TACROLIMUS capsule, gelatin coated

Tacrolimus by

Drug Labeling and Warnings

Tacrolimus by is a Prescription medication manufactured, distributed, or labeled by Panacea Biotec Limited, Panacea Biotec Pharma Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    BOXED WARNING - MALIGNANCIES AND SERIOUS INFECTIONS

    • Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions (5.2)].
    • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.3, 5.4, 5.5)].
    • Only physicians experienced in immunosuppressive therapy and management oforgan transplant patients should prescribe Tacrolimus Capsules USP. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.1)].
  • 1 INDICATIONS AND USAGE

    1.1 Prophylaxis of Organ Rejection in Kidney Transplant

    Tacrolimus Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Tacrolimus be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies (14.1)]. Therapeutic drug monitoring is recommended for all patients receiving Tacrolimus Capsules USP [see Dosage and Administration (2.6)].

    1.2 Prophylaxis of Organ Rejection in Liver Transplant

    Tacrolimus Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Tacrolimus be used concomitantly with adrenal corticosteroids [see Clinical Studies (14.2)]. Therapeutic drug monitoring is recommended for all patients receiving Tacrolimus Capsules USP [see Dosage and Administration (2.6)].

    1.3 Prophylaxis of Organ Rejection in Heart Transplant

    Tacrolimus Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Tacrolimus Capsules USP be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies (14.3)]. Therapeutic drug monitoring is recommended for all patients receiving Tacrolimus Capsules USP [see Dosage and Administration (2.6)].

    1.4 Limitations of Use

    Tacrolimus Capsules USP should not be used simultaneously with cyclosporine [see Dosage and Administration (2.5)].

    Tacrolimus Injection should be reserved for patients unable to take Tacrolimus Capsules USP orally [see Dosage and Administration (2.1) and see Warnings and Precautions (5.11)].

    Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of Tacrolimus with sirolimus has not been established in kidney transplant [see Warnings and Precautions (5.12)].

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Dosage in Adult Kidney, Liver or Heart Transplant Patients

    The initial oral dosage recommendations for adult patients with kidney, liver or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Tacrolimus Capsules USP 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 USP may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Dosage and Administration (2.6).

    Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults
    Patient PopulationRecommended Tacrolimus
    Capsules USP Initial Oral
    Dosage
    Note: daily doses should be
    administered as two divided
    doses, every 12 hours    		Observed Tacrolimus Whole
    Blood Trough Concentrations
    Adult kidney transplant patients

    In combination with azathioprine


    In combination with MMF/IL-2 receptor
    antagonist a

    0.2 mg/kg/day


    0.1 mg/kg/day

    month 1-3: 7-20 ng/mL
    month 4-12: 5-15 ng/mL

    month 1-12: 4-11 ng/mL
    Adult liver transplant patients0.10-0.15 mg/kg/daymonth 1-12: 5-20 ng/mL
    Adult heart transplant patients0.075 mg/kg/daymonth 1-3: 10-20 ng/mL
    month ≥4: 5-15 ng/mL

    a) 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)].

    Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

    The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

    Table 2. Comparative Dose and Trough Concentrations Based on Race
    Time After TransplantCaucasian
    n=114    		Black
    n=56
    Dose (mg/kg)Trough Concentrations(ng/mL)Dose  (mg/kg)Trough Concentrations(ng/mL)
    Day 70.1812.00.2310.9
    Month 10.1712.80.2612.9
    Month 60.1411.80.2411.5
    Month 120.1310.10.1911.0

    Initial Dose - Injection

    Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Tacrolimus Capsules USP. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of Tacrolimus Capsules USP, usually within 2-3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

    The observed trough concentrations described above pertain to oral administration of Tacrolimus Capsules USP only; while monitoring tacrolimus concentrations in patients receiving Tacrolimus injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

    The recommended starting dose of Tacrolimus injection is 0.03-0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

    Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Tacrolimus injection [see Warnings and Precautions (5.11)].

    2.2 Dosage in Pediatric Liver Transplant Patients

    The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03-0.05 mg/kg/day.

    Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children
    Patient PopulationRecommended Tacrolimus Capsules USP Initial Oral Dosage
    Note: daily doses should be administered as two divided doses, every 12 hours    		Observed Tacrolimus Whole Blood Trough Concentrations
    Pediatric liver transplant patients0.15- 0.20 mg/kg/dayMonth 1-12: 5-20 ng/ mL

    Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

    Experience in pediatric kidney and heart transplantation patients is limited.

    2.3 Dosage Adjustment in Patients with Renal Impairment

    Due to its potential for nephrotoxicity, consideration should be given to dosing Tacrolimus Capsules USP 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 USP 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.

    2.4 Dosage Adjustments in Patients with Hepatic Impairment

    Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of Tacrolimus. Close monitoring of blood concentrations is warranted.

    The use of Tacrolimus Capsules USP 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

    2.5 Administration Instructions

    It is recommended that patients initiate oral therapy with Tacrolimus Capsules USP if possible.Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

    It is important to take Tacrolimus Capsules USP consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Clinical Pharmacology (12.3)].

