TACROLIMUS: 91,009 Adverse Event Reports & Safety Profile

Tacrolimus USP, previously known as FK506, is the active ingredient in Tacrolimus capsules, USP. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus USP is designated as 15,19-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hy-droxy-3-methoxy cyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8- (2-propenyl)-, mono-hydrate, [3S [3R*,E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,-14R*,15S*,16R*,18S*,19S*,26aR*]]-; (-)- (3S,4R,5S,8R, 9E,12S,14S,15R,16S,18R,19R,26aS)-8-Allyl-5,6,8,11,12,13,14,15,16,17,18,19,24, 25,26,26ahexadecahydro- 5,19-dihydroxy-3-[(E)-2-[(1R,3R,4R)-4- hydroxy-3-methoxycyclohexyl]-1-methylvinyl]-14,16- dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3Hpyrido[ 2,1-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)- te-trone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus USP has an empirical formula of C 44 H 69 NO 12

• H 2 O and a formula weight of 822.03. Tacrolimus USP appears as white to off-white powder. It is soluble in methanol, ethanol, acetone, ethyl acetate and chloroform. Insoluble in water. Tacrolimus USP 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 anhydrous NF, croscarmellose sodium NF, hypromellose USP, magnesium stearate NF.

The

0.5 mg capsule shell contains ferric oxide yellow, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains ferric oxide red, gelatin NF, and titanium dioxide USP. Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye). The components of red ink used in Tacrolimus capsules USP, 0.5 mg and 1 mg are Shellac, Propylene glycol, Sodium hydroxide, Titanium dioxide, Povidone and FD&C Red Aluminium Lake. The components of white ink used in Tacrolimus capsules USP, 5 mg are Shellac, Propylene glycol, Ammonia solution, Titanium dioxide and Potassium Hydroxide. Tacrolimus capsules meet USP Organic Impurities, Procedure 2. FDA approved dissolution test specifications differ from USP. Tacrolimus-structural-formula

AND USAGE Tacrolimus capsules, USP are a calcineurin-inhibitor immunosuppressant indicated for:

• Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants ( 1.1 , 1.2 , 1.3 )
• Use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF) ( 1.1 , 1.2 , 1.3 )
• Limitations of Use ( 1.4 ):
• Do not use simultaneously with cyclosporine
• Intravenous use reserved for patients who cannot tolerate capsules orally
• Use with sirolimus is not recommended in liver and heart transplant; use with sirolimus in kidney transplant has not been established

1.1 Prophylaxis of Organ Rejection in Kidney Transplant Tacrolimus capsules, USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that tacrolimus capsules be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span>.

1.2 Prophylaxis of Organ Rejection in Liver Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that tacrolimus capsules be used concomitantly with adrenal corticosteroids <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

1.3 Prophylaxis of Organ Rejection in Heart Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that tacrolimus capsules be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span> . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

1.4 Limitations of Use Tacrolimus capsules should not be used simultaneously with cyclosporine <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> . Tacrolimus injection should be reserved for patients unable to take tacrolimus capsules orally <span class="opacity-50 text-xs">[see Warnings and Precautions (5.11) ]</span>. Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of tacrolimus capsules with sirolimus has not been established in kidney transplant <span class="opacity-50 text-xs">[see Warnings and Precautions (5.12) ]</span>.

AND ADMINISTRATION

• Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules or suspension). ( 2.1 , 2.2 )
• Administer capsules or suspension consistently with or without food. ( 2.1 )
• Therapeutic drug monitoring is recommended. ( 2.1 , 2.6 )
• Avoid eating grapefruit or drinking grapefruit juice. ( 2.1 )
• See dosage adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 )
• For complete dosing information, see Full Prescribing Information.

