Tacrolimus (tacrolimus 5 mg) Dailymed

Generic: tacrolimus is used for the treatment of Dermatitis, Atopic Graft vs Host Disease

IMPRINT: MYLAN 2045 SHAPE: capsule

Boxed Warning

Warning: Malignancies And Serious Infections

Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. ( 5.1, 5.2) WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. ( 5.1, 5.2)

FDA Adverse Reactions

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Recent Major Changes Section

Warnings and Precautions, Cannabidiol Drug Interactions ( 5.17) 08/2023

Warning: Malignancies And Serious Infections

Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. ( 5.1, 5.2)

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS

See full prescribing information for complete boxed warning.

Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. ( 5.1, 5.2)

1 Indications And Usage

Tacrolimus capsules are a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney, or heart transplants, and pediatric patients receiving allogenic liver transplants in combination with other immunosuppressants. ( 1.1)

1.1 Prophylaxis of Organ Rejection in Kidney, Liver, or Heart Transplant

Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [see Clinical Studies (14.1)] , liver transplant [see Clinical Studies (14.2)] , and heart transplant [see Clinical Studies (14.3)] , and pediatric patients receiving allogeneic liver transplants [see Clinical Studies (14.2)] in combination with other immunosuppressants.

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2 Dosage And Administration

Administer capsules 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.

MMF = Mycophenolate mofetil

ADULT

Patient

Population

Initial Oral Dosage

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

PEDIATRIC

Patient Population

Initial Oral Dosage

Whole Blood Trough Concentration Range

Liver Transplant

0.15-0.2 mg/kg/day capsules divided in two doses, every 12 hours

Month 1-12: 5-20 ng/mL



2.1 Important Administration Instructions

Tacrolimus capsules should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus capsules 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 [see Warnings and Precautions (5.3)] .

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus capsules may be taken with or without food. However, since the presence of food affects the bioavailability of tacrolimus, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology (12.3)] .

Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)] .

Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration (2.6)] .

2.2 Dosage Recommendations for Adult Kidney, Liver, or Heart Transplant Patients - Capsules

If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.

The initial oral tacrolimus capsule dosage recommendations for adult patients with kidney, liver, or heart 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 uled in Table 1.

Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults

Patient Population

Tacrolimus 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

Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus capsules 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

Caucasian N = 114

African-American N = 56

Time After Transplant

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

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions (5.9)] .

2.3 Dosage Recommendations for Pediatric Liver Transplant Patients

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 uled in Table 3.

Table 3. Summary of Initial Tacrolimus Capsule Dosage Recommendations and Whole Blood Trough Concentration Range in Children

Patient Population

Initial Tacrolimus Capsule Dosing

Whole Blood Trough Concentration Range

Pediatric liver transplant patients See Clinical Studies (14.2), Liver Transplantation.

0.15-0.2 mg/kg/day capsules divided in two doses, administered every 12 hours

Month 1-12: 5-20 ng/mL

For conversion of pediatric patients from tacrolimus for oral suspension to tacrolimus capsules or from tacrolimus capsules to tacrolimus for oral suspension, 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)] .

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.4 Dosage Modification for Patients with Renal Impairment

Due to its potential for nephrotoxicity, consider dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules 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 [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)] .

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 tacrolimus capsules. Close monitoring of blood concentrations is warranted.

The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

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 > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.

3 Dosage Forms And Strengths

Tacrolimus Capsules, USP are available containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP.

The 0.5 mg capsules are hard-shell gelatin capsules with a light orange opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLANover 2045in black ink on both the cap and the body.

The 1 mg capsules are hard-shell gelatin capsules with a light blue opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLANover 2046in black ink on both the cap and the body.

The 5 mg capsules are hard-shell gelatin capsules with a rubine red opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLANover 2047in black ink on both the cap and the body.

Capsules: 0.5 mg, 1 mg and 5 mg ( 3)

4 Contraindications

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)] .

Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4)

5 Warnings And Precautions

Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors: Instruct patients or caregivers to recognize the appearance of tacrolimus capsules. ( 5.3)

New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4)

Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5)

Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules. ( 5.6)

Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7)

Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8)

Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis. ( 5.9)

Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10)

Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13)

Immunizations: Avoid live vaccines. ( 5.14)

Pure Red Cell Aplasia: Consider discontinuation of tacrolimus. ( 5.15)

Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16)

5.1 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. 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, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum 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. Monitor EBV serology during treatment.

5.2 Serious Infections

Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

Polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection

JC virus-associated progressive multifocal leukoencephalopathy (PML)

Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1, 6.2)] .

5.3 Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or overexposure to tacrolimus. Tacrolimus capsules are not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of tacrolimus dosage forms [see Dosage Forms and Strengths (3)] and to confirm with the healthcare provider if a different product is dispensed.

5.4 New Onset Diabetes After Transplant

Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, or heart transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American 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)] .

5.5 Nephrotoxicity Due to Tacrolimus and Drug Interactions

Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1)] .

Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.

The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2)] .

5.6 Neurotoxicity

Tacrolimus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1, 6.2)] . As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus if neurotoxicity occurs.

5.7 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)] . Monitor serum potassium levels periodically during treatment.

5.8 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 (5.7)] . Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.2)].

5.9 Anaphylactic Reactions with Tacrolimus Injection

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus injection, 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 orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Error! Hyperlink reference not valid. ].

5.10 Not Recommended for Use with Sirolimus

Tacrolimus is not recommended for use with sirolimus:

The 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.

The 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)] .

The use of sirolimus with tacrolimus may increase the risk of thrombotic microangiopathy [see Warnings and Precautions (5.16)] .

5.11 Interactions with CYP3A4 Inhibitors and Inducers

When co-administering 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. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)] .

5.12 QT Prolongation

Tacrolimus 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 co-administering tacrolimus 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 with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7.2)] .

5.13 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)] .

5.14 Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus.

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.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.

5.15 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)] .

5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura)

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.

In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.

5.17 Cannabidiol Drug Interactions

When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6)and Drug Interactions (7.3)] .