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

    Tacrolimus Capsules USP should not be used simultaneously with cyclosporine. Tacrolimus Capsules USP 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.

    In patients unable to take oral Tacrolimus Capsules USP, therapy may be initiated with Tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Tacrolimus Capsules USP is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

    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. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

    The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

    Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery >90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months.

  • 3 DOSAGE FORMS AND STRENGTHS

    Oblong shape, hard gelatin capsules for oral administration contains tacrolimus USP as follows:

    • Tacrolimus Capsules USP, 0.5 mg: Light yellow color, oblong shape , size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on cap and body respectively.
    • Tacrolimus Capsules USP, 1 mg:  White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.
    • Tacrolimus Capsules USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.
  • 4 CONTRAINDICATIONS

    Tacrolimus capsule USP is 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) or any components of the formulation. Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Management of Immunosuppression

    Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Tacrolimus Capsules USP. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow up of the patient [see Boxed Warning].

    5.2 Lymphoma and Other Malignancies

    Patients receiving immunosuppressants, including Tacrolimus Capsules USP, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Boxed Warning]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

    As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

    Post transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.

    5.3 Serious Infections

    Patients receiving immunosuppressants, including Tacrolimus Capsules USP, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Boxed Warning and Warnings and Precautions (5.4, 5.5)]. These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

    5.4 Polyoma Virus Infections

    Patients receiving immunosuppressants, including Tacrolimus Capsules USP, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus [see Adverse Reactions (6.2)].

    PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.2)]. Patient monitoring may help detect patients at risk for PVAN.

    Cases of PML have been reported in patients treated with Tacrolimus Capsules USP. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

    Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

    5.5 Cytomegalovirus (CMV) Infections

    Patients receiving immunosuppressants, including Tacrolimus Capsules USP, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease.

    5.6 New Onset Diabetes After Transplant

    Tacrolimus Capsules USP was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions (6.1)].

    5.7 Nephrotoxicity

    Tacrolimus Capsules USP, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely as the dosage of Tacrolimus Capsules USP may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy.

    Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Tacrolimus Capsules USP in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial [see Adverse Reactions (6.1)].

    Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Tacrolimus Capsules USP with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism [see Drug Interactions (7.3, 7.4, 7.5, 7.6)].

    5.8 Neurotoxicity

    Tacrolimus Capsules USP may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with tacrolimus have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

    Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in adult and pediatric patients receiving tacrolimus [see Adverse Reactions (6.1)].

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

    5.9 Hyperkalemia

    Hyperkalemia has been reported with Tacrolimus Capsules USP use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy [see Adverse Reactions (6.1)].

    5.10 Hypertension

    Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.9)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.5)].

    5.11 Anaphylactic Reactions with Tacrolimus Injection

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

    Patients receiving Tacrolimus injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.

    5.12 Use with Sirolimus

    The safety and efficacy of tacrolimus with sirolimus has not been established in kidney transplant patients. Use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended [see Indications and Usage (1.4)].

    Use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)].

    5.13 Use with CYP3A4 Inhibitors and Inducers

    When coadministering Tacrolimus with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of Tacrolimus and subsequent frequent  monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see Drug Interactions (7)].

    5.14 QT Prolongation

    Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid Tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. 

    When coadministering tacrolimus 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)].

    5.15 Myocardial Hypertrophy

    Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Tacrolimus Capsules USP should be considered [see Adverse Reactions (6.2)].

    5.16 Immunizations

    The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

    5.17 Pure Red Cell Aplasia

    Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of Tacrolimus Capsules USP should be considered [see Adverse Reactions(6.2)].

    5.18 Gastrointestinal Perforation

    Gastrointestinal perforation has been reported in patients treated with Tacrolimus; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly [see Adverse Reactions (6.1)].

  • 6 ADVERSE REACTIONS

    The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

    6.1 Clinical Studies Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

    Kidney Transplant

    The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

    Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in 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%), Black (25%), Hispanic (12%) and Other (5%). The 12 month post-transplant information from this trial is presented below.

    The most common adverse reactions (≥ 30%) observed in 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.

    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 Capsules USP
    /AZA
    (N=205)    		Cyclosporine/AZA
    (N=207)
    Nervous system
    Tremor 54%34%
    Headache 44%38%
    Insomnia32%30%
    Paresthesia23%16%
    Dizziness19%16%
    Gastrointestinal
    Diarrhea44%41%
    Nausea38%36%
    Constipation35%43%
    Vomiting 29%23%
    Dyspepsia28%20%
    Cardiovascular
    Hypertension50%52%
    Chest Pain19%13%
    Urogenital
    Creatinine increased 45%42%
    Urinary tract infection34%35%
    Metabolic and Nutritional
    Hypophosphatemia49%53%
    Hypomagnesemia34%17%
    Hyperlipemia31%38%
    Hyperkalemia 31%32%
    Diabetes mellitus 24%9%
    Hypokalemia22%25%
    Hyperglycemia22%16%
    Edema18%19%
    Hemic and Lymphatic
    Anemia30%24%
    Leucopenia15%17%
    Miscellaneous
    Infection45%49%
    Peripheral edema36%48%
    Asthenia34%30%
    Abdominal pain33%31%
    Pain32%30%
    Fever29%29%
    Back pain24%20%
    Respiratory System
    Dyspnea22%18%
    Cough increased18%15%
    Musculoskeletal
    Arthralgia25%24%
    Skin
    Rash17%12%
    Pruritus15%7%

    Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received Tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76), the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below.

    Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with Tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

    Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)




    Diarrhea
    Urinary tract infection
    Anemia
    Hypertension
    Leucopenia
    Edema peripheral
    Hyperlipidemia    		Tacrolimus Capsules USP
    (group C)
    (N=403)
    25%
    24%
    17%
    13%
    13%
    11%
    10%    		Cyclosporine
    (Group A)
    (N=384)
    16%
    28%
    19%
    14%
    10%
    12%
    15%    		Cyclosporine
    (Group B)
    (N=408)
    13%
    24%
    17%
    12%
    10%
    13%
    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%), Black (20%), Asian (3%) and other (3%). The 12 month post-transplant information from this trial is presented below.

    Adverse reactions that occurred in ≥15% of kidney transplant patients treated with Tacrolimus in conjunction with MMF in Study 2 are presented below:

    Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

    Tacrolimus Capsules USP / MMF
    (N=212)    		Cyclosporine / MMF
    (N=212)
    Gastrointestinal Disorder
    Diarrhea44%26%
    Nausea39%47%
    Constipation36%41%
    Vomiting26%25%
    Dyspepsia18%15%
    Injury, Poisoning, and Procedural Complications
    Post Procedural Pain29%27%
    Incision Site Complication28%23%
    Graft Dysfunction24%18%
    Metabolism and Nutrition Disorder
    Hypomagnesemia28%22%
    Hypophosphatemia28%21%
    Hyperkalemia 26%19%
    Hyperglycemia21%15%
    Hyperlipidemia18%25%
    Hypokalemia16%18%
    Nervous System Disorder
    Tremor34%20%
    Headache24%25%
    Blood and Lymphatic  System Disorders
    Anemia30%28%
    Leukopenia16%12%
    Miscellaneous
    Edema Peripheral35%46%
    Hypertension 32%35%
    Insomnia30%21%
    Urinary Tract Infection26%22%
    Blood Creatinine Increased23%23%

    Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

    Liver Transplantation

    There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to70), the distribution was 52% male, and the composition was White (78%), Black (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68), the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%) and Other (2%).

    The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

    The most common adverse reactions (≥40%) observed in 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.

    Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus

    U.S. TRIALEUROPEAN TRIAL
    Tacrolimus Capsules USP  (N=250)Cyclosporine/AZA(N=250)Tacrolimus Capsules USP  (N=264)Cyclosporine/AZA(N=265)
    Nervous system
    Headache 64%60%37%26%
    Insomnia64%68%32%23%
    Tremor56%46%48%32%
    Paresthesia40%30%17%17%
    Gastrointestinal
    Diarrhea72%47%37%27%
    Nausea46%37%32%27%
    LFT Abnormal36%30%6%5%
    Anorexia34%24%7%5%
    Vomitting27%15%14%11%
    Constipation24%27%23%21%
    Cardiovascular
    Hypertension47%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 Infection16%18%21%19%
    Metabolic and Nutritional
    Hypomagnesemia48%45%16%9%
    Hyperglycemia47%38%33%22%
    Hyperkalemia45%26%13%9%
    Hypokalemia29%34%13%16%
    Hemic and Lymphatic
    Anemia47%38%5%1%
    Leukocytosis32%26%8%8%
    Thrombocytopenia24%20%14%19%
    Miscellaneous
    Pain63%57%24%22%
    Abdominal Pain59%54%29%22%
    Asthenia52%48%11%7%
    Fever48%56%19%22%
    Back pain30%29%17%17%
    Ascites27%22%7%8%
    Peripheral edema26%26%12%14%
    Respiratory System
    Pleural effusion30%32%36%35%
    Dyspnea29%23%5%4%
    Atelectasis28%30%5%4%
    Skin and Appendages
    Pruritus36%20%15%7%
    Rash24%19%10%4%

    Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

    Heart Transplantation

    The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine (AZA) in combination with 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.

    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 Capsules USP in Conjunction with Azathioprine (AZA)

    Tacrolimus
    Capsules
    USP/AZA
    (n=157)    		Cyclosporine/AZA
    (n=157)
    Cardiovascular System
    Hypertension62%69%
    Pericardial Effusion
    		15%14%
    Body as a Whole
    CMV Infection32%30%
    Infection24%21%
    Metabolic and Nutritional Disorders
    Diabetes Mellitus26%16%
    Hyperglycemia23%17%
    Hyperlipemia18%27%
    Hemic and Lymphatic System
    Anemia50%36%
    Leukopenia48%39%
    Urogenital System
    Kidney Function Abnormal56%57%
    Urinary Tract Infection16%12%
    Respiratory System
    Bronchitis17%18%
    Nervous System
    Tremor15%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%), Black (13%) and other (4%).

    Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin <10.0 g/dL) (65%), fasting blood glucose >140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs <3000 cells/mcL (34%), serious bacterial infections (30%), magnesium <1.2 mEq/L (24%), platelet count <75,000 cells/mcL (19%), and other opportunistic infections (15%).

    Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome.

    New Onset Diabetes After Transplant

    Kidney Transplant

    New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA1C ≥ 6%, insulin use ≥ 30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the Neoral-treated patients without pre-transplant history of diabetes mellitus (Table 9) [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)

    ParameterTreatment Group
    Tacrolimus Capsules USP / MMF
    (n = 212)    		Neoral / MMF
    (n = 212)
    NODAT112/150 (75%)93/152 (61%)
    Fasting Plasma Glucose ≥ 126 mg/dL96/150 (64%)80/152 (53%)
    HbA1C ≥ 6%59/150 (39%)28/152 (18%)
    Insulin Use ≥ 30 days9/150 (6%)4/152 (3%)
    Oral Hypoglycemic Use15/150 (10%)5/152 (3%)

    In early trials of Tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 10 to 13. PTDM was reported in 20% of Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 10). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 11).

    Table 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)
  • * a) 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.
  • † a) 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.
  • ‡ a) 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.
  • § a) Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
    • Status of PTDM *Tacrolimus Capsules USP/AZACsA/AZA
    Patients without pretransplant history of diabetes
    mellitus.    		151151
    New onset PTDM †, 1st Year30/151 (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 year10
    Patients with PTDM § at 2 years16/151 (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

  • * a) 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.
    		•
    Patient RacePatients Who Developed PTDM *
    Tacrolimus Capsules USPCyclosporine
    Black15/41 (37%)3 (8%)
    Hispanic5/17 (29%)1 (6%)
    Caucasian10/82 (12%)1 (1%)
    Other0/11 (0%)1 (10%)
    Total30/151 (20%)6 (4%)

    Liver Transplant

    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 12). Hyperglycemia was associated with the use of Tacrolimus Capsules USP 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

  • * a) 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.
  • † b) Patients without pre-transplant history of diabetes mellitus
  • ‡ a) Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
    		•
    Status of PTDM *US TrialEuropean Trial
    Tacrolimus
    Capsules USP    		CyclosporineTacrolimus
    Capsules USP    		Cyclosporine
    Patients at risk †239236239249
    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%)

    Heart Transplant

    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 13). 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

  • * a) Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus.
  • † b) Patients without pre-transplant history of diabetes mellitus.
  • ‡ a) Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus.
  • § c) 7-12 months for the U.S. trial.
    		•
    Status of
    PTDM *    		US TrialEuropean Trial
    Tacrolimus
    Capsules
    USP/MMF     		Cyclosporine/MMFTacrolimus
    Capsules
    USP/AZA    		Cyclosporine/AZA
    Patients at
    risk †    		7583132138
    New Onset
    PTDM ‡    		10 (13%)6 (7%)29 (22%)5 (4%)
    Patients still
    on insulin at
    1 year §    		7 (9%)1 (1%)24 (18%)4 (3%)

    Less Frequently Reported Adverse Reactions (>3% and <15%)

    The following adverse reactions were reported in either liver, kidney and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

    Nervous System [see Warnings and Precautions (5.8)]

    Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired

    Special Senses

    Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

    Gastrointestinal

    Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis

    Cardiovascular

    Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation

    Urogenital

    Acute kidney failure [see Warnings and Precautions (5.7)], albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis

    Metabolic/Nutritional

    Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain

    Endocrine

    Cushing’s syndrome

    Hemic/Lymphatic

    Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased

    Miscellaneous

    Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer

    Musculoskeletal

    Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis

    Respiratory

    Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

    Skin

    Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

    6.2 Postmarketing Adverse Reactions

    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 ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy [see Warnings and Precautions (5.15)].

    Gastrointestinal

    Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease

    Hemic/Lymphatic

    Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia [see Warnings and Precautions (5.17)]

    Infections

    Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virus-associated nephropathy, (PVAN) including graft loss [see Warnings and Precautions (5.4)]

    Metabolic/Nutritional

    Glycosuria, increased amylase including pancreatitis, weight decreased

    Miscellaneous

    Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction

    Nervous System

    Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.8)], progressive multifocal leukoencephalopathy (PML) [see Warnings and Precautions (5.4)], quadriplegia, speech disorder, syncope

    Respiratory

    Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure

    Skin

    Stevens-Johnson syndrome, toxic epidermal necrolysis

    Special Senses

    Blindness, blindness cortical, hearing loss including deafness, photophobia

    Urogenital

    Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder

  • 7 DRUG INTERACTIONS

    Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see Warnings and Precautions (5.13) and Clinical Pharmacology (12.3)]. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Tacrolimus is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation [see Warnings and Precautions (5.7) and (5.14)].