Adult

Patient Population Initial Oral Dosage (formulation)

Whole Blood Trough Concentration Range

Kidney Transplant With azathioprine 0.2 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist 0.1 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL Lung Transplant With azathioprine or MMF 0.075 mg/kg/day Patients with cystic fibrosis may require higher doses due to lower bioavailability. capsules, divided in two doses, every 12 hours Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL PEDIATRIC Patient Population Initial Oral Dosage (formulation)

Whole Blood Trough Concentration Range

Kidney Transplant 0.3 mg/kg/day capsules or oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Liver Transplant 0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant 0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Lung Transplant 0.3 mg/kg/day , capsules or oral suspension, divided in two doses, every 12 hours Weeks 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL MMF= Mycophenolate mofetil

2.1 Important Administration Instructions PROGRAF should not be used without supervision by a physician with experience in immunosuppressive therapy. PROGRAF capsules and PROGRAF Granules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended- release dosage forms must occur under physician supervision <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>.

Intravenous

Formulation - Administration Precautions due to Risk of Anaphylaxis Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral PROGRAF is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions ( 5.9 )] . 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.

Oral

Formulations (Capsules and Oral Suspension) If patients are able to initiate oral therapy, the recommended starting doses should be initiated.

Prograf

Granules for oral suspension or PROGRAF capsules may be taken with or without food. However, since the presence of food affects the bioavailability of PROGRAF, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology ( 12.3 )].

General Administration Instructions

Patients should not eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions ( 7.2 )]. 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. Therapeutic drug monitoring (TDM) is recommended for all patients receiving PROGRAF [see Dosage and Administration ( 2.6 )].

2.2 Dosage Recommendations for Adult Kidney, Liver, Heart, or Lung Transplant Patients - Capsules and Injection Capsules If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of PROGRAF capsules should be administered no sooner than 6 hours after transplantation in the liver, heart, or lung transplant patients. In kidney transplant patients, the initial dose of PROGRAF capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. The initial oral PROGRAF capsule dosage recommendations for adult patients with kidney, liver, heart, or lung transplants and whole blood trough concentration range are shown in Table 1 . Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1 .

Table

1. Summary of Initial Oral PROGRAF Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults Patient Population PROGRAF Capsules African-American patients may require higher doses compared to Caucasians (see Table 2 ).

Initial Oral Dosage Whole Blood

Trough Concentration Range Kidney Transplant With Azathioprine 0.2 mg/kg/day, divided in two doses, administered every 12 hours Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist 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 ( 14.1 )]. 0.1 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day, divided in two doses, administered every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL Lung Transplant With azathioprine or MMF 0.075 mg/kg/day Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology ( 12.3 )]. , divided in two doses, administered every 12 hours Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL Dosage should be titrated based on clinical assessments of rejection and tolerability. PROGRAF dosages lower 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 African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2 ) [see Use in Specific Populations ( 8.8 ) and Clinical Pharmacology ( 12.3 )] .

Table

2.

Comparative

Dose and Trough Concentrations Based on Race Time After Transplant Caucasian N = 114 African-American 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 In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

Intravenous

Injection PROGRAF injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of PROGRAF capsules should be given 8-12 hours after discontinuing the intravenous infusion. The recommended starting dose of PROGRAF injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 0.01 mg/kg/day in heart transplant, and 0.01-0.03 mg/kg/day in lung transplant, given as a continuous intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. The whole blood trough concentration range described in Table 1 pertains to oral administration of PROGRAF only; while monitoring PROGRAF concentrations in patients receiving PROGRAF injection as a continuous intravenous 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. Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as PROGRAF injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions ( 5.9 )] .

2.3 Dosage Recommendations for Pediatric Kidney, Liver, Heart, or Lung Transplant Patients Oral formulations (capsules or oral suspension) Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3 . Perform TDM to ensure that patients are within the ranges listed in Table 3 .

Table

3. Summary of Initial PROGRAF Capsule and PROGRAF Granules Dosage Recommendations and Whole Blood Trough Concentration Range in Children Patient Population Initial PROGRAF Capsule and PROGRAF Granules Dosing Whole Blood Trough Concentration Range Pediatric kidney transplant patients See Clinical Pharmacology ( 12.3 ) , PROGRAF Granules Pharmacokinetics in Pediatric Patients. 0.3 mg/kg/day capsules or oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric liver transplant patients See Clinical Studies ( 14.2 ) , Liver Transplantation. 0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric heart transplant patients 0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric lung transplant patients 0.3 mg/kg/day , Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology ( 12.3 )]. capsules or oral suspension, divided in two doses, administered every 12 hours Week 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly. For conversion of pediatric patients from PROGRAF Granules to PROGRAF capsules or from PROGRAF capsules to PROGRAF Granules, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration ( 2.6 )].

