Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-α, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to down regulate the expression of FcεRI on Langerhans cells. Pharmacokinetics Absorption The pooled results from three pharmacokinetic studies in 88 adult atopic dermatitis patients indicate that tacrolimus is minimally absorbed after the topical application of PROTOPIC Ointment. Peak tacrolimus blood concentrations ranged from undetectable to 20 ng/mL after single or multiple doses of 0.03% and 0.1% PROTOPIC Ointment, with 85% (75/88) of the patients having peak blood concentrations less than 2 ng/mL. In general as treatment continued, systemic exposure declined as the skin returned to normal. In clinical studies with periodic blood sampling, a similar distribution of tacrolimus blood levels was also observed in adult patients, with 90% (1253/1391) of patients having a blood concentration less than 2 ng/mL. The absolute bioavailability of tacrolimus from PROTOPIC in atopic dermatitis patients is approximately 0.5%. In adults with an average of 53% BSA treated, exposure (AUC) of tacrolimus from PROTOPIC is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. Mean peak tacrolimus blood concentrations following oral administration (0.3 mg/kg/day) in adult kidney transplant (n=26) and liver transplant (n=17) patients are 24.2±15.8 ng/mL and 68.5±30.0 ng/mL, respectively. The lowest tacrolimus blood level at which systemic effects (e.g., immunosuppression) can be observed is not known. Systemic levels of tacrolimus have also been measured in pediatric patients (see Special Populations: Pediatrics). Distribution The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a US study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year. As with other topical calcineurin inhibitors, it is not known whether tacrolimus is distributed into the lymphatic system. Metabolism Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro . The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. Excretion The mean clearance following IV administration of tacrolimus is 0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant patients and adult liver transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine. In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus 0.172 ± 0.088 L/hr/kg. Special Populations Pediatrics In a pharmacokinetic study of 14 pediatric atopic dermatitis patients, between the ages of 2-5 years, peak blood concentrations of tacrolimus ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03% PROTOPIC Ointment, with 86% (12/14) of patients having peak blood concentrations below 2 ng/mL throughout the study. The highest peak concentration was observed in one patient with 82% BSA involvement on day 1 following application of 0.03% PROTOPIC Ointment. The peak concentrations for this subject were 14.8 ng/mL on day 1 and 4.1 ng/mL on day 14. Mean peak tacrolimus blood concentrations following oral administration in pediatric liver transplant patients (n = 9) were 48.4 ± 27.9 ng/mL. In a similar pharmacokinetic study with 61 enrolled pediatric patients (ages 6-12 years) with atopic dermatitis, peak tacrolimus blood concentrations ranged from undetectable to 5.3 ng/mL after single or multiple doses of 0.1% PROTOPIC Ointment, with 91% (52/57) of evaluable patients having peak blood concentrations below 2 ng/mL throughout the study period. When detected, systemic exposure generally declined as treatment continued. In clinical studies with periodic blood sampling, a similar distribution of tacrolimus blood levels was also observed, with 98% (509/522) of pediatric patients having a blood concentration below 2 ng/mL. Renal Insufficiency The effect of renal insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated. The mean clearance of IV administered tacrolimus in patients with renal was similar to that of normal volunteers. On the basis of this information dose-adjustment is not expected to be needed.dysfunction 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. 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. Global Improvement over Baseline at the End-Of-Treatment in Three Phase 3 Studies Physician's Global Evaluation of Clinical Response (% Improvement) Pediatric Study (2-15 Years of Age) Adult Studies Vehicle Ointment N= 116 PROTOPIC Ointment 0.03% N = 117 Vehicle Ointment N = 212 PROTOPIC Ointment 0.03% N = 211 PROTOPIC 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 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-oftreatment. 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. 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.

CLINICAL PHARMACOLOGY Mechanism Of Action Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds 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 inhibited. This effect may 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). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression). Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb. In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collageninduced arthritis, experimental allergic encephalomyelitis, and graft versus host disease. Pharmacokinetics Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 14). Table 14: Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients Population N Route (Dose) Parameters Cmax (ng/mL) Tmax (hr) AUC (ng•hr/mL) t½(hr) CI (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4hr) * * 598†± 125 34.2 ± 7.7 0.040 ± 0.009 1.91 ± 0.31 16 PO (5 mg) 29.7 ± 7.2 1.6 ± 0.7 243‡ ± 73 34.8 ± 11.4 0.041§ ± 0.008 1.94§ ± 0.53 Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) * * 294¶ ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66 PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203¶ ± 42 # # # PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288¶± 93 # # # Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) * * 3300¶ ± 2130 11.7 ± 3.9 0.053 ± 0.017 0.85 ± 0.30 PO (0.3 mg/kg/day) 68.5 ± 30.0 2.3 ± 1.5 519¶ ± 179 # # # Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) * * 954Þ ± 334 23.6 ± 9.22 0.051 ± 0.015 # 11 PO(0.075 mg/kg/day)β 14.7 + 7.79 2.1 [0.5-6.0]à 82.7è ± 63.2 * # # 14 PO (0.15 mg/kg/day)β 24.5 ± 13.7 1.5 [0.4-4.0]à 142è±116 * # # *not applicable †AUC0-120 ‡AUC0-72 §Corrected for individual bioavailability ¶AUC0-inf #not available ÞAUC0-t ßDetermined after the first dose àMedian [range] èAUC0-12 Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see DOSAGE AND ADMINISTRATION]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics. Absorption Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), 23±9% in adult heart transplant patients (N=11) and 18±5% in healthy volunteers (N=16). A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state. Food Effects The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers. The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively. In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, Prograf administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27±18%) and Cmax (50±19%), as compared to a fasted state. Prograf capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see DOSAGE AND ADMINISTRATION]. 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 U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). 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, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart 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. Specific Populations Pediatric Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal halflife, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and Cmax were 337±167 ng•hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see DOSAGE AND ADMINISTRATION]. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 (range 0.06 - 0.09) mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5.0 (range 3.4-25) hours and 0.12±0.04 (range 0.06-0.17) L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181±65 (range 81-300) ng•hr/mL and 30±11 (range 14-49) ng/mL, respectively. The absolute bioavailability was 19±14 (range 5.2-56) %. Renal and Hepatic Impairment The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in Table 15. Table 15: Pharmacokinetic In Renal and Hepatic Impaired Patients Population (No. of Patients) Dose AUC0-t (ng•hr/mL) t½(hr) V (L/kg) CI (L/hr/kg) Renal Impairment (n=12) 0.02 mg/kg/4hr IV 393 ± 123 (t=60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n=6) 0.02 mg/kg/4hr IV 367 ± 107 (t=72 hr) 60.6 ± 43.8 Range: 27.8 - 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t=72 hr) 66.1 ± 44.8 Range: 29.5 - 138 3.7 ± 4.7* 0.034 ± 0.019* Severe Hepatic Impairment (n=6, IV) 0.02 mg/kg/4hr IV (n=2) 0.01 mg/kg/8hr IV (n=4) 762 ± 204 (t=120 hr) 289 ± 117 (t=144 hr) 198 ± 158 Range: 81-436 3.9 ± 1.0 0.017 ± 0.013 (n=5, PO)† 8 mg PO (n=1) 658 (t=120 hr) 119 ± 35 Range: 85-178 3.1 ± 3.4* 0.016 ± 0.011* 5 mg PO (n=4) 4 mg PO (n=1) 533 ± 156 (t=144 hr) *corrected for bioavailability †1 patient did not receive the PO dose Renal Impairment: Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 15) [see DOSAGE AND ADMINISTRATION and Use in Specific Populations]. Hepatic Impairment: Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see DOSAGE AND ADMINISTRATION and Use in Specific Populations]. Race The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of Prograf to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p < 0.01). Mean AUC0-inf tended to be lower in African-Americans (203±115 ng•hr/mL) than Caucasians (344±186 ng•hr/mL) and Latino-Americans (274±150 ng•hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T½ among the three ethnic groups (range from corrected for bioavailability approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see DOSAGE AND ADMINISTRATION]. Gender A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver and heart transplant patients indicated no gender-based differences. Drug Interactions Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see DRUG INTERACTIONS]. Telaprevir: In a single dose study in 9 healthy volunteers, coadministration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see DRUG INTERACTIONS]. Boceprevir: In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see DRUG INTERACTIONS]. Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of Prograf and nelfinavir unless the benefits outweigh the risks [see DRUG INTERACTIONS]. Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration [see DRUG INTERACTIONS]. Magnesium-aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see DRUG INTERACTIONS]. Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see DRUG INTERACTIONS]. Voriconazole (see complete prescribing information for VFEND ®): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cma and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see DRUG INTERACTIONS]. Posaconazole (see complete prescribing information for Noxafil ®): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see DRUG INTERACTIONS]. Caspofungin (see complete prescribing information for CANCIDAS ®): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS® 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see DRUG INTERACTIONS]. Clinical Studies Kidney Transplantation Prograf/azathioprine (AZA) Prograf-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded. There were 205 patients randomized to Prograf-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall 1 year patient and graft survival was 96.1% and 89.6%, respectively. Data from this trial of Prograf in conjunction with azathioprine indicate that during the first three months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year. Prograf/mycophenolate mofetil (MMF) Prograf-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received Prograf (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving Prograf/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the Prograf group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 16) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 17) in comparison to each of the other three groups. Patients randomized to Prograf/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see ADVERSE REACTIONS]. Table 16: Estimated Creatinine Clearance at 12 Months (Study 1) Group eCLcr [mL/min] at Month 12* N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI†) (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7) (B) C s A/MMF/C S/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2,-1.2) (C) T ac/MMF/C S/Daclizumab 401 65.1 27.4 66.2 - (D) Siro/MMF/C S/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1,-3.9) Total 1589 59.2 26.8 60.5 *All death/graft loss (n=4 1, 27, 23 and 4 2 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D, respectively) were inputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. †Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. Table 17: Incidence of BPAR, Graft Loss , Death or Loss to Follow-up at 12 Months (Study 1) Group A N=390 Group B N=399 Group C N=401 Group D N=399 Overall Failure Components of efficacy failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%) BPAR 113(29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%) Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%) Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%) Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%) Treatment Difference of efficacy failure compared to Group C (99.2% CI*) 15.8% (7.1%, 24.3%) 11.2% (2.7%, 19.5%) - 26.0% (17.2%, 34.7%) Key: Group A=CsA/MMF/CS, B=CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab *Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. The protocol-specified target tacrolimus trough concentrations (Ctrough,Tac) were 3-7 ng/mL; however, the observed median Ctrough,Tac , approximated 7 ng/mL throughout the 12 month trial (Table 18). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant. Table 18: Tacrolimus Whole Blood Trough Concentrations (Study 1) Time Median (P10-P90*) tacrolimus whole blood trough concentrations (ng/mL) Day 30 (N=366) 6.9 (4.4-11.3) Day 90 (N=351) 6.8 (4.1-10.7) Day 180 (N=355) 6.5 (4.0-9.6) Day 365 (N=346) 6.5(3.8-10.0) *10 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough,Tac The protocol-specified target cyclosporine trough concentrations (C trough, CsA) for Group B were 50-100 ng/mL; however, the observed median C trough, CsA approximated 100 ng/mL throughout the 12 month trial. The protocol-specified target C trough, CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C , approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12. While patients in all groups started MMF at 1gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 19); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions. Table 19: MMF Dos e Over Time in Prograf/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (grams per day)* Less than 2.0 2.0 Greater than 2.0 0-30 (N=364) 37% 60% 2% 0-90 (N=373) 47% 51% 2% 0-180 (N=377) 56% 42% 2% 0-365 (N=380) 63% 36% 1% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) *Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. In a second randomized, open-label, multi-center trial (Study 2), 424 kidney transplant patients received Prograf (N=212) or cyclosporine (N=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the Prograf/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving Prograf/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to overimmunosuppression (Table 20). Table 20: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 2) Prograf/MMF (N=212) Cyclosporine/MMF (N=212) Overall Failure 32 (15.1%) 36 (17.0%) Components of efficacy failure BPAR 16 (7.5%) 29 (13.7%) Graft loss excluding death 6 (2.8%) 4 (1.9%) Mortality 9 (4.2%) 5 (2.4%) Lost to follow-up 4 (1.9%) 1 (0.5%) Treatment Difference of efficacy failure compared to Prograf/MMF group (95% CI*) 1.9% (-5.2%, 9.0%) *95% confidence interval calculated using Fisher's Exact Test The protocol-specified target tacrolimus whole blood trough concentrations (C trough,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C trough,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 21). Approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year. Table 21: Tacrolimus Whole Blood Trough Concentrations (Study 2) Time Median (P10-P90*) tacrolimus whole blood trough concentrations (ng/mL) Day 30 (N=174) 10.5(6.3-16.8) Day 60 (N=179) 9.2 (5.9-15.3) Day 120 (N=176) 8.3(4.6-13.3) Day 180 (N=171) 7.8 (5.5-13.2) Day 365 (N=178) 7.1(4.2-12.4) *10 to 90 Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough,Tac The protocol-specified target cyclosporine whole blood concentrations (C trough, CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C trough, CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12. Patients in both groups started MMF at 1gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the Prograf/MMF group (Table 22) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the Prograf/MMF group and the cyclosporine/MMF group, respectively [see ADVERSE REACTIONS]. Table 22: MMF Dose Over Time in the Prograf/MMF Group (Study 2) Time period (Days) Time-averaged MMF dose (g/day)* Less than 2.0 2.0 Greater than 2.0 0-30 (N=212) 25% 69% 6% 0-90 (N=212) 41% 53% 6% 0-180 (N=212) 52% 41% 7% 0-365 (N=212) 62% 34% 4% Key: Time-averaged MMF dose=(total MMF dose)/(duration of treatment) *Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. Liver Transplantation The safety and efficacy of Prograf-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation. In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the Prograf-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients ( ≤ 12 years old) were allowed. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the Prograf-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases. One-year patient survival and graft survival in the Prograf-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and Prograf-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and Prograf-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral Prograf dosing was 2 days. Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation ranged from 9.8 ng/mL to 19.4 ng/mL. Heart Transplantation Two open-label, randomized, comparative trials evaluated the safety and efficacy of Prograf-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine in combination with Prograf or cyclosporine modified for 18 months. In a 3-arm trial conducted in the US, 331 patients received corticosteroids and Prograf plus sirolimus, Prograf plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year. In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the Prograf plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32 to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74 to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months posttransplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to18 ng/mL. The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose Prograf; however, this regimen was associated with increased risk of wound healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see WARNINGS AND PRECAUTIONS].