    7.1 Mycophenolic Acid Products

    With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Tacrolimus Capsules USP co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Tacrolimus in patients concomitantly receiving MPA-containing products.

    7.2 Grapefruit Juice

    Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with tacrolimus [see Dosage and Administration (2.5)].

    7.3 Protease Inhibitors

    Most protease inhibitors inhibit CYP3A enzymes and may increase tacrolimus whole blood concentrations. It is recommended to avoid concomitant use of tacrolimus with nelfinavir unless the benefits outweigh the risks [see Clinical Pharmacology (12.3)]. Whole blood concentrations of tacrolimus are markedly increased when co-administered with telaprevir or with boceprevir [see Clinical Pharmacology (12.3)]. Monitoring of tacrolimus whole blood concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen are recommended when tacrolimus and other protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) are used concomitantly.

    7.4 Antifungal Agents

    Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following antifungal drugs with tacrolimus is initiated or discontinued [see Clinical Pharmacology (12.3)].

    Azoles: Voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. When initiating therapy with voriconazole or posaconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be initially reduced to one-third of the original dose and the subsequent tacrolimus doses be adjusted based on the tacrolimus whole blood concentrations.

    Caspofungin is an inducer of CYP3A and decreases whole blood concentrations of tacrolimus.

    7.5 Calcium Channel Blockers

    Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these calcium channel blocking drugs and tacrolimus are used concomitantly.

    7.6 Antibacterials

    Erythromycin, clarithromycin, troleandomycin and chloramphenicol inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

    7.7 Antimycobacterials

    Rifampin [see Clinical Pharmacology (12.3)] and rifabutin are inducers of CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these antimycobacterial drugs and tacrolimus are used concomitantly.

    7.8 Anticonvulsants

    Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. Concomitant administration of phenytoin with tacrolimus may also increase phenytoin plasma concentrations. Thus, frequent monitoring phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly.

    7.9 St. John’s Wort (Hypericum perforatum)

    St. John’s Wort induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when St. John’s Wort and tacrolimus are co-administered.

    7.10 Gastric Acid Suppressors/Neutralizers

    Lansoprazole and omeprazole, as CYP2C19 and CYP3A4 substrates, may potentially inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. Cimetidine may also inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations.

    Coadministration with magnesium and aluminum hydroxide antacids increase tacrolimus whole blood concentrations [see Clinical Pharmacology (12.3)]. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

    7.11 Others

    Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone and methylprednisolone, and herbal products containing schisandra sphenanthera extracts may inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are co-administered.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus given orally to pregnant rabbits at 0.5 to 4.3 times the clinical dose and pregnant rats at 0.8 to 6.9 times the clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Tacrolimus Capsules USP should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg, 0.5 to 4.3 times the clinical dose range (0.075 – 0.2 mg/kg) based on body surface area, was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg, 2.6 to 6.9 times the clinical dose range was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg, 0.8 to 6.9 times the recommended clinical dose range was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

    8.3 Nursing Mothers

    Tacrolimus is excreted in human milk. As the effect of chronic exposure to tacrolimus in healthy infants is not established, patients maintained on tacrolimus should discontinue nursing taking into consideration importance of drug to the mother.

    8.4 Pediatric Use

    The safety and efficacy of Tacrolimus Capsules USP in pediatric kidney and heart transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Tacrolimus Capsules USP. Two randomized active controlled trials of Tacrolimus Capsules USP in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Tacrolimus Capsules USP to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration(2.2)].

    8.5 Geriatric Use

    Clinical trials of Tacrolimus Capsules USP 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 and renal function, and of concomitant disease or other drug therapy.

    8.6 Use in 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 Capsules USP 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 (2.3) and Clinical Pharmacology (12.3)].

    8.7 Use in Hepatic Impairment

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

    The use of Tacrolimus Capsules USP 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 (2.3) and Clinical Pharmacology (12.3)].

  • 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 listed in Adverse Reactions (6) (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

    In acute oral studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; (all based on body surface area corrections).

  • 11 DESCRIPTION

    Tacrolimus is available for oral administration as capsules (Tacrolimus Capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of tacrolimus USP. Inactive ingredients include anhydrous lactose, hypromellose 2910, croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide.

    Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus Capsules USP. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*, 14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16- dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

    The chemical structure of tacrolimus USP is:

    Structural Formula

    Tacrolimus USP has a molecular formula of C44H69NO12H2O and a formula weight of 822.03. Tacrolimus appears as white to off white powder. It is soluble in acetone, chloroform, ethyl acetate and insoluble in water.