Intravenous

Injection If a patient is unable to receive an oral formulation, the patient may be started on PROGRAF injection. For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.

2.4 Dosage Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received a liver, heart, or lung 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]</span> .

2.5 Dosage Modification for 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )]</span>.

2.6 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. Whole blood trough concentration range 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) anticoagulant. Heparin anticoagulation 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 &gt; 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.

2.7 Preparation and Administration Instructions of PROGRAF Injection for Pharmacists Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 <span class="opacity-50 text-xs">[see How Supplied/ Storage and Handling ( 16.4 )]</span> . 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 polyvinyl chloride (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).

2.8 Preparation and Administration Instructions of PROGRAF Granules Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 <span class="opacity-50 text-xs">[see How Supplied/ Storage and Handling ( 16.4 )]</span> . The required dose for PROGRAF Granules is calculated based on the weight of the patient. Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose. Do not use tubing, syringes and other equipment (cups) containing PVC to prepare or administer tacrolimus products. Do not sprinkle PROGRAF Granules on food. Prepare and administer PROGRAF Granules as follows:

• To prepare the dose, empty the entire contents of each PROGRAF Granules packet into a glass cup. Check for any remaining granules in the packet(s) and empty these into the cup.
• Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the cup containing the PROGRAF Granules.
• Mix and administer the entire contents of the cup. The granules will not completely dissolve. The suspension should be given immediately after preparation.
• For younger patients, the suspension can be drawn up via a non-PVC oral syringe that will be dispensed with the prescription.
• The cup or syringe should be rinsed with the same quantity of water (15 to 30 milliliters) and given to the patient to ensure all of the medication is taken.
• The pharmacy must dispense with the Instructions for Use. Alert the patient to read the Instructions for Use.

4 CONTRAINDICATIONS

• Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 ) Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus 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 ( 6 ))] .

REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies [see Warnings and Precautions ( 5.1 )]

Serious

Infections [see Warnings and Precautions ( 5.2 )]

New Onset Diabetes After

Transplant [see Warnings and Precautions ( 5.4 )] Nephrotoxicity [see Warnings and Precautions ( 5.5 )] Neurotoxicity [see Warnings and Precautions ( 5.6 )] Hyperkalemia [see Warnings and Precautions ( 5.7 )] Hypertension [see Warnings and Precautions ( 5.8 )]

Anaphylactic

Reactions with Tacrolimus Injection [see Warnings and Precautions ( 5.9 )]

Myocardial

Hypertrophy [see Warnings and Precautions ( 5.13 )]

Pure Red Cell

Aplasia [see Warnings and Precautions ( 5.15 )]

Thrombotic

Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [ see Warnings and Precautions ( 5.16 )] The most common adverse reactions (≥15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jubilant Cadista Pharmaceutical Inc. at 1-800-313-4623 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Transplantation

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. Tacrolimus based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus 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 tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (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 tacrolimus-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. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below: Table 4.

Kidney

Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/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 tacrolimus-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 tacrolimus (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 tacrolimus 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 Tacrolimus in Conjunction with MMF (Study 1)

Tacrolimus

Capsules USP (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% Leucopenia 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 tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF1 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%), African-American (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 tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6.

Kidney

Transplantation: Adverse Reactions Occurring in ≥15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

Tacrolimus

Capsules USP / MMF (N=212) Cyclosporine / MMF (N=212)

Gastrointestinal Disorder 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 Disorder Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorder 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 kidney transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies".

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 to 70), the distribution was 52% male, and the composition was White (78%), African-American (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 tacrolimus-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 Tacrolimus 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. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.

Table

7.

Liver

Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus U.S.TRIAL EUROPEAN TRIAL Tacrolimus (N=250) Cyclosporine/AZA (N=250) Tacrolimus (N=264) Cyclosporine /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% Table 8.