6 Adverse 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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.

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 reaction 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-U.S. 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

(Group C)

(N = 403)

Cyclosporine (Group A)

(N = 384)

Cyclosporine (Group B)

(N = 408)

Diarrhea

25%

16%

13%

Urinary Tract Infection

24%

28%

24%

Anemia

17%

19%

17%

Hypertension

13%

14%

12%

Leukopenia

13%

10%

10%

Edema Peripheral

11%

12%

13%

Hyperlipidemia

10%

15%

13%

Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), 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/MMF (N = 212)

Cyclosporine/MMF (N = 212)

Gastrointestinal Disorders

     Diarrhea

44%

26%

     Nausea

39%

47%

     Constipation

36%

41%

     Vomiting

26%

25%

     Dyspepsia

18%

15%

Injury, Poisoning, and Procedural Complications

     Post-Procedural Pain

29%

27%

     Incision Site Complication

28%

23%

     Graft Dysfunction

24%

18%

Metabolism and Nutrition Disorders

     Hypomagnesemia

28%

22%

     Hypophosphatemia

28%

21%

     Hyperkalemia

26%

19%

     Hyperglycemia

21%

15%

     Hyperlipidemia

18%

25%

     Hypokalemia

16%

18%

Nervous System Disorders

     Tremor

34%

20%

     Headache

24%

25%

Blood and Lymphatic System Disorders

     Anemia

30%

28%

     Leukopenia

16%

12%

Miscellaneous

     Edema Peripheral

35%

46%

     Hypertension

32%

35%

     Insomnia

30%

21%

     Urinary Tract Infection

26%

22%

     Blood Creatinine Increased

23%

23%

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

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 reaction 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%

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.”

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 reaction 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 8. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

Tacrolimus/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, Candidainfection, 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

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA _1C≥ 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 9. 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/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%)

     HbA _1c≥ 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 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)

Status of PTDM 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.

Tacrolimus/AZA

CsA/AZA

Patients without pre-transplant history of diabetes mellitus

151

151

New onset PTDM , 1 ^stYear

30/151 (20%)

6/151 (4%)

Still insulin-dependent at one year in those without prior history of diabetes

25/151 (17%)

5/151 (3%)

New onset PTDM post 1 year

1

0

Patients with PTDM at 2 years

16/151 (11%)

5/151 (3%)

Table 11. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

Patient Race

Patients Who Developed PTDM 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.

Tacrolimus

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%)

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 12. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

Status of PTDM Patients without pre-transplant history of diabetes mellitus.

U.S. Trial

European Trial

Tacrolimus

Cyclosporine

Tacrolimus

Cyclosporine

Patients at risk 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.

239

236

239

249

New Onset PTDM

42 (18%)

30 (13%)

26 (11%)

12 (5%)

Patients still on insulin at 1 year

23 (10%)

19 (8%)

18 (8%)

6 (2%)

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 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

Status of PTDM Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

U.S. Trial

European Trial

Tacrolimus/ MMF

Cyclosporine/ MMF

Tacrolimus/ AZA

Cyclosporine/ AZA

Patients at risk Patients without pre-transplant history of diabetes mellitus.

75

83

132

138

New Onset PTDM

10 (13%)

6 (7%)

29 (22%)

5 (4%)

Patients still on insulin at 1 year 7-12 months for the U.S. trial.

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 increased, 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

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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, febrile neutropenia, pancytopenia, thrombocytopenic purpura, 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

7 Drug Interactions

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)

CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11, 7.2)

CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11, 7.2)

Therapeutic drug monitoring and dose reduction for tacrolimus should be considered when tacrolimus is co-administered with cannabidiol ( 5.17, 7.3).

7.1 Mycophenolic Acid

When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

7.2 Effects of Other Drugs on Tacrolimus

Table 15 displays the effects of other drugs on tacrolimus.

Table 14: Effects of Other Drugs/Substances on Tacrolimus Tacrolimus dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.

Drug/Substance Class or Name

Drug Interaction Effect

Recommendations

Grapefruit or grapefruit juice High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor.

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)] .

Avoid grapefruit or grapefruit juice.

Strong CYP3A Inducers Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate). :

     Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort

May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.11)] .

Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] .

Strong CYP3A Inhibitors :

     Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenantheraextracts

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions (5.6, 5.11, 5.12)] .

Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] . Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions (5.11)] .

Mild or Moderate CYP3A Inhibitors:

     Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)] .

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] .

Other drugs, such as:

     Magnesium and aluminum hydroxide antacids

     Metoclopramide

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)] .

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] .

Mild or Moderate CYP3A Inducers

     Methylprednisolone, prednisone

May decrease tacrolimus whole blood trough concentrations.

Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)] .

Caspofungin

May decrease tacrolimus whole blood trough concentrations.

Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)] .

The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus capsules is warranted to ensure continued efficacy and safety [see Dosage and Administration ( 2.2, 2.6)] .

7.3 Cannabidiol

The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6)and Warnings and Precautions (5.17)] .

8 Use In Specific Populations

Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1, 8.3)

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

8.1 Pregnancy

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in uteroare at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m ²basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m ²basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m ²basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data] .

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.

Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.

Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4)] .

Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions (5.7, 5.8)].

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking tacrolimus.

There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus.

There are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in uterohave an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.

TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 16. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.

Table 15. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus

Kidney

Liver

Pregnancy Outcomes Includes multiple births and terminations.

462

253

   Miscarriage

24.5%

25%

   Live births

331

180

      Pre-term delivery (< 37 weeks)

49%

42%

      Low birth weight (< 2500 g)

42%

30%

      Birth defects

8% Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.

5%

Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients, and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m ²basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 to 6.9 times the recommended clinical dose range) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 to 2.2 times the recommended clinical dose range).

Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation, produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology (13.1)] .

8.2 Lactation

Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies; exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Use in Specific Populations (8.1)and Nonclinical Toxicology (13.1)] .

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Tacrolimus can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with tacrolimus [see Use in Specific Populations (8.1)and Nonclinical Toxicology (13.1)] .

Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus [see Nonclinical Toxicology (13.1)] .

8.4 Pediatric Use

Safety and effectiveness have been established in pediatric liver transplant patients.

Safety and efficacy in pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see Error! Hyperlink reference not valid. , Adverse Reactions (6.1), Clinical Pharmacology (12.3)and Clinical Studies (14.2)] .

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)] .

The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)].

8.8 Race or Ethnicity

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)] .

African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)] .

10 Overdosage

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of tacrolimus [see Adverse Reactions (6.1, 6.2)], including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

11 Description

Tacrolimus, previously known as FK506, is the active ingredient in tacrolimus capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as (‒)-(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-8-Allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-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-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone monohydrate.

The chemical structure of tacrolimus is:

Tacrolimus has a molecular formula of C ₄₄H ₆₉NO ₁₂•H ₂O and a formula weight of 822.03. Tacrolimus, USP appears as a white to off-white powder. It is insoluble in water, very soluble in ethanol, and soluble in methanol and chloroform.