    The Dissolution Test criteria of Tacrolimus Capsules USP as outlined below: 

    Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mgComplies with USP dissolution test 4

    Tacrolimus Capsules USP comply with USP Organic Impurities test criteria as outlined below:

    Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mgUSP Procedure 1 and 2
  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12.A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

    Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

    In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

    12.3 Pharmacokinetics

    Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 14).

    Table 14. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients

  • * a) not applicable
  • † a) not applicable
  • ‡ b) AUC0-120;
  • § c) AUC0-72
  • d) Corrected for individual bioavailability
  • # d) Corrected for individual bioavailability
  • Þ a) not applicable
  • ß a) not applicable
  • à e) AUC0-inf;
  • è f) not available
  • ð f) not available
  • ø f) not available
  • ý e) AUC0-inf;
  • £ f) not available
  • ¥ f) not available
  • Œ f) not available
  • œ a) not applicable
  • Ɖ a) not applicable
  • A e) AUC0-inf;
  • B e) AUC0-inf;
  • C f) not available
  • D f) not available
  • E f) not available
  • F a) not applicable
  • G a) not applicable
  • H g) AUC0-t
  • I f) not available
  • J h) Determined after the first dose
  • K i) Median [range]
  • L j) AUC0-12
  • M a) not applicable
  • N f) not available
  • O f) not available
  • P h) Determined after the first dose
  • Q i) Median [range]
  • R j) AUC0-12
  • S a) not applicable
  • T f) not available
  • U f) not available
    		•
    PopulationNRoute
     (Dose)    		Parameters
    Cmax
    (ng/mL)    		Tmax
    (hr)    		AUC
    (nghr/mL)    		t1/2
    (hr)    		CI
    (L/hr/kg)    		V
    (L/kg)
    Healthy Volunteers8IV
    (0.025 mg/kg/4hr)    		*†598‡
    ± 125    		34.2
    ± 7.7    		0.040
    ± 0.009    		1.91
    ± 0.31
    16PO
    (5 mg)    		29.7
    ± 7.2    		1.6
    ± 0.7    		243§
    ± 73    		34.8
    ± 11.4    		0.041
    ±0.008    		1.94#
    ± 0.53
    Kidney
    Transplant
    Patients    		26IV
    (0.02 mg/kg/12 hr)    		Þß294 e
    ± 262    		18.8
    ± 16.7    		0.083
    ± 0.050    		1.41
    ± 0.66
    PO
    (0.2 mg/kg/day)    		19.2
    ± 10.3    		3.0203à
    ± 42    		èðø
    PO
    (0.3 mg/kg/day)    		24.2
    ± 15.8    		1.5288ý
    ± 93    		£¥Œ
    Liver
    Transplant
    Patients    		17IV
    (0.05 mg/kg/12 hr)    		œƉ3300A
    ± 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    		519B
    ± 179    		CDE
    Heart
    Transplant
    Patients    		11IV
    (0.01 mg/kg/day as a
    continuous infusion)    		FG954H
    ± 334    		23.6
    ± 9.22    		0.051
    ± 0.015    		I
    11PO
    (0.075 mg/kg/day)J    		14.7 ± 7.792.1
    [0.5-6.0]K    		82.7L
    ± 63.2    		MNO
    14PO
    (0.15 mg/kg/day)P    		24.5 ± 13.71.5
    [0.4-4.0]Q    		142R
    ± 116    		STU

    Due to intersubject variability in tacrolimus pharmacokinetics, individualization of 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

    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), and 18±5% in healthy volunteers (N=16).

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

    In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94.

    In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

    Food Effects

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

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

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

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

    Tacrolimus Capsules USP 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 (2.5)].

    Distribution

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

    Metabolism

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

    Excretion

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

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


    Specific Populations

    Pediatric

    Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and Cmax were 337±167 ng·hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%.

    Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration (2.2)].

    Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 (range 0.06 – 0.09) mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5.0 (range 3.4-25) hours and 0.12±0.04 (range 0.06-0.17) L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181±65 (range 81-300) ng·hr/mL and 30±11 (range 14-49) ng/mL, respectively. The absolute bioavailability was 19±14 (range 5.2-56) %.

    Renal and Hepatic Impairment

    The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in Table 15.

    Table 15.Pharmacokinetics In Renal and Hepatic Impaired Patients

  • * a corrected for bioavailability
  • † a corrected for bioavailability
  • ‡ b 1 patient did not receive the PO dose
  • § a corrected for bioavailability
  • a corrected for bioavailability
    		•
    Population
    (No. of
    Patients)    		DoseAUC0-t
    (ng-hr/mL)    		t1/2
    (hr)    		V
    (L/kg)    		CI
    (L/hr/kg)
    Renal
    Impairment
    (n=12)    		0.02
    mg/kg/4hr
    IV    		393±123
    (t=60 hr)    		26.3±9.21.07±0.200.038±0.014
    Mild Hepatic
    Impairment
    (n=6)    		0.02
    mg/kg/4hr
    IV    		367±107
    (t=72 hr)    		60.6±43.8
    Range: 27.8-141    		3.1±1.60.042±0.02
    7.7 mg
    PO    		488±320
    (t=72 hr)    		66.1±44.8
    Range: 29.5-138    		3.7±4.7 *0.034±0.019 †
    Severe
    Hepatic
    Impairment
    (n=6, IV)    		0.02 mg/kg/4hr
    IV (n=2)