Pediatric Liver

Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with Tacrolimus Granules (STUDY 01-13)

Tacrolimus

Granules (N=91) Cyclosporine (N=90) Body as a Whole Fever 46% 51% Infection 25% 29% Sepsis 22% 20% CMV Infection 15% 24% EBV Infection 26% 11% Ascites 17% 20% Peritonitis 12% 7% Cardiovascular System Hypertension 39% 47% Digestive System Liver Function Tests Abnormal 37% 28% Diarrhea 26% 26% Vomiting 15% 13% Gastrointestinal Hemorrhage 11% 12% Bile Duct Disorder 12% 8% Gastroenteritis 12% 4% Hemic and Lymphatic System Anemia 29% 19% Metabolic and Nutritional Disorders Hypomagnesemia 40% 29% Acidosis 26% 17% Hyperkalemia 12% 10% Respiratory System Pleural Effusion 22% 19% Bronchitis 11% 8% Urogenital System Kidney Function Abnormal 13% 14% Less frequently observed adverse reactions in liver transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies" 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 Tacrolimus (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 tacrolimus-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. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9.

Heart

Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus Capsules USP in Conjunction with Azathioprine (AZA)

Tacrolimus

Capsules USP /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 tacrolimus in combination with sirolimus (n=109), tacrolimus 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%), African-American (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 tacrolimus 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 tacrolimus-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. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies." New Onset Diabetes After Transplant Kidney Transplantation 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 tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies ( 14.1 )

Table

10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)

Parameter Treatment Group Tacrolimus

Capsules USP/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 tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion 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 11 to 14. PTDM was reported in 20% of Tacrolimus /Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). 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. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12)

Table

11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) 1 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. Status of PTDM1 Tacrolimus Capsules USP/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus. 151 151 New onset PTDM 1 , 1 st 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 1 post 1 year 1 0 Patients with PTDM 1 at 2 years 16/151 (11%) 5/151 (3%)

Table

12. 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 1 Tacrolimus Capsules USP Cyclosporine African-American 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%)

Liver Transplantation

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-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 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1 )]

Table

13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients 1Use 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. 2 Patients without pre-transplant history of diabetes mellitus Status of PTDM 1 US Trial European Trial Tacrolimus Capsules USP Cyclosporine Tacrolimus Capsules USP Cyclosporine Patients at risk 2 239 236 239 249 New Onset PTDM 1 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%)

Heart Transplantation

Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-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 14). Hyperglycemia defined as two fasting plasma glucose levels ≥ 126 mg/dL was reported with the use of tacrolimus 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 Adverse Reactions ( 6.1 )]

Table

14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients 1 Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. 2 Patients without pre-transplant history of diabetes mellitus. 3 7-12 months for the U.S. trial. Status of PTDM 1 US Trial European Trial Tacrolimus Capsules USP/MMF Cyclosporine/MMF Tacrolimus Capsules USP/AZA Cyclosporine/AZA Patients at risk 2 75 83 132 138 New Onset PTDM 1 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year 3 7 (9%) 1 (1%) 24 (18%) 4 (3%)

Less Frequently Reported Adverse

Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies 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 : Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic 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, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital: Acute kidney failure, 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, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating Lung Transplantation Adverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with Tacrolimus Capsules USP [see Adverse Reactions ( 6.2 )].

6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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 ischemia, pericardial effusion, QT prolongation, Torsade de Pointes venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy. Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy. Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus- associated nephropathy, (PVAN) including graft loss. Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)

Nervous

System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES) , progressive multifocal leukoencephalopathy (PML), 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, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome Postmarketing Adverse Reactions in Lung Transplantation. Based on U.S.

Scientific

Registry of Transplant Recipients (SRTR) data, published clinical trials, and postmarketing reports, the safety profile for lung transplant patients treated with Tacrolimus Capsules USP is consistent with the safety profile in kidney, liver, and heart transplant patients treated with Tacrolimus Capsules USP. The primary adverse reactions described include renal dysfunction, infection, diabetes, gastrointestinal disturbances (e.g., diarrhea), hypertension, and neurological events (e.g., tremor). As expected, lung transplant patients have a higher incidence of pulmonary complications (e.g., pneumonia, bronchiolitis obliterans syndrome) than other solid organ transplant patients, which is in part due to the underlying disease and to the nature of the transplanted organ.