Tacrolimus capsules, USP are available for oral administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.

The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.

In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Meets USP Dissolution Test 5.

12 Clinical Pharmacology

12.1 Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

12.3 Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17).

Table 16. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients

Population

N

Route (Dose)

Parameters

C _max (ng/mL)

T _max

(hr)

AUC (ng•hr/mL)

t _1/2 (hr)

CL (L/hr/kg)

V (L/kg)

Healthy Volunteers

8

IV (0.025 mg/kg/4hr)

Not applicable

652 AUC 0-inf± 156

34.2 ± 7.7

0.040 ± 0.009

1.91 ± 0.31

16

PO (5 mg) (capsules)

28.8 ± 8.9

1.5 ± 0.7

266 ± 95

32.3 ± 8.8

Not available

IV (0.02 mg/kg/12 hr)

294 ± 262

18.8 ± 16.7

0.083 ± 0.050

1.41 ± 0.66

Kidney Transplant Patients

26

PO (0.2 mg/kg/day)

19.2 ± 10.3

3.0

203 ± 42

PO (0.3 mg/kg/day)

24.2 ± 15.8

1.5

288 ± 93

Liver Transplant Patients

17

IV (0.05 mg/kg/12 hr)

3300 ± 2130

11.7 ± 3.9

0.053 ± 0.017

0.85 ± 0.30

PO (0.3 mg/kg/day)

68.5 ± 30.0

2.3 ± 1.5

519 ± 179

11

IV (0.01 mg/kg/day as a continuous infusion)

954 AUC 0-t± 334

23.6 ± 9.22

0.051 ± 0.015

Heart Transplant Patients

11

PO (0.075 mg/kg/day) Determined after the first dose

14.7 ± 7.79

2.1 [0.5-6.0] Median [range]

82.7 AUC 0-12± 63.2

14

PO (0.15 mg/kg/day)

24.5 ± 13.7

1.5 [0.4-4.0]

142 ± 116

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)] . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17 ± 10% in adult kidney transplant patients (N = 26), 22 ± 6% in adult liver transplant patients (N = 17), 23 ± 9% in adult heart transplant patients (N = 11) and 18 ± 5% in healthy volunteers (N = 16).

A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (C _max) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (C _min) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and C _maxwere decreased 37% and 77%, respectively; T _maxwas lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C _maxby 28% and 65%, respectively.

In healthy volunteers (N = 16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean C _maxwas reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C _maxwas reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

In 11 liver transplant patients, tacrolimus administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C _max(50 ± 19%), as compared to a fasted state.

Tacrolimus capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Dosage and Administration (2.1)] .

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A and CYP3A5). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitrostudies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

The mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19.

Table 17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients

Population (No. of Patients)

Dose

AUC _0-t (ng•hr/mL)

t _1/2 (hr)

V (L/kg)

CL (L/hr/kg)

Renal Impairment (n = 12)

0.02 mg/kg/4 hr IV

393 ± 123 (t = 60 hr)

26.3 ± 9.2

1.07 ± 0.20

0.038 ± 0.014

Mild Hepatic Impairment (n = 6)

0.02 mg/kg/4 hr IV

367 ± 107 (t = 72 hr)

60.6 ± 43.8 Range: 27.8 ˗ 141

3.1 ± 1.6

0.042 ± 0.02

7.7 mg PO

488 ± 320 (t = 72 hr)

66.1 ± 44.8 Range: 29.5˗138

3.7 ± 4.7 Corrected for bioavailability

0.034 ± 0.019

Severe Hepatic Impairment (n = 6, IV)

0.02 mg/kg/4 hr IV (n = 2)

762 ± 204 (t = 120 hr)

198 ± 158 Range:81 ˗ 436

3.9 ± 1.0

0.017 ± 0.013

0.01 mg/kg/8 hr IV (n = 4)

289 ± 117 (t = 144 hr)

(n = 5, PO) 1 patient did not receive the PO dose

8 mg PO (n = 1)

658 (t = 120 hr)

119 ± 35 Range: 85 ˗ 178

3.1 ± 3.4

0.016 ± 0.011

5 mg PO (n = 4)

533 ± 156 (t = 144 hr)

4 mg PO (n = 1)

Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2)and Use in Specific Populations (8.6)] .

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5)and Use in Specific Populations (8.7)] .

Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2, 2.3)] .

The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C _maxin African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC _0-inftended to be lower in African-Americans (203 ± 115 ng•hr/mL) than Caucasians (344 ± 186 ng•hr/mL) and Latino-Americans (274 ± 150 ng•hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T _1/2among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2)].

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences.

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 9 healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized C _maxby 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)] .

Boceprevir: In a single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus C _maxby 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.2)] .

Nelfinavir:Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.2)] .

Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 ± 6% vs. 7 ± 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036 ± 0.008 L/hr/kg vs. 0.053 ± 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.2)] .

Magnesium and 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 _maxrelative to tacrolimus administration alone [see Drug Interactions (7.2)].

Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2)] .

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 _maxand AUC _τin 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 (7.2)] .

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 _maxand AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2)] .

Caspofungin (see complete prescribing information for CANCIDAS ^®): Caspofungin reduced the blood AUC _0-12of tacrolimus by approximately 20%, peak blood concentration (C _max) by 16%, and 12-hour blood concentration (C _12hr) 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 (7.2)] . The mechanism of interaction has not been confirmed.

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1)] .

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). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.

No evidence of genotoxicity was seen in bacterial ( Salmonellaand E. coli) or mammalian (Chinese hamster lung-derived cells) in vitroassays of mutagenicity, the in vitroCHO/HGPRT assay of mutagenicity, or in vivoclastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m ²basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

14 Clinical Studies

14.1 Kidney Transplantation

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively.

Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received tacrolimus (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) regimens (Group A, n = 390 and Group B, n = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCL _cr) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions (6.1)].

Table 18. Estimated Creatinine Clearance at 12 Months (Study 1)

Group

eCL _cr[mL/min] at Month 12 All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.

