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 clinical pharmacology , boxed warning , indications and usage , and dosage and administration ).

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 ).

ts in four safety studies, regardless of relationship to study drug. incidence of treatment emergent adverse events † may be reasonably associated with the use of this drug product ‡ 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. ‡‡ generally "warts". 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=4682) % (n=4481) % (n=9163) % skin burning† 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‡‡ 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† ‡ 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. post-marketing events the following adverse reactions have been identified during postapproval use of tacrolimus 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 infections bullous impetigo, osteomyelitis, septicemia neoplasms lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma renal acute renal failure in patients with or without netherton’s syndrome, renal impairment skin rosacea, application site edema

release of pre-formed mediators from skin mast cells and basophils, and to down regulate the expression of fcɛri 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 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% (1,253/1,391) 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 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 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. 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 0.04, 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% 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 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 to 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. 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.

ly 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 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 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. 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 0.04, 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% 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 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 to 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. 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.

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 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.

e pre-defined primary efficacy endpoint) in the tacrolimus ointment 0.03% treatment group compared to the vehicle treatment group, but there was insufficient evidence that tacrolimus ointment 0.1% provided more efficacy than tacrolimus 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 tacrolimus ointment 0.03% and tacrolimus ointment 0.1% treatment groups compared to the vehicle treatment group. there was evidence that tacrolimus ointment 0.1% may provide more efficacy than tacrolimus ointment 0.03%. the difference in efficacy between tacrolimus 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 physician’s global evaluation of clinical response (% improvement) pediatric study (2 to 15 years of age) adult studies vehicle ointment n = 116 tacrolimus ointment 0.03% n = 117 vehicle ointment n = 212 tacrolimus ointment 0.03% n = 211 tacrolimus ointment 0.1% n = 209 100% 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 ≥90% improvement was achieved by week 1 for those treated with tacrolimus ointment 0.1%, and by week 3 for those treated with tacrolimus 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 tacrolimus ointment 0.03%. in adult patients who had achieved ≥90% improvement at the end of treatment, 35% of those treated with tacrolimus ointment 0.03% and 41% of those treated with tacrolimus 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 tacrolimus 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 tacrolimus ointment treatment groups in adults and in the tacrolimus 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. figure 1 - adult patients body surface area over time 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. fig1.jpg fig2.jpg fig3.jpg fig4.jpg

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 tacrolimus ointment be used? 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. to apply tacrolimus ointment: advise patients: • wash their hands before applying tacrolimus. • 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. this should remove any ointment left on the hands. • do not bathe, shower, or swim right after applying tacrolimus. 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. what should patients avoid while using 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.