    0.01 mg/kg/8hr
    IV (n=4)    		762±204
    (t=120hr)

    289±117
    (t=144 hr)    		198±158
    Range: 81-436    		3.9±1.00.017±0.013
    (n=5, PO) ‡8 mg PO
    (n=1)

    5 mg PO
    (n=4)
    4 mg PO
    (n=1)    		658
    (t=120 hr)

    533±156
    (t=144 hr)    		119±35
    Range: 85-178    		3.1±3.4 §0.016±0.011

    Renal Impairment

    Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 13) [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

    Hepatic Impairment

    Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].

    Race

    The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of Tacrolimus Capsules USP to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and Latino- Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T1/2 among 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 (2.1)]

    Gender

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

    Drug Interactions

    Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].

    Telaprevir

    In a single dose study in 9 healthy volunteers, coadministration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.3)].

    Boceprevir

    In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.3)].

    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 Capsules USP and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.3)].

    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 (7.7)].

    Magnesium-aluminum-hydroxide

    In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions (7.10)].

    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) [see Drug Interactions (7.4)].

    Voriconazole (see complete prescribing information for VFEND®)

    Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.4)].

    Posaconazole (see complete prescribing information for Noxafil®)

    Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.4)].

    Caspofungin (see complete prescribing information for CANCIDAS®)

    Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS® 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions (7.4)].

  • 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 Boxed Warning and Warnings and Precautions (5.2)].

    A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

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

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

    Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range of 0.075 to 0.2 mg/kg/day based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

  • 14 CLINICAL STUDIES

    14.1 Kidney Transplantation

    Tacrolimus/azathioprine (AZA)

    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 survival was 96.1% and 89.6%, respectively.

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

    Tacrolimus/mycophenolate mofetil (MMF)

    Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received 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 (eCLcr) using the Cockcroft-Gault formula (Table 16) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 17) in comparison to each of the other three groups. Patients randomized to 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 16. Estimated Creatinine Clearance at 12 Months (Study 1)

  • * a) 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 inputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.
  • † b) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
    		•
    GroupeCLcr[mL/min] at Month 12 *
    NMEANSDMEDIANTreatment
    Difference with
    Group C
    (99.2%CI †)
    (A) Cs A/MMF/CS39056.525.856.9-8.6 (-13.7, -3.7)
    (B) CsA/ MMF/CS/Daclizumab39958.925.660.9-6.2 (-11.2, -1.2)
    (C) Tac/ MMF/CS/Daclizumab40165.127.466.2-
    (D) Siro/ MMF/CS/Daclizumab39956.227.457.3-8.9 (-14.1, -3.9)
    Total158959.226.860.5
    Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus

    Table 17: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 1)

  • * a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
    		•
    Group A
    N=390    		Group B
    N=399    		Group C
    N=401    		Group D
    N=399
    Overall Failure
    Components of efficacy failure
    BPAR
    Graft loss excluding death
    Mortality
    Lost to follow-up
    Treatment Difference of efficacy
    failure compared to Group C
    (99.2% CI *)    		141 (36.2%)
    113 (29.0%)
    28 (7.2%)
    13 (3.3%)
    5 (1.3%)
    15.8% (7.1%, 
    24.3%)    		126 (31.6%)
    106 (26.6%)
    20 (5.0%)
    7 (1.8%)
    7 (1.8%)
    11.2% (2.7%, 
    19.5%)    		82 (20.4%)
    60 (15.0%)
    12 (3.0%)
    11 (2.7%)
    5 (1.3%)
    -    		185 (46.4%)
    152 (38.1%)
    30 (7.5%)
    12 (3.0%)
    6 (1.5%)
    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 (Ctrough, Tac) were 3-7 ng/mL; however, the observed median Ctroughs, Tac approximated 7 ng/mL throughout the 12 month trial (Table 18). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

    Table 18: Tacrolimus Whole Blood Trough Concentrations (Study 1)

  • * a) 10 to 90th Percentile: range of Ctrough, Tac that excludes lowest 10% and highest 10% of Ctrough,Tac
    • TimeMedian (P10-P90*) tacrolimus whole blood trough concentrations
    (ng/mL)
    Day 30 (N=366) 6.9 (4.4 – 11.3)
    Day 90 (N=351) 6.8 (4.1 – 10.7)
    Day 180(N=355) 6.5 (4.0 – 9.6)
    Day 365 (N=346) 6.5 (3.8 – 10.0)

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

    While patients in all groups started MMF at 1gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 19); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.

    Table 19: MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)

  • * a) 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.
    		•
    Time period (Days)Time-averaged MMF dose (g/day)*
    Less than 2.02.0Greater 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, multi-center 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 overimmunosuppression (Table 20).