AND PRECAUTIONS

• Lymphoma and Other Malignancies: Risk of lymphomas, including post transplant lymphoproliferative disorder (PLTD); appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight ( 5.2 )
• Serious infections: Increased risk of bacterial, viral, fungal and protozoal infections, including opportunistic infections: combination immunosuppression should be used with caution ( 5.3 )
• Polyoma Virus Infections: Serious, sometimes fatal outcomes, including polyoma virus-associated nephropathy (PVAN), mostly due to BK virus, and JC virus-associated progressive multifocal leukoencephalopathy (PML); consider reducing immunosuppression ( 5.4 )
• Cytomegalovirus (CMV) Infections: Increased risk of CMV viremia and disease; consider reducing immunosuppression ( 5.5 )
• New Onset Diabetes After Transplant: Monitor blood glucose ( 5.6 )
• Nephrotoxicity: Acute and/or chronic; reduce the dose; use caution with other nephrotoxic drugs ( 5.7 )
• Neurotoxicity: Risk of Posterior Reversible Encephalopathy Syndrome, monitor for neurologic abnormalities; reduce or discontinue tacrolimus and other immunosuppressants ( 5.8 )
• Hyperkalemia: Monitor serum potassium levels. Careful consideration should be given prior to use of other agents also associated with hyperkalemia ( 5.9 )
• Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions ( 5.10 )
• Anaphylactic Reactions with IV formulation: Observe patients receiving Tacrolimus injection for signs and symptoms of anaphylaxis ( 5.11 )
• Use with Sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions ( 5.12 )
• Myocardial Hypertrophy: Consider dosage reduction or discontinuation ( 5.15 )
• Immunizations: Use of live vaccines should be avoided ( 5.16 )
• Pure Red Cell Aplasia: Discontinuation should be considered ( 5.17 )

5.1 Management of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use tacrolimus. 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 ].

5.2 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including tacrolimus, 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.

5.3 Serious Infections Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [ see Boxed Warning and Warnings and Precautions ( 5.4 , 5.5 )]. 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.

5.4 Polyoma Virus Infections Patients receiving immunosuppressants, including Tacrolimus, 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 ( 6.2 )]. PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss [ see Adverse Reactions ( 6.2 )]. Patient monitoring may help detect patients at risk for PVAN. Cases of PML have been reported in patients treated with Tacrolimus. 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.

5.5 Cytomegalovirus (CMV)

Infections

Patients receiving immunosuppressants, including tacrolimus, 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.

5.6 New Onset Diabetes After Transplant Tacrolimus capsules 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 Tacrolimus [ see Adverse Reactions ( 6.1 )].

5.7 Nephrotoxicity Tacrolimus, 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 tacrolimus 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 tacrolimus in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial [ see Adverse Reactions ( 6.1 )]. Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus 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 ( 7.3 , 7.4 , 7.5 , 7.6 )].

5.8 Neurotoxicity Tacrolimus 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 tacrolimus [ see Adverse Reactions ( 6.1 )]. Less severe neurotoxicities, include tremors, paresthesias, headache, and other changes in motor function, mental status, and sensory function [ see Adverse Reactions ( 6.1 )]. Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment.

5.9 Hyperkalemia Hyperkalemia has been reported with Tacrolimus 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 Tacrolimus therapy [ see Adverse Reactions ( 6.1 )].

5.10 Hypertension Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [ see Adverse Reactions ( 6.1 )]. 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 Warnings and Precautions (5.9 )]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [ see Drug Interactions ( 7.5 )].

5.11 Anaphylactic Reactions with Tacrolimus Injections Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take Tacrolimus capsules [ see Indications and Usage ( 1.4 )]. Patients receiving Tacrolimus 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.

5.12 Use with Sirolimus The safety and efficacy of tacrolimus with sirolimus has not been established in kidney transplant patients. Use of sirolimus with tacrolimus 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 ( 1.4 )]. Use of sirolimus (2 mg per day) with tacrolimus 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 ( 14.3 )].