N

MEAN

SD

MEDIAN

Treatment Difference with Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. )

(A) CsA/MMF/CS

390

56.5

25.8

56.9

-8.6 (-13.7, -3.7)

(B) CsA/MMF/CS/Daclizumab

399

58.9

25.6

60.9

-6.2 (-11.2, -1.2)

(C) Tac/MMF/CS/Daclizumab

401

65.1

27.4

66.2

-

(D) Siro/MMF/CS/Daclizumab

399

56.2

27.4

57.3

-8.9 (-14.1, -3.9)

Total

1589

59.2

26.8

60.5

Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus

Table 19. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)

Group A N = 390

Group B N = 399

Group C N = 401

Group D N = 399

Overall Failure

141 (36.2%)

126 (31.6%)

82 (20.4%)

185 (46.4%)

Components of efficacy failure

     BPAR

113 (29.0%)

106 (26.6%)

60 (15.0%)

152 (38.1%)

     Graft loss excluding death

28 (7.2%)

20 (5.0%)

12 (3.0%)

30 (7.5%)

     Mortality

13 (3.3%)

7 (1.8%)

11 (2.7%)

12 (3.0%)

     Lost to follow-up

5 (1.3%)

7 (1.8%)

5 (1.3%)

6 (1.5%)

Treatment Difference of efficacy failure compared to Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.)

15.8%

(7.1%, 24.3%)

11.2% (2.7%, 19.5%)

-

26.0% (17.2%, 34.7%)

Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab

The protocol-specified target tacrolimus trough concentrations (C _trough, _Tac) were 3-7 ng/mL; however, the observed median C _troughs, _Tacapproximated 7 ng/mL throughout the 12-month trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

Table 20. Tacrolimus Whole Blood Trough Concentration Range (Study 1)

Time

Median (P10-P90 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac ) tacrolimus whole blood trough concentration range (ng/mL)

Day 30 (N = 366)

6.9 (4.4 – 11.3)

Day 90 (N = 351)

6.8 (4.1 – 10.7)

Day 180 (N = 355)

6.5 (4.0 – 9.6)

Day 365 (N = 346)

6.5 (3.8 – 10.0)

The protocol-specified target cyclosporine trough concentrations (C _trough, _CsA) for Group B were 50-100 ng/mL; however, the observed median C _troughs, _CsAapproximated 100 ng/mL throughout the 12-month trial. The protocol-specified target C _troughs, _CsAfor Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C _troughs, _CsAapproximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.

While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.

Table 21. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)

Time period (Days)

Time-averaged MMF dose (grams per day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.

Less than 2.0

2.0

Greater than 2.0

0-30 (N = 364)

37%

60%

2%

0-90 (N = 373)

47%

51%

2%

0-180 (N = 377)

56%

42%

2%

0-365 (N = 380)

63%

36%

1%

Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received tacrolimus (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24).

Table 22. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)

Tacrolimus/MMF

(N = 212)

Cyclosporine/MMF

(N = 212)

Overall Failure

32 (15.1%)

36 (17.0%)

Components of efficacy failure

     BPAR

16 (7.5%)

29 (13.7%)

     Graft loss excluding death

6 (2.8%)

4 (1.9%)

     Mortality

9 (4.2%)

5 (2.4%)

     Lost to follow-up

4 (1.9%)

1 (0.5%)

Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI 95% confidence interval calculated using Fisher's Exact Test.)

1.9% (-5.2%, 9.0%)

The protocol-specified target tacrolimus whole blood trough concentrations (C _trough, _Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C _troughs, _Tacapproximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

Table 23. Tacrolimus Whole Blood Trough Concentration Range (Study 2)

Time

Median (P10-P90 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac. ) tacrolimus whole blood trough concentration range (ng/mL)

Day 30 (N = 174)

10.5 (6.3 – 16.8)

Day 60 (N = 179)

9.2 (5.9 – 15.3)

Day 120 (N = 176)

8.3 (4.6 – 13.3)

Day 180 (N = 171)

7.8 (5.5 – 13.2)

Day 365 (N = 178)

7.1 (4.2 – 12.4)

The protocol-specified target cyclosporine whole blood concentrations (C _trough, _CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C _troughs, _CsAapproximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].

Table 24. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)

Time period (Days)

Time-averaged MMF dose (g/day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.

Less than 2.0

2.0

Greater than 2.0

0-30 (N = 212)

25%

69%

6%

0-90 (N = 212)

41%

53%

6%

0-180 (N = 212)

52%

41%

7%

0-365 (N = 212)

62%

34%

4%

Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

14.2 Liver Transplantation

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral tacrolimus dosing was 2 days.

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

14.3 Heart Transplantation

Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL.

The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10)] .

15 References

“OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/storage And Handling

16.1 Tacrolimus Capsules

Tacrolimus Capsules, USP are available containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP.

The 0.5 mg capsules are hard-shell gelatin capsules with a light orange opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLANover 2045in black ink on both the cap and the body. They are available as follows:

NDC 51079-817-20 – Unit dose buler packages of 100 (10 cards of 10 capsules each).

The 1 mg capsules are hard-shell gelatin capsules with a light blue opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLANover 2046in black ink on both the cap and the body. They are available as follows:

NDC 51079-818-20 – Unit dose buler packages of 100 (10 cards of 10 capsules each).

The 5 mg capsules are hard-shell gelatin capsules with a rubine red opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLANover 2047in black ink on both the cap and the body. They are available as follows:

NDC 51079-028-20 – Unit dose buler packages of 100 (10 cards of 10 capsules each).

Store and Dispense: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

16.4 Handling and Disposal

Tacrolimus can cause fetal harm. Tacrolimus capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in tacrolimus capsules. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures ¹.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

17.1 Administration

Advise the patient or caregiver to:

Inspect their tacrolimus capsules medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for tacrolimus capsules.

Take tacrolimus capsules at the same 12-hour intervals every day to achieve consistent blood concentrations.

Take tacrolimus capsules consistently either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus.

Not to eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)] .

17.2 Development of Lymphoma and Other Malignancies

Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions (5.1)] .

17.3 Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions (5.2)] .

17.4 New Onset Diabetes After Transplant

Inform patients that tacrolimus capsules can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions (5.4)] .

17.5 Nephrotoxicity

Inform patients that tacrolimus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.5)] .

17.6 Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.6)] .

17.7 Hyperkalemia

Inform patients that tacrolimus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.7)].

17.8 Hypertension

Inform patients that tacrolimus can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions (5.8)].

17.9 Thrombotic Microangiopathy

Inform patients that tacrolimus can cause blood clotting problems. The risk of this occurring increases when patients take tacrolimus and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see Warnings and Precautions (5.16)] .

17.10 Drug Interactions

Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions (7)] .

17.11 Pregnancy, Lactation and Infertility

Inform women of childbearing potential that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations (8.1, 8.2, 8.3)] .

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations (8.1)] .

Based on animal studies, tacrolimus may affect fertility in males and females [see Nonclinical Toxicology (13.1)] .

