacrolimus ointment for a long period of time is not known. A very small number of people who have used tacrolimus ointment have had cancer (for example, skin or lymphoma). However, a link with tacrolimus ointment has not been shown. Because of this concern, instruct patients:
- Do not use tacrolimus ointment continuously for a long time.
- Use tacrolimus ointment only on areas of skin that have eczema.
- Do not use tacrolimus ointment on a child under 2 years old.
- Only tacrolimus ointment 0.03% is for use on children aged 2 to 15 years.
- Either tacrolimus 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.
Advise patients to:
- Use tacrolimus ointment exactly as prescribed.
- Use tacrolimus ointment only on areas of skin that have eczema.
- Use tacrolimus ointment for short periods, and if needed, treatment may be repeated with breaks in between.
- Stop tacrolimus 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 tacrolimus ointment.
- Call their doctor if:
- Their symptoms get worse with tacrolimus 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.
Advise patients:
- Wash their hands before applying tacrolimus ointment.
- Apply a thin layer of tacrolimus ointment twice daily to the areas of skin affected by eczema.
- Use the smallest amount of tacrolimus ointment needed to control the signs and symptoms of eczema.
- If they are a caregiver applying tacrolimus 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 tacrolimus ointment. This should remove any ointment left on the hands.
- Do not bathe, shower, or swim right after applying tacrolimus ointment. This could wash off the ointment.
- Moisturizers can be used with tacrolimus 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 tacrolimus ointment.
Advise patients:
- Do not use ultraviolet light therapy, sun lamps, or tanning beds during treatment with tacrolimus ointment.
- Limit sun exposure during treatment with tacrolimus ointment even when the medicine is not on their skin. If patients need to be outdoors after applying tacrolimus 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 tacrolimus ointment in the eyes or mouth. Do not swallow tacrolimus ointment. Patients should call their doctor if they swallow tacrolimus ointment.
Formal topical drug interaction studies with tacrolimus ointment have not been conducted. Based on its extent of absorption, interactions of tacrolimus ointment with systemically administered drugs are unlikely to occur but cannot be ruled out (see
No evidence of genotoxicity was seen in bacterial (
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% to 3%), equivalent to tacrolimus doses of 1.1 to 118 mg/kg/day or 3.3 to 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.
There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women. The experience with tacrolimus ointment when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.
Reproduction studies were carried out with systemically administered tacrolimus in rats and rabbits. Adverse effects on the fetus were observed mainly at oral dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.04X to 0.12X MRHD based on BSA) during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (0.04X to 0.12X MRHD based on BSA) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies of systemically administered tacrolimus in pregnant women. Tacrolimus is transferred across the placenta. The use of systemically administered tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus ointment should be used during pregnancy only if the potential benefit to the mother justifies a potential risk to the fetus.
Although systemic absorption of tacrolimus following topical applications of tacrolimus ointment is minimal relative to systemic administration, it is known that tacrolimus is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tacrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Only the lower concentration, 0.03%, of tacrolimus ointment is recommended for use as a
The long-term safety and effects of tacrolimus ointment on the developing immune system are unknown (see boxed
Four studies were conducted involving a total of about 4,400 patients 2 to 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 tacrolimus ointment application in pediatric patients were skin burning and pruritus (see
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 tacrolimus 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 tacrolimus ointment 0.03% (n=121), a hydrocortisone ointment regimen (n=111), or normal children (n=44).
Four hundred and four (404) patients ≥ 65 years old received tacrolimus ointment in phase 3 studies. The adverse event profile for these patients was consistent with that for other adult patients.
Only the lower concentration, 0.03%, of tacrolimus ointment is recommended for use as a
The long-term safety and effects of tacrolimus ointment on the developing immune system are unknown (see boxed
Four studies were conducted involving a total of about 4,400 patients 2 to 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 tacrolimus ointment application in pediatric patients were skin burning and pruritus (see
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 tacrolimus 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 tacrolimus ointment 0.03% (n=121), a hydrocortisone ointment regimen (n=111), or normal children (n=44).
- Apply a thin layer of tacrolimus 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 tacrolimus ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
The safety of tacrolimus ointment under occlusion, which may promote systemic exposure, has not been evaluated. Tacrolimus ointment should not be used with occlusive dressings.
Tacrolimus ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.
No phototoxicity and no photoallergenicity were detected in clinical studies with 12 and 216 normal volunteers, respectively. One out of 198 normal volunteers showed evidence of sensitization in a contact sensitization study.
In three 12 week randomized vehicle-controlled studies and four safety studies, 655 and 9,163 patients respectively, were treated with tacrolimus ointment. The duration of follow-up for adult and pediatric patients in the safety studies is tabulated below.
Time on Study | Adult | Pediatrics | Total |
| < 1 year | 4682 | 4481 | 9163 |
| ≥ 1 year | 1185 | 1349 | 2534 |
| ≥ 2 years | 200 | 275 | 475 |
| ≥ 3 years | 118 | 182 | 300 |
The following table depicts the adjusted incidence of adverse events pooled across the 3 identically designed 12-week controlled studies for patients in vehicle, tacrolimus ointment 0.03%, and tacrolimus ointment 0.1% treatment groups. The table also depicts the unadjusted incidence of adverse events in four safety studies, regardless of relationship to study drug.