Find Lowest Prices on PROTOPIC® (tacrolimus) Ointment 0.03%, 0.1% See BOXED WARNING concerning long-term safety of topical calcineurin inhibitors DESCRIPTION PROTOPIC (tacrolimus) Ointment contains tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It is for topical dermatologic use only. Chemically, tacrolimus is designated as [3S[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy3-[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.

PROGRAF® (tacrolimus) Capsules and Injection WARNING MALIGNANCIES AND SERIOUS INFECTIONS Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see WARNINGS AND PRECAUTIONS]. Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see WARNINGS AND PRECAUTIONS]. Only physicians experienced in immunosuppressive therapy and management of organ Transplant patients should prescribe Prograf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see WARNINGS AND PRECAUTIONS]. DESCRIPTION Prograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose sodium NF, and magnesium stearate NF. The 0.5 mg capsule shell contains gelatin NF, titanium dioxide USP and ferric oxide NF, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains gelatin NF, titanium dioxide USP and ferric oxide NF. Prograf is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80.0% v/v. Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. Tacrolimus, previously known as FK506, is the active ingredient in Prograf. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. 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. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

INDICATIONS PROTOPIC Ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2 to 15 years, is indicated as second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable. PROTOPIC Ointment is not indicated for children younger than 2 years of age (see BOXED WARNING, WARNINGS and PRECAUTIONS: Pediatric Use). DOSAGE AND ADMINISTRATION Adult PROTOPIC Ointment 0.03% and 0.1% Apply a thin layer of PROTOPIC (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 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 (tacrolimus) 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. HOW SUPPLIED PROTOPIC® (tacrolimus) Ointment 0.03% NDC 0469-5201-30 Product Code 520130 30 gram laminate tube NDC 0469-5201-60 Product Code 520160 60 gram laminate tube NDC 0469-5201-11 Product Code 520111 100 gram laminate tube PROTOPIC® (tacrolimus) Ointment 0.1% NDC 0469-5202-30 Product Code 520230 30 gram laminate tube NDC 0469-5202-60 Product Code 520260 60 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by: Astellas Pharma US, Inc. Deerfield, IL 60015-2548. Manufactured by: Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 9300809, Japan. Revised: 11/2011

INDICATIONS Prophylaxis Of Organ Rejection In Kidney Transplant Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidneytransplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION]. Prophylaxis Of Organ Rejection In Liver Transplant Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION]. Prophylaxis Of Organ Rejection In Heart Transplant Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION]. Limitations Of Use Prograf should not be used simultaneously with cyclosporine [see DOSAGE AND ADMINISTRATION]. Prograf injection should be reserved for patients unable to take Prograf capsules orally [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of Prograf with sirolimus has not been established in kidney transplant [see WARNINGS AND PRECAUTIONS]. DOSAGE AND ADMINISTRATION Dosage In Adult Kidney, Liver, Or Heart Transplant Patients The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of Prograf may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Therapeutic Drug Monitoring. Table 1: Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults Patient Population Recommended Prograf Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients In combination with azathioprine 0.2 mg/kg/day month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL In combination with MMF/IL-2 receptor antagonist* 0.1 mg/kg/day month 1-12: 4-11 ng/mL Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Adult heart transplant patients 0.075 mg/kg/day month 1-3: 10-20 ng/mL month ≥ 4: 5-15 ng/mL *In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4 -12 [see Clinical Studies]. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf dosages than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant. The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2). Table 2: Comparative Dose and Trough Concentrations Based on Race Time After Transplant Caucasian n=114 Black n=56 Dose (mg/kg) Trough Concentrations (ng/mL) Dose (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12.0 0.23 10.9 Month 1 0.17 12.8 0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19 11.0 Initial Dose - Injection Prograf injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Prograf capsules. Prograf injection should be discontinued as soon as the patient can tolerate oral administration of Prograf capsules, usually within 2-3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The observed trough concentrations described above pertain to oral administration of Prograf only; while monitoring Prograf concentrations in patients receiving Prograf injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy. The recommended starting dose of Prograf injection is 0.03-0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Prograf injection [see WARNINGS AND PRECAUTIONS]. Dosage In Pediatric Liver Transplant Patients The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Therapeutic Drug Monitoring. If necessary, pediatric patients may start on an IV dose of 0.03-0.05 mg/kg/day. Table 3: Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population Recommended Prograf Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15-0.20 mg/kg/day Month 1-12: 5-20 ng/mL Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Experience in pediatric kidney and heart transplantation patients is limited. Dosage Adjustment In Patients With Renal Impairment Due to its potential for nephrotoxicity, consideration should be given to dosing Prograf at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required. In kidney transplant patients with post-operative oliguria, the initial dose of Prograf should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery. Dosage Adjustments In Patients With Hepatic Impairment Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of Prograf. Close monitoring of blood concentrations is warranted. The use of Prograf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage In Adult Kidney, Liver, Or Heart Transplant Patients, Use in Specific Populations and CLINICAL PHARMACOLOGY]. Administration Instructions It is recommended that patients initiate oral therapy with Prograf capsules if possible. Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage In Adult Kidney, Liver, Or Heart Transplant Patients]; for blood concentration monitoring details in kidney transplant patients [see Dosage In Adult Kidney, Liver, Or Heart Transplant Patients]. It is important to take Prograf capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see CLINICAL PHARMACOLOGY]. Patients should not eat grapefruit or drink grapefruit juice in combination with Prograf [see DRUG INTERACTIONS]. Prograf should not be used simultaneously with cyclosporine. Prograf or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Prograf or cyclosporine concentrations, dosing with the other drug usually should be further delayed. In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. Therapeutic Drug Monitoring Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation. The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure. Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery > 90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months. Preparation For Intravenous Product Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir). HOW SUPPLIED Dosage Forms And Strengths Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows: 0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “logo607”* on capsule body 1 mg, white color, imprinted in red “1 mg” on the capsule cap and “logo617”* on capsule body 5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “logo657”* on capsule body *The logo is a letter 'f' in a box as shown on the capsules --f 1 mL ampule for IV infusion contains anhydrous tacrolimus USP as follows: 5 mg/mL, sterile solution Storage And Handling Prograf (tacrolimus ) Capsules USP strength 0.5 mg (containing the equivalent of 0.5 mg anhydrous tacrolimus USP) Img (containing the equivalent of 1 mg anhydrous tacrolimus USP) 5 mg (containing the equivalent of 5 mg anhydrous tacrolimus USP) shape/color oblong/light yellow oblong/white oblong/grayish red branding on capsule cap/body f607 f 617 f657 100 count bottle NDC 0469-0607-73 NDC 0469-0617-73 NDC 0469-0657-73 10 blister cards of 10 capsules -- NDC 0469-0617-11 NDC 0469-0657-11 Note: Prograf capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount. Store And Dispense Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Prograf (tacrolimus ) Injection (for IV infusion only) NDC 0469-3016-01 Product Code 301601 5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1mL ampule, in boxes of 10 ampules Store And Dispense Store between 5°C and 25°C (41°F and 77°F). Manufactured by: Astellas Ireland Co., Ltd., Killorglin, County Kerry, Ireland. Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062. Revised: May 2015

PATIENT INFORMATION MEDICATION GUIDE PROTOPIC® [pro-TOP-ik] (tacrolimus) Ointment 0.03% Ointment 0.1% Read the Medication Guide every time you or a family member gets PROTOPIC Ointment. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. If you have questions about PROTOPIC Ointment, ask your doctor or pharmacist. What is the most important information I 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: Do not use PROTOPIC Ointment continuously for a long time. Use PROTOPIC Ointment only on areas of your 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. Talk to your doctor for more information. What is PROTOPIC Ointment? PROTOPIC Ointment is a prescription medicine used on the skin (topical) to treat eczema (atopic dermatitis). PROTOPIC Ointment is in a class of medicines called topical calcineurin inhibitors. It is for adults and children 2 years of age and older who do not have a weakened immune system. PROTOPIC Ointment is used on the skin for short periods, and if needed, treatment may be repeated with breaks in between. PROTOPIC Ointment is for use after other prescription medicines have not worked for you, or if your doctor recommends that other prescription medicines should not be used. Who should not use PROTOPIC Ointment? PROTOPIC Ointment should not be used: on children younger than 2 years of age. if you are allergic to PROTOPIC Ointment or anything in it. See the end of this Medication Guide for a complete list of ingredients. What should I tell my doctor before starting PROTOPIC Ointment? Before you start using PROTOPIC, you and your doctor should talk about all of your medical conditions, including if you: have a skin disease called Netherton’s syndrome (a rare inherited condition). have any infection on your skin including chicken pox or herpes. have been told you have a weakened immune system. are pregnant, breastfeeding, or planning to become pregnant. Tell your doctor about all the medicines you take and skin products you use including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine. How should I use PROTOPIC Ointment? Use PROTOPIC Ointment exactly as prescribed. Use PROTOPIC Ointment only on areas of your 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 by your doctor. Follow your doctor’s advice if symptoms of eczema return after treatment with PROTOPIC Ointment. Call your doctor if : your symptoms get worse with PROTOPIC Ointment. you get an infection on your skin. your symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema. To apply PROTOPIC Ointment: Wash your hands before applying PROTOPIC. 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 you are a caregiver applying PROTOPIC Ointment to a patient, or if you are a patient who is not treating your hands, wash your hands with soap and water after applying PROTOPIC. This should remove any ointment left on the hands. Do not bathe, shower, or swim right after applying PROTOPIC. This could wash off the ointment. You can use moisturizers with PROTOPIC Ointment. Make sure you check with your doctor first about the products that are right for you. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If you use moisturizers, apply them after PROTOPIC Ointment. What should I avoid while using PROTOPIC Ointment? 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 your skin. If you need to be outdoors after applying PROTOPIC Ointment, wear loose fitting clothing that protects the treated area from the sun. Ask your doctor what other types of protection from the sun you should use. Do not cover the skin being treated with bandages, dressings or wraps. You can wear normal clothing. Avoid getting PROTOPIC Ointment in the eyes or mouth. Do not swallow PROTOPIC Ointment. If you do, call your doctor. What are the possible side effects of PROTOPIC Ointment? Please read the first section of this Medication Guide. The most common side effects of PROTOPIC Ointment at the skin application site are stinging, burning, or itching of the skin treated with PROTOPIC. These side effects are usually mild to moderate, are most common during the first few days of treatment, and usually go away as your skin heals. Other side effects include acne, swollen or infected hair follicles, headache, increased sensitivity of the skin to hot or cold temperatures, or flu-like symptoms such as the common cold and stuffy nose, skin tingling, upset stomach, muscle pain, swollen glands (enlarged lymph nodes), or skin infections including cold sores, chicken pox or shingles. Talk to your doctor if you have a skin infection or if side effects (for example, swollen glands) continue or bother you. While you are using PROTOPIC, drinking alcohol may cause the skin or face to become flushed or red and feel hot. These are not all the side effects with PROTOPIC Ointment. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 How should I store PROTOPIC Ointment? Store PROTOPIC Ointment at room temperature (59° to 86°F). Do not leave PROTOPIC Ointment in your car in cold or hot weather. Make sure the cap on the tube is tightly closed. Keep PROTOPIC Ointment and all medicines out of the reach of children. General advice about PROTOPIC Ointment Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROTOPIC Ointment for a condition for which it was not prescribed. Do not give PROTOPIC Ointment to other people, even if they have the same symptoms you have. It may not be right for them. This Medication Guide summarizes the most important information about PROTOPIC Ointment. If you would like more information, talk with your doctor. Your doctor or pharmacist can give you information about PROTOPIC Ointment that is written for health care professionals. For more information, you can also visit the PROTOPIC website at www.protopic.com or call 1-800-727-7003. What are the ingredients in PROTOPIC Ointment? Active Ingredient: tacrolimus, either 0.03% or 0.1% Inactive Ingredients: mineral oil, paraffin, propylene carbonate, white petrolatum and white wax. This Medication Guide has been approved by the U.S. Food and Drug Administration