17.12 Myocardial Hypertrophy

Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).

17.13 Immunizations

Inform patients that tacrolimus can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.14)] .

Patient Information

Tacrolimus Capsules, USP, for oral use

(ta kroe′ li mus)

Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about tacrolimus capsules?

Tacrolimus capsules can cause serious side effects, including:

Increased risk of cancer.People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).

Increased risk of infection.Tacrolimus capsules are a medicine that affect your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including:

fever

sweats or chills

cough or flu-like symptoms

muscle aches

warm, red, or painful areas on your skin

What are tacrolimus capsules?

Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant.

Tacrolimus capsules are a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.

Who should not take tacrolimus capsules?

Do not take tacrolimus capsules if you:

are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete ul of ingredients in tacrolimus capsules.

What should I tell my healthcare provider before taking tacrolimus capsules?

Before taking tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you:

plan to receive any vaccines. People taking tacrolimus capsules should not receive live vaccines.

have or have had liver, kidney, or heart problems.

are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby.

If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.

Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.

There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus capsules. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/.

are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules.

plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems).

Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine,including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements.

Especially tell your healthcare provider if you take:

sirolimus (RAPAMUNE ^®): You should not take tacrolimus capsules if you take sirolimus.

cyclosporine (GENGRAF ^®, NEORAL ^®, and SANDIMUNE ^®)

medicines called aminoglycosides that are used to treat bacterial infections

ganciclovir (CYTOVENE ^®IV, VALCYTE ^®)

amphotericin B (ABELCET ^®, AMBISOME ^®)

cisplatin

antiviral medicines called nucleoside reverse transcriptase inhibitors

antiviral medicines called protease inhibitors

water pill (diuretic)

medicine to treat high blood pressure

nelfinavir (VIRACEPT ^®)

telaprevir (INCIVEK ^®)

boceprevir

ritonavir (KALETRA ^®, NORVIR ^®, TECHNIVIE ^TM, VIEKIRA PAK ^TM, VIEKIRA, XR ^TM)

letermovir (PREVYMIS ^TM)

ketoconazole

itraconazole (ONMEL ^TM, SPORANOX ^®)

voriconazole (VFEND ^®)

caspofungin (CANCIDAS ^®)

clarithromycin (BIAXIN ^®, BIAXIN XL ^®, PREVPAC ^®)

rifampin (RIFADIN ^®, RIFAMATE ^®, RIFATER ^®, RIMACTANE ^®)

rifabutin (MYCOBUTIN ^®)

amiodarone (NEXTERONE ^®, PACERONE ^®)

cannabidiol (EPIDIOLEX ^®)

Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines uled above.

Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work.

Know the medicines you take. Keep a ul of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take tacrolimus capsules?

Take tacrolimus capsules exactly as your healthcare provider tells you to take them.

Your healthcare provider will tell you how many tacrolimus capsules to take and when to take them. Your healthcare provider may change your tacrolimus capsules dose if needed. Do notstop taking or change your dose of tacrolimus capsules without talking to your healthcare provider.

Take tacrolimus capsules with or without food.

Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.

Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.

Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.

If you take too many tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away.

Tacrolimus capsules:

Do notopen or crush tacrolimus capsules.

What should I avoid while taking tacrolimus capsules?

While you take tacrolimus capsules you should not receive any live vaccines.

Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).

Do not eat grapefruit or drink grapefruit juice during treatment with tacrolimus capsules.

What are the possible side effects of tacrolimus capsules?

Tacrolimus capsules may cause serious side effects, including:

See “What is the most important information I should know about tacrolimus capsules?”

problems from medicine errors.People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as tacrolimus capsules and cannot be substituted for each other. Check your tacrolimus capsules when you get a new prescription and before you take it to make sure you have received tacrolimus capsules.

Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.

high blood sugar (diabetes).Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:

frequent urination

increased thirst or hunger

blurred vision

confusion

drowsiness

loss of appetite

fruity smell on your breath

nausea, vomiting, or stomach pain

kidney problems.Kidney problems are a serious and common side effect of tacrolimus capsules. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules.

nervous system problems.Nervous system problems are a serious and common side effect of tacrolimus capsules. Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem:

headache

confusion

seizures

changes in your vision

changes in behavior

coma

tremors

numbness and tingling

high levels of potassium in your blood.Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules.

high blood pressure.High blood pressure is a serious and common side effect of tacrolimus capsules. Your healthcare provider will monitor your blood pressure while you take tacrolimus capsules and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.

changes in the electrical activity of your heart (QT prolongation).

heart problems (myocardial hypertrophy).Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules:

shortness of breath

chest pain

feel lightheaded

feel faint

severe low red blood cell count (anemia).

blood clotting problems:Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.

The most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are:

infections in general, including cytomegalovirus (cmv) infection

tremors (shaking of the body)

constipation

diarrhea

headache

stomach pain

trouble sleeping

nausea

high blood sugar (diabetes)

low levels of magnesium in your blood

low levels of phosphate in your blood

swelling of the hands, legs, ankles, or feet

weakness

pain

high levels of fat in your blood

high levels of potassium in your blood

low red blood cell count (anemia)

low white blood cell count

fever

numbness or tingling in your hands and feet

inflammation of your airway (bronchitis)

fluid around your heart

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store tacrolimus capsules?

Tacrolimus capsules

Store tacrolimus capsules at room temperature between 20° to 25°C (68° to 77°F).

Keep tacrolimus capsules and all medicines out of the reach of children.

General information about the safe and effective use of tacrolimus capsules.

Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which they were not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals.

This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider.

What are the ingredients in tacrolimus capsules?

Active ingredient:tacrolimus

Inactive ingredients:

Tacrolimus capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.

The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.

In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Manufactured for:Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

The brands uled are trademarks of their respective owners.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Manufactured by: Haupt Pharma Amareg GmbH Donaustaufer Strasse 378 Regensburg, Bayern, 93055, Germany

Distributed by: Mylan Institutional Inc. Rockford, IL 61103 U.S.A.