12-Week, Randomized, Double-Blind, Phase 3 Studies 12-Week Adjusted Incidence Rate (%) | Open-Label Studies (up to 3 years) 0.1% and 0.03% Tacrolimus Ointment Incidence Rate (%) | |||||||
Adult | Pediatric | Adult | Pediatric | Total | ||||
Vehicle (n=212) % | 0.03% Tacrolimus Ointment (n=210) % | 0.1% Tacrolimus Ointment (n=209) % | Vehicle (n=116) % | 0.03% Tacrolimus Ointment (n=118) % | (n=4682)% | (n=4481)% | (n=9163) % | |
| Skin Burning May be reasonably associated with the use of this drug product | 26 | 46 | 58 | 29 | 43 | 28 | 20 | 24 |
| Pruritus | 37 | 46 | 46 | 27 | 41 | 25 | 19 | 22 |
| Flu-like symptoms | 19 | 23 | 31 | 25 | 28 | 22 | 34 | 28 |
| Allergic Reaction | 8 | 12 | 6 | 8 | 4 | 9 | 13 | 11 |
| Skin Erythema | 20 | 25 | 28 | 13 | 12 | 12 | 7 | 9 |
| Headache | 11 | 20 | 19 | 8 | 5 | 13 | 9 | 11 |
| Skin Infection | 11 | 12 | 5 | 14 | 10 | 9 | 16 | 12 |
| Fever | 4 | 4 | 1 | 13 | 21 | 2 | 14 | 8 |
| Infection | 1 | 1 | 2 | 9 | 7 | 6 | 10 | 8 |
| Cough Increased | 2 | 1 | 1 | 14 | 18 | 3 | 10 | 6 |
| Asthma | 4 | 6 | 4 | 6 | 6 | 4 | 13 | 8 |
| Herpes Simplex | 4 | 4 | 4 | 2 | 0 | 4 | 3 | 3 |
| Eczema Herpeticum | 0 | 1 | 1 | 0 | 2 | 0 | 0 | 0 |
| Pharyngitis | 3 | 3 | 4 | 11 | 6 | 4 | 12 | 8 |
| Accidental Injury | 4 | 3 | 6 | 3 | 6 | 6 | 8 | 7 |
| Pustular Rash | 2 | 3 | 4 | 3 | 2 | 2 | 7 | 5 |
| Folliculitis | 1 | 6 | 4 | 0 | 2 | 4 | 2 | 3 |
| Rhinitis | 4 | 3 | 2 | 2 | 6 | 2 | 4 | 3 |
| Otitis Media | 4 | 0 | 1 | 6 | 12 | 2 | 11 | 6 |
| Sinusitis | 1 | 4 | 2 | 8 | 3 | 6 | 7 | 6 |
| Diarrhea | 3 | 3 | 4 | 2 | 5 | 2 | 4 | 3 |
| Urticaria | 3 | 3 | 6 | 1 | 1 | 3 | 4 | 4 |
| Lack of Drug Effect | 1 | 1 | 0 | 1 | 1 | 6 | 6 | 6 |
| Bronchitis | 0 | 2 | 2 | 3 | 3 | 4 | 4 | 4 |
| Vomiting | 0 | 1 | 1 | 7 | 6 | 1 | 4 | 3 |
| Maculopapular Rash | 2 | 2 | 2 | 3 | 0 | 2 | 1 | 1 |
| Rash | 1 | 5 | 2 | 4 | 2 | 2 | 3 | 3 |
| Abdominal Pain | 3 | 1 | 1 | 2 | 3 | 1 | 3 | 2 |
| Fungal Dermatitis | 0 | 2 | 1 | 3 | 0 | 2 | 4 | 3 |
| Gastroenteritis | 1 | 2 | 2 | 3 | 0 | 2 | 4 | 3 |
| Alcohol Intolerance | 0 | 3 | 7 | 0 | 0 | 4 | 0 | 2 |
| Acne | 2 | 4 | 7 | 1 | 0 | 3 | 2 | 3 |
| Sunburn | 1 | 2 | 1 | 0 | 0 | 2 | 1 | 1 |
| Skin Disorder | 2 | 2 | 1 | 1 | 4 | 2 | 2 | 2 |
| Conjunctivitis | 0 | 2 | 2 | 2 | 1 | 3 | 3 | 3 |
| Pain | 1 | 2 | 1 | 0 | 1 | 2 | 1 | 2 |
| Vesiculobullous Rash | 3 | 3 | 2 | 0 | 4 | 2 | 1 | 1 |
| Lymphadenopathy | 2 | 2 | 1 | 0 | 3 | 1 | 2 | 1 |
| Nausea | 4 | 3 | 2 | 0 | 1 | 2 | 1 | 2 |
| Skin Tingling | 2 | 3 | 8 | 1 | 2 | 2 | 1 | 1 |
| Face Edema | 2 | 2 | 1 | 2 | 1 | 1 | 1 | 1 |
| Dyspepsia | 1 | 1 | 4 | 0 | 0 | 2 | 2 | 2 |
| Dry Skin | 7 | 3 | 3 | 0 | 1 | 1 | 1 | 1 |
| Hyperesthesia | 1 | 3 | 7 | 0 | 0 | 2 | 0 | 1 |
| Skin Neoplasm Benign Generally “warts”. | 1 | 1 | 1 | 0 | 0 | 1 | 2 | 2 |
| Back Pain | 0 | 2 | 2 | 1 | 1 | 3 | 0 | 2 |
| Peripheral Edema | 2 | 4 | 3 | 0 | 0 | 2 | 0 | 1 |
| Varicella Zoster/Herpes Zoster All the herpes zoster cases in the pediatric 12-week study and the majority of cases in the open-label pediatric studies were reported as chicken pox. | 0 | 1 | 0 | 0 | 5 | 1 | 2 | 2 |
| Contact Dermatitis | 1 | 3 | 3 | 3 | 4 | 2 | 2 | 2 |
| Asthenia | 1 | 2 | 3 | 0 | 0 | 1 | 0 | 1 |
| Pneumonia | 0 | 1 | 1 | 2 | 0 | 1 | 3 | 2 |
| Eczema | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 1 |
| Insomnia | 3 | 4 | 3 | 1 | 1 | 2 | 0 | 1 |
| Exfoliative Dermatitis | 3 | 3 | 1 | 0 | 0 | 0 | 1 | 0 |
| Dysmenorrhea | 2 | 4 | 4 | 0 | 0 | 2 | 1 | 1 |
| Periodontal Abscess | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 |