PATIENT INFORMATION PROGRAF [PRO-graf] (tacrolimus) capsules USP Read this Patient Information before you start taking PROGRAF and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about PROGRAF? Prograf can cause serious side effects, including: Increased risk of cancer. People who take Prograf have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). Increased risk of infection. PROGRAF is a medicine that affects your immune system. Prograf can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving Prograf that can cause death. Call your doctor right away if you have symptoms of an infection such as : fever sweats or chills cough or flu-like symptoms muscle aches warm, red, or painful areas on your skin What is PROGRAF? PROGRAF is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant and PROGRAF is not for use with medicines called cyclosporines (Gengraf®, Neoral®, and Sandimune®). PROGRAF is not for use with a medicine called sirolimus (Rapamune®) in people who have had a liver or heart transplants. It is not known if PROGRAF is safe and effective when used with sirolimus in people who have had kidney transplants. It is not known if PROGRAF is safe and effective in children who have had a kidney or heart transplants. Who Should Not Take PROGRAF? Do not take PROGRAF if you are allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for a complete list of ingredients in PROGRAF. What should I tell my doctor before taking PROGRAF? Before you take PROGRAF, tell your doctor if you: plan to receive any live vaccines have or have had liver, kidney or heart problems are pregnant or plan to become pregnant. PROGRAF may harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. Are breastfeeding or plan to breastfeed. PROGRAF can pass into your breast milk. You and your doctor should decide if you will take PROGRAF or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take: cyclosporine (Gengraf®, Neoral®, and Sandimune®) sirolimus (Rapamune®) nelfinavir (Viracept®) telaprevir (Incivek™) boceprevir (Victrelis™) amiodarone (Cordarone™, Nexterone™, Pacerone™) Ask your doctor or pharmacist if you are not sure if you take any of the medicines listed above. PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How Should I Take PROGRAF? Take PROGRAF exactly as your doctor tells you to take it. Your doctor will tell you how many PROGRAF to take and when to take them. Your doctor may change your PROGRAF dose if needed. Do not stop taking or change your dose of PROGRAF without talking to your doctor. Take PROGRAF with or without food. Take PROGRAF the same way everyday. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food. Take PROGRAF at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m. you should take your second dose at 7:00 p.m. Taking PROGRAF at the same time each day helps to keep enough medicine in your body to give your transplanted organ the around-the-clock medicine it needs. Do not eat grapefruit or drink grapefruit juice while taking PROGRAF. If you take too much PROGRAF, call your doctor or go to the nearest hospital emergency room right away. What should I avoid while taking PROGRAF? While you take PROGRAF you should not receive any live vaccines such as: flu vaccine through your nose measles mumps rubella polio by mouth BCG (TB vaccine) yellow fever chicken pox (varicella) typhoid Avoid exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen. What are the possible side effects of PROGRAF? PROGRAF may cause serious side effects, including: See “What the most important information I should know about PROGRAF?” high blood sugar (diabetes). Your doctor may do certain tests to check for diabetes while you take PROGRAF. Call your doctor right away if you have: frequent urination increased thirst or hunger blurred vision confusion drowsiness loss of appetite fruity smell on your breath nausea, vomiting, or stomach pain kidney problems. Your doctor may do certain tests to check your kidney function while you take PROGRAF. nervous system problems. Call your doctor right away if you get any of these symptoms while taking PROGRAF. These could be signs of a serious nervous system problem: confusion coma muscle tremors numbness and tingling headache seizures vision changes high levels of potassium in your blood. Your doctor may do certain tests to check your potassium level while you take PROGRAF. high blood pressure. Your doctor will monitor your blood pressure while you take PROGRAF. heart problems (myocardial hypertrophy). Tell your doctor right away if you get any of these symptoms of heart problems while taking PROGRAF: shortness of breath chest pain feel lightheaded feel faint The most common side effects of PROGRAF in people receiving kidney Transplant are: infection tremors (shaking of the body) high blood pressure kidney problems constipation diarrhea headache stomach pain trouble sleeping nausea low levels of phosphate in your blood swelling of the hands, ankles, or legs weakness pain high levels of fat in your blood high levels of potassium in your blood low red blood cell count (anemia) The most common side effects of PROGRAF in people receiving liver Transplants are: shaking of the body tremors headache diarrhea high blood pressure nausea kidney problems stomach pain trouble sleeping numbness or tingling in your hands or feet anemia pain fever weakness high levels of potassium in the blood low levels of magnesium in the blood The most common side effects of PROGRAF for heart Transplant patients are: kidney problems high blood pressure Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PROGRAF. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088. How should I store PROGRAF? Store PROGRAF at 59° F to 86°F (15°C to 30° C). Safely throw away medicine that is out of date or no longer needed. Keep PROGRAF and all medicines out of reach of children. General information about the safe and effective us e of PROGRAF Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. How Does PROGRAF Protect My New Organ? The body's immune system protects the body against anything that it does not recognize as part of the body. For example, when the immune system detects a virus or bacteria it tries to get rid of it to prevent infection. When a person has a liver, kidney, or heart transplant, the immune system does not recognize the new organ as a part of the body and tries to get rid of it, too. This is called “rejection”. PROGRAF protects your new organ by slowing down the body's immune system. This Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about PROGRAF that is written for health professionals. For more information, go to www.astellas.com/us or call 1-800-727-7003. What are the ingredients in PROGRAF? Active ingredient: tacrolimus Inactive ingredients: lactose monohydrate, hypromellose, croscarmellose sodium, magnesium stearate, gelatin, titanium dioxide and ferric oxide. This Patient Information has been approved by the U.S. Food and Drug Administration.