S-13012 7/24

Principal Display Panel 0.5 Mg

NDC 51079-817-20

Tacrolimus Capsules, USP 0.5 mg

100 Capsules (10 x 10)

Each capsule contains: Tacrolimus, USP 0.5 mg

Usual Dosage:See accompanying prescribing information.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Made in Germany

Rx only

S-13009

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

Principal Display Panel 1 Mg

NDC 51079-818-20

Tacrolimus Capsules, USP 1 mg

100 Capsules (10 x 10)

Each capsule contains: Tacrolimus, USP 1 mg

Usual Dosage:See accompanying prescribing information.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Made in Germany

Rx only

S-13010

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

Principal Display Panel 5 Mg

NDC 51079-028-20

Tacrolimus Capsules, USP 5 mg

100 Capsules (10 x 10)

Each capsule contains: Tacrolimus, USP 5 mg

Usual Dosage:See accompanying prescribing information.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Made in Germany

Rx only

S-13011

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults
Patient Population	Tacrolimus 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

Table 2. Comparative Dose and Trough Concentrations Based on Race
	Caucasian N = 114	African-American N = 56
Time After Transplant	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

Table 3. Summary of Initial Tacrolimus Capsule Dosage Recommendations and Whole Blood Trough Concentration Range in Children
Patient Population	Initial Tacrolimus Capsule Dosing	Whole Blood Trough Concentration Range
Pediatric liver transplant patients See Clinical Studies (14.2), Liver Transplantation.	0.15-0.2 mg/kg/day capsules divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL

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%

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)
	Tacrolimus (Group C) (N = 403)	Cyclosporine (Group A) (N = 384)	Cyclosporine (Group B) (N = 408)
Diarrhea	25%	16%	13%
Urinary Tract Infection	24%	28%	24%
Anemia	17%	19%	17%
Hypertension	13%	14%	12%
Leukopenia	13%	10%	10%
Edema Peripheral	11%	12%	13%
Hyperlipidemia	10%	15%	13%
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)
	Tacrolimus/MMF (N = 212)	Cyclosporine/MMF (N = 212)
Gastrointestinal Disorders
Diarrhea	44%	26%
Nausea	39%	47%
Constipation	36%	41%
Vomiting	26%	25%
Dyspepsia	18%	15%
Injury, Poisoning, and Procedural Complications
Post-Procedural Pain	29%	27%
Incision Site Complication	28%	23%
Graft Dysfunction	24%	18%
Metabolism and Nutrition Disorders
Hypomagnesemia	28%	22%
Hypophosphatemia	28%	21%
Hyperkalemia	26%	19%
Hyperglycemia	21%	15%
Hyperlipidemia	18%	25%
Hypokalemia	16%	18%
Nervous System Disorders
Tremor	34%	20%
Headache	24%	25%
Blood and Lymphatic System Disorders
Anemia	30%	28%
Leukopenia	16%	12%
Miscellaneous
Edema Peripheral	35%	46%
Hypertension	32%	35%
Insomnia	30%	21%
Urinary Tract Infection	26%	22%
Blood Creatinine Increased	23%	23%

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. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)
	Tacrolimus/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%

Table 9. 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/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%)
HbA _1c≥ 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%)

Table 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)
Status of PTDM 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.	Tacrolimus/AZA	CsA/AZA
Patients without pre-transplant history of diabetes mellitus	151	151
New onset PTDM , 1 ^stYear	30/151 (20%)	6/151 (4%)
Still insulin-dependent at one year in those without prior history of diabetes	25/151 (17%)	5/151 (3%)
New onset PTDM post 1 year	1	0
Patients with PTDM at 2 years	16/151 (11%)	5/151 (3%)

Table 11. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial
Patient Race	Patients Who Developed PTDM 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.
	Tacrolimus	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%)

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

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

Table 14: Effects of Other Drugs/Substances on Tacrolimus Tacrolimus dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.
Drug/Substance Class or Name	Drug Interaction Effect	Recommendations
Grapefruit or grapefruit juice High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor.	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)] .	Avoid grapefruit or grapefruit juice.
Strong CYP3A Inducers Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate). : Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort	May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.11)] .	Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] .
Strong CYP3A Inhibitors : Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenantheraextracts	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions (5.6, 5.11, 5.12)] .	Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] . Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions (5.11)] .
Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)] .	Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] .
Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)] .	Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)and Clinical Pharmacology (12.3)] .
Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone	May decrease tacrolimus whole blood trough concentrations.	Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)] .
Caspofungin	May decrease tacrolimus whole blood trough concentrations.	Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)] .

Table 15. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus
	Kidney	Liver
Pregnancy Outcomes Includes multiple births and terminations.	462	253
Miscarriage	24.5%	25%
Live births	331	180
Pre-term delivery (< 37 weeks)	49%	42%
Low birth weight (< 2500 g)	42%	30%
Birth defects	8% Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.	5%

Table 16. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients
Population	N	Route (Dose)	Parameters
C _max (ng/mL)	T _max (hr)	AUC (ng•hr/mL)	t _1/2 (hr)	CL (L/hr/kg)	V (L/kg)
Healthy Volunteers	8	IV (0.025 mg/kg/4hr)	Not applicable		652 AUC 0-inf± 156	34.2 ± 7.7	0.040 ± 0.009	1.91 ± 0.31
16	PO (5 mg) (capsules)	28.8 ± 8.9	1.5 ± 0.7	266 ± 95	32.3 ± 8.8	Not available
		IV (0.02 mg/kg/12 hr)			294 ± 262	18.8 ± 16.7	0.083 ± 0.050	1.41 ± 0.66
Kidney Transplant Patients	26	PO (0.2 mg/kg/day)	19.2 ± 10.3	3.0	203 ± 42
		PO (0.3 mg/kg/day)	24.2 ± 15.8	1.5	288 ± 93
Liver Transplant Patients	17	IV (0.05 mg/kg/12 hr)			3300 ± 2130	11.7 ± 3.9	0.053 ± 0.017	0.85 ± 0.30
PO (0.3 mg/kg/day)	68.5 ± 30.0	2.3 ± 1.5	519 ± 179
	11	IV (0.01 mg/kg/day as a continuous infusion)			954 AUC 0-t± 334	23.6 ± 9.22	0.051 ± 0.015
Heart Transplant Patients	11	PO (0.075 mg/kg/day) Determined after the first dose	14.7 ± 7.79	2.1 [0.5-6.0] Median [range]	82.7 AUC 0-12± 63.2
	14	PO (0.15 mg/kg/day)	24.5 ± 13.7	1.5 [0.4-4.0]	142 ± 116