5.13 Use with CYP3A4 Inhibitors and Inducers When coadministering tacrolimus 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 tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus associated adverse reactions are recommended [ see Drug Interactions ( 7 )].

5.14 QT Prolongation Tacrolimus Capsules may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid tacrolimus 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 tacrolimus Capsules with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus Capsules with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [ see Drug Interactions ( 7 )].

5.15 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 tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered [ see Adverse Reactions ( 6.2 )].

5.16 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.

5.17 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 tacrolimus should be considered [ see Adverse Reactions ( 6.2 )].

5.18 Gastrointestinal Perforation Gastrointestinal perforation has been reported in patients treated with Tacrolimus Capsules, USP; 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 ( 6.1 )].

PRECAUTIONS General The use of tacrolimus ointment should be avoided on pre-malignant and malignant skin conditions. Some malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), may mimic atopic dermatitis. The use of tacrolimus ointment is not recommended in patients having skin conditions with a skin barrier defect where there is the potential for increased systemic absorption of tacrolimus, including but not limited to, Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host Disease. Oral application is also not recommended. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions. The use of tacrolimus ointment may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of tacrolimus ointment application and typically improve as the lesions of atopic dermatitis resolve. With tacrolimus ointment 0.1%, 90% of the skin burning events had a duration between 2 minutes and 3 hours (median 15 minutes). 90% of the pruritus events had a duration between 3 minutes and 10 hours (median 20 minutes) (see ADVERSE REACTIONS ). Bacterial and Viral Skin Infections Before commencing treatment with tacrolimus ointment, cutaneous bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of tacrolimus ointment in the treatment of clinically infected atopic dermatitis. While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi's varicelliform eruption), treatment with tacrolimus ointment may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum. 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 tacrolimus ointment and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, tacrolimus ointment should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Sun Exposure

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

Immunocompromised Patients

The safety and efficacy of tacrolimus 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 tacrolimus ointment. Systemic absorption is more likely to occur in patients with epidermal barrier defects especially when tacrolimus ointment is applied to large body surface areas. Caution should also be exercised in patients predisposed to renal impairment. Information for Patients (See MEDICATION GUIDE ) Patients using tacrolimus ointment should receive and understand the information in the Medication Guide. Please refer to the Medication Guide for providing instruction and information to the patient. What is the most important information patients should know about tacrolimus ointment? The safety of using tacrolimus ointment for a long period of time is not known. A very small number of people who have used tacrolimus ointment have had cancer (for example, skin or lymphoma). However, a link with tacrolimus ointment has not been shown. Because of this concern, instruct patients:

• Do not use tacrolimus ointment continuously for a long time.
• Use tacrolimus ointment only on areas of skin that have eczema.
• Do not use tacrolimus ointment on a child under 2 years old. Tacrolimus ointment comes in two strengths:
• Only tacrolimus ointment 0.03% is for use on children aged 2 to 15 years.
• Either tacrolimus ointment 0.03% or 0.1% can be used by adults and children 16 years and older. Advise patients to talk to their prescriber for more information. How should tacrolimus ointment be used? Advise patients to:
• Use tacrolimus ointment exactly as prescribed.
• Use tacrolimus ointment only on areas of skin that have eczema.
• Use tacrolimus ointment for short periods, and if needed, treatment may be repeated with breaks in between.
• Stop tacrolimus ointment when the signs and symptoms of eczema, such as itching, rash, and redness go away, or as directed.
• Follow their doctor's advice if symptoms of eczema return after treatment with tacrolimus ointment.
• Call their doctor if: ∘ Their symptoms get worse with tacrolimus ointment. ∘ They get an infection on their skin. ∘ Their symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema. To apply tacrolimus ointment: Advise patients:
• Wash their hands before applying tacrolimus ointment.
• Apply a thin layer of tacrolimus ointment twice daily to the areas of skin affected by eczema.
• Use the smallest amount of tacrolimus ointment needed to control the signs and symptoms of eczema.
• If they are a caregiver applying tacrolimus ointment to a patient, or if they are a patient who is not treating their hands, wash their hands with soap and water after applying tacrolimus ointment. This should remove any ointment left on the hands.
• Do not bathe, shower, or swim right after applying tacrolimus ointment. This could wash off the ointment.
• Moisturizers can be used with tacrolimus ointment. Make sure they check with their doctor first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If they use moisturizers, apply them after tacrolimus ointment. What should patients avoid while using tacrolimus ointment? Advise patients:
• Do not use ultraviolet light therapy, sun lamps, or tanning beds during treatment with tacrolimus ointment.
• Limit sun exposure during treatment with tacrolimus ointment even when the medicine is not on their skin. If patients need to be outdoors after applying tacrolimus ointment, wear loose fitting clothing that protects the treated area from the sun. Doctors should advise what other types of protection from the sun patients should use.
• Do not cover the skin being treated with bandages, dressings or wraps. Patients can wear normal clothing.
• Avoid getting tacrolimus ointment in the eyes or mouth. Do not swallow tacrolimus ointment. Patients should call their doctor if they swallow tacrolimus ointment.