| Myalgia | 0 | 3 | 2 | 0 | 0 | 2 | 1 | 1 |
| Cyst | 0 | 1 | 3 | 0 | 0 | 1 | 0 | 1 |
| Cellulitis | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 1 |
| Exacerbation of Untreated Area | 1 | 0 | 1 | 1 | 0 | 1 | 1 | 1 |
| Procedural Complication | 1 | 0 | 0 | 1 | 0 | 1 | 1 | 1 |
| Hypertension | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 1 |
| Tooth Disorder | 0 | 1 | 1 | 1 | 0 | 2 | 1 | 1 |
| Arthralgia | 1 | 1 | 3 | 2 | 0 | 2 | 1 | 2 |
| Depression | 1 | 2 | 1 | 0 | 0 | 1 | 0 | 1 |
| Paresthesia | 1 | 3 | 3 | 0 | 0 | 2 | 1 | 2 |
| Alopecia | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 1 |
Urinary Tract Infection | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 2 |
| Ear Pain | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 1 |
Other adverse events which occurred at an incidence between 0.2% and less than 1% in clinical studies in the above table include: abnormal vision, abscess, anaphylactoid reaction, anemia, anorexia, anxiety, arthritis, arthrosis, bilirubinemia, blepharitis, bone disorder, breast neoplasm benign, bursitis, cataract NOS, chest pain, chills, colitis, conjunctival edema, constipation, cramps, cutaneous moniliasis, cystitis, dehydration, dizziness, dry eyes, dry mouth/nose, dyspnea, ear disorder, ecchymosis, edema, epistaxis, eye pain, furunculosis, gastritis, gastrointestinal disorder, hernia, hypercholesterolemia, hypertonia, hypothyroidism, joint disorder, laryngitis, leukoderma, lung disorder, malaise, migraine, moniliasis, mouth ulceration, nail disorder, neck pain, neoplasm benign, oral moniliasis, otitis externa, photosensitivity reaction, rectal disorder, seborrhea, skin carcinoma, skin discoloration, skin hypertrophy, skin ulcer, stomatitis, tendon disorder, thinking abnormal, tooth caries, sweating, syncope, tachycardia, taste perversion, unintended pregnancy, vaginal moniliasis, vaginitis, valvular heart disease, vasodilatation, and vertigo.
Formal topical drug interaction studies with tacrolimus ointment have not been conducted. Based on its extent of absorption, interactions of tacrolimus ointment with systemically administered drugs are unlikely to occur but cannot be ruled out (see
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.
The pooled results from three pharmacokinetic studies in 88 adult atopic dermatitis patients indicate that tacrolimus is minimally absorbed after the topical application of tacrolimus ointment. Peak tacrolimus blood concentrations ranged from undetectable to 20 ng/mL after single or multiple doses of 0.03% and 0.1% tacrolimus 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 tacrolimus ointment in atopic dermatitis patients is approximately 0.5%. In adults with an average of 53% BSA treated, exposure (AUC) of tacrolimus from tacrolimus 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
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5 to 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.
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.
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.
In a pharmacokinetic study of 14 pediatric atopic dermatitis patients, between the ages of 2 to 5 years, peak blood concentrations of tacrolimus ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03% tacrolimus 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% tacrolimus 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% tacrolimus 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.
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.
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.