Table 17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients
Population (No. of Patients)	Dose	AUC _0-t (ng•hr/mL)	t _1/2 (hr)	V (L/kg)	CL (L/hr/kg)
Renal Impairment (n = 12)	0.02 mg/kg/4 hr IV	393 ± 123 (t = 60 hr)	26.3 ± 9.2	1.07 ± 0.20	0.038 ± 0.014
Mild Hepatic Impairment (n = 6)	0.02 mg/kg/4 hr IV	367 ± 107 (t = 72 hr)	60.6 ± 43.8 Range: 27.8 ˗ 141	3.1 ± 1.6	0.042 ± 0.02
7.7 mg PO	488 ± 320 (t = 72 hr)	66.1 ± 44.8 Range: 29.5˗138	3.7 ± 4.7 Corrected for bioavailability	0.034 ± 0.019
Severe Hepatic Impairment (n = 6, IV)	0.02 mg/kg/4 hr IV (n = 2)	762 ± 204 (t = 120 hr)	198 ± 158 Range:81 ˗ 436	3.9 ± 1.0	0.017 ± 0.013
0.01 mg/kg/8 hr IV (n = 4)	289 ± 117 (t = 144 hr)
(n = 5, PO) 1 patient did not receive the PO dose	8 mg PO (n = 1)	658 (t = 120 hr)	119 ± 35 Range: 85 ˗ 178	3.1 ± 3.4	0.016 ± 0.011
	5 mg PO (n = 4)	533 ± 156 (t = 144 hr)
	4 mg PO (n = 1)

Table 18. Estimated Creatinine Clearance at 12 Months (Study 1)
Group	eCL _cr[mL/min] at Month 12 All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.
	N	MEAN	SD	MEDIAN	Treatment Difference with Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. )
(A) CsA/MMF/CS	390	56.5	25.8	56.9	-8.6 (-13.7, -3.7)
(B) CsA/MMF/CS/Daclizumab	399	58.9	25.6	60.9	-6.2 (-11.2, -1.2)
(C) Tac/MMF/CS/Daclizumab	401	65.1	27.4	66.2	-
(D) Siro/MMF/CS/Daclizumab	399	56.2	27.4	57.3	-8.9 (-14.1, -3.9)
Total	1589	59.2	26.8	60.5
Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus

Table 19. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)
	Group A N = 390	Group B N = 399	Group C N = 401	Group D N = 399
Overall Failure	141 (36.2%)	126 (31.6%)	82 (20.4%)	185 (46.4%)
Components of efficacy failure
BPAR	113 (29.0%)	106 (26.6%)	60 (15.0%)	152 (38.1%)
Graft loss excluding death	28 (7.2%)	20 (5.0%)	12 (3.0%)	30 (7.5%)
Mortality	13 (3.3%)	7 (1.8%)	11 (2.7%)	12 (3.0%)
Lost to follow-up	5 (1.3%)	7 (1.8%)	5 (1.3%)	6 (1.5%)
Treatment Difference of efficacy failure compared to Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.)	15.8% (7.1%, 24.3%)	11.2% (2.7%, 19.5%)	-	26.0% (17.2%, 34.7%)
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab

Table 20. Tacrolimus Whole Blood Trough Concentration Range (Study 1)
Time	Median (P10-P90 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac ) tacrolimus whole blood trough concentration range (ng/mL)
Day 30 (N = 366)	6.9 (4.4 – 11.3)
Day 90 (N = 351)	6.8 (4.1 – 10.7)
Day 180 (N = 355)	6.5 (4.0 – 9.6)
Day 365 (N = 346)	6.5 (3.8 – 10.0)

Table 21. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)
Time period (Days)	Time-averaged MMF dose (grams per day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
	Less than 2.0	2.0	Greater than 2.0
0-30 (N = 364)	37%	60%	2%
0-90 (N = 373)	47%	51%	2%
0-180 (N = 377)	56%	42%	2%
0-365 (N = 380)	63%	36%	1%
Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

Table 22. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)
	Tacrolimus/MMF (N = 212)	Cyclosporine/MMF (N = 212)
Overall Failure	32 (15.1%)	36 (17.0%)
Components of efficacy failure
BPAR	16 (7.5%)	29 (13.7%)
Graft loss excluding death	6 (2.8%)	4 (1.9%)
Mortality	9 (4.2%)	5 (2.4%)
Lost to follow-up	4 (1.9%)	1 (0.5%)
Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI 95% confidence interval calculated using Fisher's Exact Test.)		1.9% (-5.2%, 9.0%)

Table 23. Tacrolimus Whole Blood Trough Concentration Range (Study 2)
Time	Median (P10-P90 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac. ) tacrolimus whole blood trough concentration range (ng/mL)
Day 30 (N = 174)	10.5 (6.3 – 16.8)
Day 60 (N = 179)	9.2 (5.9 – 15.3)
Day 120 (N = 176)	8.3 (4.6 – 13.3)
Day 180 (N = 171)	7.8 (5.5 – 13.2)
Day 365 (N = 178)	7.1 (4.2 – 12.4)

Table 24. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)
Time period (Days)	Time-averaged MMF dose (g/day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.
Less than 2.0	2.0	Greater than 2.0
0-30 (N = 212)	25%	69%	6%
0-90 (N = 212)	41%	53%	6%
0-180 (N = 212)	52%	41%	7%
0-365 (N = 212)	62%	34%	4%
Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

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MMF = Mycophenolate mofetil
ADULT
Patient Population	Initial Oral Dosage	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
PEDIATRIC
Patient Population	Initial Oral Dosage	Whole Blood Trough Concentration Range
Liver Transplant
	0.15-0.2 mg/kg/day capsules divided in two doses, every 12 hours	Month 1-12: 5-20 ng/mL