Drug Interactions

Formal topical drug interaction studies with tacrolimus ointment have not been conducted. Based on its extent of absorption, interactions of tacrolimus ointment with systemically administered drugs are unlikely to occur but cannot be ruled out (see CLINICAL PHARMACOLOGY ). The concomitant administration of known CYP3A4 inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice. Tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Oral (feed) carcinogenicity studies have been carried out with systemically administered tacrolimus in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found at daily doses up to 3 mg/kg [9X the Maximum Recommended Human Dose (MRHD) based on AUC comparisons] and 5 mg/kg (3X the MRHD based on AUC comparisons), respectively. A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m 2 /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: There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women. The experience with tacrolimus ointment when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy. Reproduction studies were carried out with systemically administered tacrolimus in rats and rabbits. Adverse effects on the fetus were observed mainly at oral dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.04X-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. Tacrolimus 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 tacrolimus ointment is minimal relative to systemic administration, it is known that tacrolimus is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tacrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Tacrolimus ointment is not indicated for children less than 2 years of age. Only the lower concentration, 0.03%, of tacrolimus 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 tacrolimus 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 tacrolimus 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 tacrolimus 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 tacrolimus ointment, 24 (0.5%) were reported with eczema herpeticum. Since the safety and efficacy of tacrolimus 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 tacrolimus ointment in phase 3 studies. The adverse event profile for these patients was consistent with that for other adult patients.

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 (5.13) and Clinical Pharmacology (12.3) ] . Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when tacrolimus 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 (5.7) and (5.14) ] .

• Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to tacrolimus; monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed ( 7.1 )
• Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use ( 7.2 , 7.3 )
• CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.13 , 7.3 , 7.4 , 7.5 , 7.6 )
• CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.13 , 7.7 , 7.8 , 7.9 )

7.1 Mycophenolic Acid Products With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with tacrolimus co-administration 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 tacrolimus in patients concomitantly receiving MPA-containing products.

7.2 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> .

7.3 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Whole blood concentrations of tacrolimus are markedly increased when co-administered with telaprevir or with boceprevir <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Monitoring of tacrolimus whole blood concentrations and tacrolimus-associated 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.

7.4 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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.

7.5 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.

7.6 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.

7.7 Antimycobacterials Rifampin <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> 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.

7.8 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.

7.9 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.

7.10 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. Co-administration with magnesium and aluminum hydroxide antacids increase tacrolimus whole blood concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

7.11 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.

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 (7) ] . Telaprevir In a single dose study in nine healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg 3 times daily for 13 days) increased the tacrolimus dose-normalized C max by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.3) ] . Boceprevir In a single dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg 3 times daily for 11 days) increased tacrolimus C max by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.3) ] .

Nelfinavir

Based on a clinical study of five 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 tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.3) ] . Rifampin In a study of six 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 (7.7) ] . Magnesium-aluminum-hydroxide In a single dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions (7.10) ] . Ketoconazole In a study of six 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 (7.4) ] . 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) C max and AUC τ 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 (7.4) ] . 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) C max 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 [ s ee Drug Interactions (7.4) ] . Caspofungin (see complete prescribing information for CANCIDAS ®* ) Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) 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 (7.4) ] .