OVERDOSE 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. CONTRAINDICATIONS PROTOPIC (tacrolimus) Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.

OVERDOSE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in ADVERSE REACTIONS (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage. In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; and in adult rats, 16 times the recommended human IV dose (all based on body surface area corrections). CONTRAINDICATIONS Prograf is contraindicated in patients with a hypersensitivity to tacrolimus. Prograf injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see ADVERSE REACTIONS].

SIDE EFFECTS 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 PROTOPIC Ointment. The duration of follow-up for adult and pediatric patients in the safety studies is tabulated below. Duration of Follow-up in Four Open-label Safety Studies 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, PROTOPIC Ointment 0.03%, and PROTOPIC 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. Incidence of Treatment Emergent Adverse Events 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† 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 † 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”. 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 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 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 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.

SIDE EFFECTS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies [see BOXED WARNING, WARNINGS AND PRECAUTIONS] Serious Infections [see BOXED WARNING, WARNINGS AND PRECAUTIONS] Polyoma Virus Infections [seeBOXED WARNING, WARNINGS AND PRECAUTIONS] CMV Infections [see BOXED WARNING, WARNINGS AND PRECAUTIONS] New Onset Diabetes After Transplant [see WARNINGS AND PRECAUTIONS] Nephrotoxicity [see WARNINGS AND PRECAUTIONS] Neurotoxicity [see WARNINGS AND PRECAUTIONS] Hyperkalemia [see WARNINGS AND PRECAUTIONS] Hypertension [see WARNINGS AND PRECAUTIONS] Anaphylaxis with Prograf Injection [see WARNINGS AND PRECAUTIONS] Myocardial Hypertrophy [see WARNINGS AND PRECAUTIONS] Pure Red Cell Aplasia [see WARNINGS AND PRECAUTIONS] Gastrointestinal Perforation [see WARNINGS AND PRECAUTIONS] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below. Kidney Transplant The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. Prograf-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in trial where 205 patients received Prograf based  immunosuppression and 207 patients received cyclosporine based immunosuppression. The trial population had a mean age of 43 years (mean±sd was 43±13 years on Prograf and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), Black (25%), Hispanic (12%) and Other (5%). The 12 month post-transplant information from this trial is presented below. The most common adverse reactions ( ≥ 30%) observed in Prograf-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema,  asthenia, pain, hyperlipidemia, hyperkalemia and anemia. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with Prograf in conjunction with azathioprine are presented below: Table 4: Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with Azathioprine (AZA) Prograf/AZA (N=205) Cyclosporine/AZA (N=207) Nervous System Tremor 54% 34% Headache 44% 38% Insomnia 32% 30% Paresthesia 23% 16% Dizziness 19% 16% Gastrointestinal Diarrhea 44% 41% Nausea 38% 36% Constipation 35% 43% Vomiting 29% 23% Dyspepsia 28% 20% Cardiovascular Hypertension 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leukopenia 15% 17% Miscellaneous Infection 45% 49% Peripheral Edema 36% 48% Asthenia 34% 30% Abdominal Pain 33% 31% Pain 32% 30% Fever 29% 29% Back Pain 24% 20% Respiratory System Dyspnea 22% 18% Cough Increased 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash 17% 12% Pruritus 15% 7% Two trials were conducted for Prograf-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received Prograf (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76), the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5: Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Prograf in Conjunction with MMF (Study 1) Prograf (Group C) (N=403) Cyclosporine (Group A) (N=384) Cyclosporine (Group B) (N=408) Diarrhea 25% 16% 13% Urinary Tract Infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leukopenia 13% 10% 10% Edema Peripheral 11% 12% 13% Hyperlipidemia 10% 15% 13% Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C= Tac/MMF/CS/Daclizumab CsA= Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil In the U.S. trial (Study 2) with Prograf-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received Prograf (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77), the distribution was 63% male, and the composition was White (74%), Black (20%), Asian (3%) and other (3%). The 12 month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 2 are presented below: Table 6: Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with MMF (Study 2) Prograf/MMF (N=212) Cyclosporine/MMF (N=212) Gastrointestinal Disorders Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions. Liver Transplantation There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to70), the distribution was 52% male, and the composition was White (78%), Black (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68), the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%) and Other (2%). The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation. The most common adverse reactions ( ≥ 40%) observed in Prograf-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of Prograf and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Table 7: Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf U.S. TRIAL Prograf (N=250) EUROPEAN TRIAL Cyclos porine/AZA (N=250) Prograf (N=264) Cyclos porine/AZA (N=265) Nervous System Headache 64% 60% 37% 26% Insomnia 64% 68% 32% 23% Tremor 56% 46% 48% 32% Paresthesia 40% 30% 17% 17% Gastrointestinal Diarrhea 72% 47% 37% 27% Nausea 46% 37% 32% 27% LFT Abnormal 36% 30% 6% 5% Anorexia 34% 24% 7% 5% Vomiting 27% 15% 14% 11% Constipation 24% 27% 23% 21% Cardiovascular Hypertension 47% 56% 38% 43% Urogenital Kidney Function Abnormal 40% 27% 36% 23% Creatinine Increased 39% 25% 24% 19% BUN Increased 30% 22% 12% 9% Oliguria 18% 15% 19% 12% Urinary Tract Infection 16% 18% 21% 19% Metabolic and Nutritional Hypomagnesemia 48% 45% 16% 9% Hyperglycemia 47% 38% 33% 22% Hyperkalemia 45% 26% 13% 9% Hypokalemia 29% 34% 13% 16% Hemic and Lymphatic Anemia 47% 38% 5% 1% Leukocytosis 32% 26% 8% 8% Thrombocytopenia 24% 20% 14% 19% Miscellaneous Pain 63% 57% 24% 22% Abdominal Pain 59% 54% 29% 22% Asthenia 52% 48% 11% 7% Fever 48% 56% 19% 22% Back Pain 30% 29% 17% 17% Ascites 27% 22% 7% 8% Peripheral Edema 26% 26% 12% 14% Respiratory System Pleural Effusion 30% 32% 36% 35% Dyspnea 29% 23% 5% 4% Atelectasis 28% 30% 5% 4% Skin and Appendages Pruritus 36% 20% 15% 7% Rash 24% 19% 10% 4% Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions. Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine (AZA) in combination with Prograf (n=157) or cyclosporine (n=157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65), the distribution was 82% male, and the composition was White (96%), Black (3%) and other (1%). The most common adverse reactions ( ≥ 15%) observed in Prograf-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection and hyperlipemia. Adverse reactions in heart transplant patients in the European trial are presented below: Table 8: Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with Azathioprine (AZA) Prograf/AZA (n=157) Cyclosporine/AZA (n=157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% Nervous System Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32 to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74 to 86% of the patients in the tacrolimus treatment arm. In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and Prograf in combination with sirolimus (n=109), Prograf in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75), the distribution was 78% male, and the composition was White (83%), Black (13%) and other (4%). Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with Prograf and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%). Other targeted treatment-emergent adverse reactions in Prograf-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. New Onset Diabetes After Transplant Kidney Transplant New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA1C ≥ 6%, insulin use ≥ 30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the Prograf-treated and 61% in the Neoral-treated patients without pre-transplant history of diabetes mellitus (Table 9) [see Clinical Studies]. Table 9: Incidence of New Onset Diabetes After Trans plant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group Prograf/MMF (n = 212) Neoral/MMF (n = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥ 126 mg/dL 96/150 (64%) 80/152 (53%) HbA1c ≥ 6% 59/150 (39%) 28/152 (18%) Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of Prograf, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 10 to 13. PTDM was reported in 20% of Prograf/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 10). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 11). Table 10: Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM* Prograf/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM*, 1st Year 30/151 (20%) 6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%) New onset PTDM* post 1 year 1 0 Patients with PTDM* at 2 years 16/151 (11%) 5/151 (3%) *Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Table 11: Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial Patient Race Patients Who Developed PTDM* Prograf Cyclosporine Black 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) *Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Liver Transplant Insulin-dependent PTDM was reported in 18% and 11% of Prograf-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 12). Hyperglycemia was associated with the use of Prograf in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Clinical Studies Experience]. Table 12: Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM* US Trial European Trial Prograf Cyclosporine Prograf Cyclosporine Patients at risk† 239 236 239 249 New Onset PTDM* 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) *Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. †Patients without pre-transplant history of diabetes mellitus. Heart Transplant Insulin-dependent PTDM was reported in 13% and 22% of Prograf-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia defined as two fasting plasma glucose levels ≥ 126 mg/dL was reported with the use of Prograf plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Clinical Studies Experience]. Table 13: Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM* US Trial European Trial Prograf/ MMF Cyclosporine/ MMF Prograf/ AZA Cyclosporine/ AZA Patients at risk† 75 83 132 138 New Onset PTDM * 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year‡ 7 (9%) 1 (1%) 24 (18%) 4 (3%) *Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. †Patients without pre-transplant history of diabetes mellitus. ‡7-12 months for the U.S. trial. Less Frequently Reported Adverse Reactions ( > 3% and < 15%) The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials. Nervous System [see WARNINGS AND PRECAUTIONS] Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis Cardiovascular Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital Acute kidney failure [see WARNINGS AND PRECAUTIONS], albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain Endocrine Cushing's syndrome Hemic/Lymphatic Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Respiratory Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration Skin Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating Postmarketing Adverse Reactions The following adverse reactions have been reported from worldwide marketing experience with Prograf. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug. Other Reactions Include Cardiovascular Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy [see WARNINGS AND PRECAUTIONS]. Gastrointestinal Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease Hemic/Lymphatic Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia [see WARNINGS AND PRECAUTIONS] Infections Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virusassociated nephropathy, (PVAN) including graft loss [see WARNINGS AND PRECAUTIONS] Metabolic/Nutritional Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Nervous System Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES) [see WARNINGS AND PRECAUTIONS], progressive multifocal leukoencephalopathy (PML) [see WARNINGS AND PRECAUTIONS], quadriplegia, speech disorder, syncope Respiratory Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses Blindness, blindness cortical, hearing loss including deafness, photophobia Urogenital Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder DRUG INTERACTIONS Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Prograf is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation [see WARNINGS AND PRECAUTIONS]. Mycophenolic Acid Products With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Prograf coadministration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Prograf in patients concomitantly receiving MPA-containing products. Grapefruit Juice Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with tacrolimus [see DOSAGE AND ADMINISTRATION]. Protease Inhibitors Most protease inhibitors inhibit CYP3A enzymes and may increase tacrolimus whole blood concentrations. It is recommended to avoid concomitant use of tacrolimus with nelfinavir unless the benefits outweigh the risks [see CLINICAL PHARMACOLOGY]. Whole blood concentrations of tacrolimus are markedly increased when co-administered with telaprevir or with boceprevir [see CLINICAL PHARMACOLOGY]. Monitoring of tacrolimus whole blood concentrations and tacrolimusassociated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended when tacrolimus and protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) are used concomitantly. Antifungal Agents Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following antifungal drugs with tacrolimus is initiated or discontinued [see CLINICAL PHARMACOLOGY]. Azoles: Voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. When initiating therapy with voriconazole or posaconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be initially reduced to one-third of the original dose and the subsequent tacrolimus doses be adjusted based on the tacrolimus whole blood concentrations. Caspofungin is an inducer of CYP3A and decreases whole blood concentrations of tacrolimus. Calcium Channel Blockers Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these calcium channel blocking drugs and tacrolimus are used concomitantly. Antibacterials Erythromycin, clarithromycin, troleandomycin and chloramphenicol inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. Antimycobacterials Rifampin [see CLINICAL PHARMACOLOGY] and rifabutin are inducers of CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these antimycobacterial drugs and tacrolimus are used concomitantly. Anticonvulsants Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. Concomitant administration of phenytoin with tacrolimus may also increase phenytoin plasma concentrations. Thus, frequent monitoring phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly. St. John's Wort (Hypericum perforatum) St. John's Wort induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when St. John's Wort and tacrolimus are co-administered. Gastric Acid Suppressors /Neutralizers Lansoprazole and omeprazole, as CYP2C19 and CYP3A4 substrates, may potentially inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. Cimetidine may also inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. Coadministration with magnesium and aluminum hydroxide antacids increase tacrolimus whole blood concentrations [see CLINICAL PHARMACOLOGY]. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. Others Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone, methylprednisolone, and herbal products containing schisandra sphenanthera extracts may inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are co-administered.