Tacrolimus Capsules, USP, for oral use (ta kroe′ li mus)
Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about tacrolimus capsules? Tacrolimus capsules can cause serious side effects, including: Increased risk of cancer.People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). Increased risk of infection.Tacrolimus capsules are a medicine that affect your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including:
	fever sweats or chills cough or flu-like symptoms	muscle aches warm, red, or painful areas on your skin
What are tacrolimus capsules? Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant. Tacrolimus capsules are a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.
Who should not take tacrolimus capsules? Do not take tacrolimus capsules if you: are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete ul of ingredients in tacrolimus capsules.
What should I tell my healthcare provider before taking tacrolimus capsules? Before taking tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you: plan to receive any vaccines. People taking tacrolimus capsules should not receive live vaccines. have or have had liver, kidney, or heart problems. are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby. If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you. Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you. There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus capsules. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/. are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules. plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems). Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine,including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements. Especially tell your healthcare provider if you take: sirolimus (RAPAMUNE ^®): You should not take tacrolimus capsules if you take sirolimus. cyclosporine (GENGRAF ^®, NEORAL ^®, and SANDIMUNE ^®) medicines called aminoglycosides that are used to treat bacterial infections ganciclovir (CYTOVENE ^®IV, VALCYTE ^®) amphotericin B (ABELCET ^®, AMBISOME ^®) cisplatin antiviral medicines called nucleoside reverse transcriptase inhibitors antiviral medicines called protease inhibitors water pill (diuretic) medicine to treat high blood pressure nelfinavir (VIRACEPT ^®) telaprevir (INCIVEK ^®) boceprevir ritonavir (KALETRA ^®, NORVIR ^®, TECHNIVIE ^TM, VIEKIRA PAK ^TM, VIEKIRA, XR ^TM) letermovir (PREVYMIS ^TM) ketoconazole itraconazole (ONMEL ^TM, SPORANOX ^®) voriconazole (VFEND ^®) caspofungin (CANCIDAS ^®) clarithromycin (BIAXIN ^®, BIAXIN XL ^®, PREVPAC ^®) rifampin (RIFADIN ^®, RIFAMATE ^®, RIFATER ^®, RIMACTANE ^®) rifabutin (MYCOBUTIN ^®) amiodarone (NEXTERONE ^®, PACERONE ^®) cannabidiol (EPIDIOLEX ^®) Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines uled above. Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work. Know the medicines you take. Keep a ul of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take tacrolimus capsules? Take tacrolimus capsules exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many tacrolimus capsules to take and when to take them. Your healthcare provider may change your tacrolimus capsules dose if needed. Do notstop taking or change your dose of tacrolimus capsules without talking to your healthcare provider. Take tacrolimus capsules with or without food. Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food. Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m. Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level. If you take too many tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away. Tacrolimus capsules: Do notopen or crush tacrolimus capsules.
What should I avoid while taking tacrolimus capsules? While you take tacrolimus capsules you should not receive any live vaccines. Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF). Do not eat grapefruit or drink grapefruit juice during treatment with tacrolimus capsules.
What are the possible side effects of tacrolimus capsules? Tacrolimus capsules may cause serious side effects, including: See “What is the most important information I should know about tacrolimus capsules?” problems from medicine errors.People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as tacrolimus capsules and cannot be substituted for each other. Check your tacrolimus capsules when you get a new prescription and before you take it to make sure you have received tacrolimus capsules. Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. high blood sugar (diabetes).Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:
	frequent urination increased thirst or hunger blurred vision confusion	drowsiness loss of appetite fruity smell on your breath nausea, vomiting, or stomach pain
kidney problems.Kidney problems are a serious and common side effect of tacrolimus capsules. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules. nervous system problems.Nervous system problems are a serious and common side effect of tacrolimus capsules. Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem:
	headache confusion seizures changes in your vision	changes in behavior coma tremors numbness and tingling
high levels of potassium in your blood.Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules. high blood pressure.High blood pressure is a serious and common side effect of tacrolimus capsules. Your healthcare provider will monitor your blood pressure while you take tacrolimus capsules and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home. changes in the electrical activity of your heart (QT prolongation). heart problems (myocardial hypertrophy).Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules:
	shortness of breath chest pain	feel lightheaded feel faint
severe low red blood cell count (anemia). blood clotting problems:Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase. The most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are:
infections in general, including cytomegalovirus (cmv) infection tremors (shaking of the body) constipation diarrhea headache stomach pain trouble sleeping nausea high blood sugar (diabetes) low levels of magnesium in your blood low levels of phosphate in your blood		swelling of the hands, legs, ankles, or feet weakness pain high levels of fat in your blood high levels of potassium in your blood low red blood cell count (anemia) low white blood cell count fever numbness or tingling in your hands and feet inflammation of your airway (bronchitis) fluid around your heart
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store tacrolimus capsules? Tacrolimus capsules Store tacrolimus capsules at room temperature between 20° to 25°C (68° to 77°F). Keep tacrolimus capsules and all medicines out of the reach of children.
General information about the safe and effective use of tacrolimus capsules. Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which they were not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals. This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider.
What are the ingredients in tacrolimus capsules? Active ingredient:tacrolimus Inactive ingredients: Tacrolimus capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10. In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Manufactured for:Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. The brands uled are trademarks of their respective owners. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

Tacrolimus (tacrolimus 5 mg) Dailymed

Drug Classes

Version History

Generic: tacrolimus is used for the treatment of Dermatitis, Atopic Graft vs Host Disease

Boxed Warning

Warning: Malignancies And Serious Infections

FDA Adverse Reactions

Recent Major Changes Section

Warning: Malignancies And Serious Infections

1 Indications And Usage

1.1 Prophylaxis of Organ Rejection in Kidney, Liver, or Heart Transplant

2 Dosage And Administration

2.1 Important Administration Instructions

2.2 Dosage Recommendations for Adult Kidney, Liver, or Heart Transplant Patients - Capsules

2.3 Dosage Recommendations for Pediatric Liver Transplant Patients

2.4 Dosage Modification for Patients with Renal Impairment

2.5 Dosage Modification for Patients with Hepatic Impairment

2.6 Therapeutic Drug Monitoring

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1 Lymphoma and Other Malignancies

5.2 Serious Infections

5.3 Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors

5.4 New Onset Diabetes After Transplant

5.5 Nephrotoxicity Due to Tacrolimus and Drug Interactions

5.6 Neurotoxicity

5.7 Hyperkalemia

5.8 Hypertension

5.9 Anaphylactic Reactions with Tacrolimus Injection

5.10 Not Recommended for Use with Sirolimus

5.11 Interactions with CYP3A4 Inhibitors and Inducers

5.12 QT Prolongation

5.13 Myocardial Hypertrophy

5.14 Immunizations

5.15 Pure Red Cell Aplasia

5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura)

5.17 Cannabidiol Drug Interactions

6 Adverse Reactions

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 Drug Interactions

7.1 Mycophenolic Acid

7.2 Effects of Other Drugs on Tacrolimus

7.3 Cannabidiol

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Race or Ethnicity

10 Overdosage

11 Description

12 Clinical Pharmacology

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1 Kidney Transplantation

14.2 Liver Transplantation

14.3 Heart Transplantation

15 References

16 How Supplied/storage And Handling

16.1 Tacrolimus Capsules

16.4 Handling and Disposal

17 Patient Counseling Information

17.1 Administration

17.2 Development of Lymphoma and Other Malignancies

17.3 Increased Risk of Infection

17.4 New Onset Diabetes After Transplant

17.5 Nephrotoxicity

17.6 Neurotoxicity

17.7 Hyperkalemia

17.8 Hypertension

17.9 Thrombotic Microangiopathy

17.10 Drug Interactions