WARNINGS WARNING Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established 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 PROTOPIC Ointment. Therefore: Continuous long-term use of topical calcineurin inhibitors, including PROTOPIC Ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis. PROTOPIC Ointment is not indicated for use in children less than 2 years of age. Only 0.03% PROTOPIC Ointment is indicated for use in children 2-15 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 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). PRECAUTIONS 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 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 is applied to large body surface areas. Caution should also be exercised in patients predisposed to renal impairment. Information For The Patient (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. 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. This should remove any ointment left on the hands. Do not bathe, shower, or swim right after applying PROTOPIC. 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. 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 Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women. The experience with PROTOPIC 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-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-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. PROTOPIC Ointment should be used during pregnancy only if the potential benefit to the mother justifies a potential risk to the fetus. Nursing Mothers Although systemic absorption of tacrolimus following topical applications of PROTOPIC 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. 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 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). 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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Management Of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Prograf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow up of the patient [see BOXED WARNING]. Lymphoma And Other Malignancies Patients receiving immunosuppressants, including Prograf, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see BOXED WARNING]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Post transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Serious Infections Patients receiving immunosuppressants, including Prograf, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see BOXED WARNING and Polyoma Virus Infections and Cytomegalovirus (CMV) Infections]. These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution. Polyoma Virus Infections Patients receiving immunosuppressants, including Prograf, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus [see ADVERSE REACTIONS]. PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss [see ADVERSE REACTIONS]. Patient monitoring may help detect patients at risk for PVAN. Cases of PML have been reported in patients treated with Prograf. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. Cytomegalovirus (CMV) Infections Patients receiving immunosuppressants, including Prograf, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease. New Onset Diabetes After Transplant Prograf was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using Prograf [see ADVERSE REACTIONS]. Nephrotoxicity Prograf, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely as the dosage of Prograf may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Prograf in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial [see ADVERSE REACTIONS]. Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Prograf with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism [see DRUG INTERACTIONS]. Neurotoxicity Prograf may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with tacrolimus have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression. Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in adult and pediatric patients receiving Prograf [see ADVERSE REACTIONS]. Less severe neurotoxicities, include tremors, paresthesias, headache, and other changes in motor function, mental status, and sensory function [see ADVERSE REACTIONS]. Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Hyperkalemia Hyperkalemia has been reported with Prograf use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during Prograf therapy [see ADVERSE REACTIONS]. Hypertension Hypertension is a common adverse effect of Prograf therapy and may require antihypertensive therapy [see ADVERSE REACTIONS]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Hyperkalemia]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of Prograf [see DRUG INTERACTIONS]. Anaphylactic Reactions With Prograf Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including Prograf, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Prograf injection should be reserved for patients who are unable to take Prograf capsules [see INDICATIONS AND USAGE]. Patients receiving Prograf injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen. Use With Sirolimus The safety and efficacy of Prograf with sirolimus has not been established in kidney transplant patients. Use of sirolimus with Prograf in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended [see INDICATIONS AND USAGE]. Use of sirolimus (2 mg per day) with Prograf in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies]. Use With CYP3A4 Inhibitors And Inducers When coadministering Prograf with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of Prograf and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see DRUG INTERACTIONS]. QT Prolongation Prograf may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid Prograf in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When coadministering Prograf with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in Prograf dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of Prograf with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see DRUG INTERACTIONS]. Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving Prograf therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Prograf should be considered [see ADVERSE REACTIONS]. Immunizations The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of Prograf should be considered [see ADVERSE REACTIONS]. Gastrointestinal Perforation Gastrointestinal perforation has been reported in patients treated with Prograf; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly [see ADVERSE REACTIONS]. Patient Counseling Information Administration Advise patients to: Take Prograf at the same 12-hour intervals everyday to achieve consistent blood concentrations. Take Prograf consistently either with or without food because the presence and composition of food decreases the bioavailability of Prograf. Not to eat grapefruit or drink grapefruit juice in combination with Prograf [see DRUG INTERACTIONS]. Development Of Lymphoma And Other Malignancies Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor [see WARNINGS AND PRECAUTIONS]. Increased Risk of Infection Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection [see WARNINGS AND PRECAUTIONS]. New Onset Diabetes After Transplant Inform patients that Prograf can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger [see WARNINGS AND PRECAUTIONS]. Nephrotoxicity Inform patients that Prograf can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see WARNINGS AND PRECAUTIONS]. Neurotoxicity Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, deliriums, or tremors [see WARNINGS AND PRECAUTIONS]. Hyperkalemia Inform patients that Prograf can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see WARNINGS AND PRECAUTIONS]. Hypertension Inform patients that Prograf can cause high blood pressure which may require treatment with antihypertensive therapy [see WARNINGS AND PRECAUTIONS]. Drug Interactions Instruct patients to tell their health care providers when they start or stop taking all the medicines, including prescription medicines and non-prescription medicines, natural or herbal remedies, nutritional supplements and vitamins [see DRUG INTERACTIONS]. Pregnant Women And Nursing Mothers Instruct patients to tell their healthcare provider if they plan to become pregnant or breast-feed their infant [see Use in Specific Populations] Immunizations Inform patients that Prograf can interfere with the usual response to immunizations and that they should avoid live vaccines [see WARNINGS AND PRECAUTIONS]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. 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). 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). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals impairing their immune system’s ability to inhibit unrelated carcinogenesis. 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. Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range of 0.075 to 0.2 mg/kg/day based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and 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 (2.6 to 6.9 times the clinical dose range based on body surface area), 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. Use In Specific Populations Pregnancy Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus given orally to pregnant rabbits at 0.5 to 4.3 times the clinical dose and pregnant rats at 0.8 to 6.9 times the clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Prograf should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg, 0.5 to 4.3 times the clinical dose range (0.075 - 0.2 mg/kg) based on body surface area, was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg, 2.6 to 6.9 times the clinical dose range was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg, 0.8 to 6.9 times the recommended clinical dose range was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed. Nursing Mothers Tacrolimus is excreted in human milk. As the effect of chronic exposure to tacrolimus in healthy infants is not established, patients maintained on Prograf should discontinue nursing taking into consideration importance of drug to the mother. Pediatric Use The safety and efficacy of Prograf in pediatric kidney and heart transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Prograf. Two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients [see DOSAGE AND ADMINISTRATION]. Geriatric Use Clinical trials of Prograf did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Use In Renal Impairment The pharmacokinetics of Prograf in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Prograf at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Use In Hepatic Impairment The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. The use of Prograf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].