    Table 20: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 2)

  • * a) 95% confidence interval calculated using Fisher's Exact Test
    		•
    Tacrolimus/MMF
    (n=212)     		Cyclosporin/MMF
    (n=212)
    Overall Failure
    Components of efficacy failure
    BPAR
    Graft loss excluding death
    Mortality
    Lost to follow-up
    Treatment Difference of efficacy
    failure compared to
    Tacrolimus/MMF group (95% CI*)    		32 (15.1%)
    16 (7.5%)
    6 (2.8%)
    9 (4.2%)
    4 (1.9%)
    -     		36 (17.0%)
    29 (13.7%)
    4 (1.9%)
    5 (2.4%)
    1 (0.5%)
    1.9% (-5.2%, 9.0%)

    The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median Ctroughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 21). Approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

    Table 21: Tacrolimus Whole Blood Trough Concentrations (Study 2)

  • * a) 10 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough, Tac
    • TimeMedian (P10-P90*) tacrolimus whole blood trough concentrations
    (ng/mL)
    Day 30 (N=174) 10.5 (6.3 - 16.8)
    Day 60 (N=179) 9.2 (5.9 - 15.3)
    Day 120 (N=176) 8.3 (4.6 - 13.3)
    Day 180 (N=171) 7.8 (5.5 - 13.2)
    Day 365 (N=178) 7.1 (4.2 - 12.4)

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

    Patients in both groups started MMF at 1gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the Tacrolimus/MMF group (Table 22) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the Tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].

    Table 22: MMF Dose Over Time in the Tacrolimus/MMF group (Study 2)

  • * a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
    • Time Period (Days)Time-averaged MMF dose (g/day) *
    Less than 2.02.0Greater 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 Capsules USP dosing was 2 days.

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

    14.3 Heart Transplantation

    Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporinebased 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 US, 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 to18 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 (5.12)].

  • 16 HOW SUPPLIED / STORAGE AND HANDLING

    16.1 Tacrolimus Capsules USP

    Tacrolimus Capsules USP, 0.5 mg: Light yellow color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on cap and body respectively.

    Capsules are supplied as follows:
    NDC     43817-421-01               Bottle of 100

    Tacrolimus Capsules USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.

    Capsules are supplied as follows:
    NDC 43817-422-01               Bottle of 100

    Tacrolimus Capsules USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.

    Capsules are supplied as follows:
    NDC 43817-423-01               Bottle of 100

    Storage:
    Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F)

  • 17 PATIENT COUNSELING INFORMATION

    17.1 Administration

    Advise patients to:

    • Take Tacrolimus Capsules USP at the same 12-hour intervals everyday to achieve consistent blood concentrations.
    • Take Tacrolimus Capsules USP 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 [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 use a sunscreen with a high protection factor [see Warnings and Precautions (5.2)].

    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 [see Warnings and Precautions (5.3, 5.4, 5.5)].

    17.4 New Onset Diabetes After Transplant

    Inform patients that Tacrolimus Capsules USP 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 (5.6)].

    17.5 Nephrotoxicity

    Inform patients that Tacrolimus Capsules USP 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 (5.7)].

    17.6 Neurotoxicity

    Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, deliriums, or tremors [see Warnings and Precautions (5.8)].

    17.7 Hyperkalemia

    Inform patients that Tacrolimus Capsules USP 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 (5.9)].

    17.8 Hypertension

    Inform patients that Tacrolimus Capsules USP can cause high blood pressure which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.10)].

    17.9 Drug Interactions

    Instruct patients to tell their health care providers when they start or stop taking all the medicines, including prescription medicines and non-prescription medicines, natural or herbal remedies, nutritional supplements and vitamins [see Drug Interactions (7)].

    17.10 Pregnant Women and Nursing Mothers

    Instruct patients to tell their healthcare provider if they plan to become pregnant or breast-feed their infant [see Use in Specific Populations (8.1, 8.3)].

    17.11 Immunizations

    Inform patients that Tacrolimus Capsules USP can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.16)].

  • SPL UNCLASSIFIED SECTION

    Rx only

    Manufactured by:
    Panacea Biotec Ltd
    Malpur, Baddi,
    Distt. Solan (H.P.) – 173205, India

    Mfg.Lic.No: MB/05/203

    Distributed by:
    Bionpharma Inc., 600 Alexander Road,
    Princeton, NJ 08540, USA.

    Item Code: SRTP001
    Revised Date:     July 2017

  • Patient Information

    Tacrolimus Capsules USP
    (tacrolimus) capsules USP

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

    What is the most important information I should know about Tacrolimus Capsules USP?

    Tacrolimus Capsules USP can cause serious side effects, including:

    1. Increased risk of cancer. People who take Tacrolimus Capsules USP have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
    2. Increased risk of infection. Tacrolimus Capsules USP is a medicine that affects your immune system. Tacrolimus Capsules USP can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving Tacrolimus Capsules USP that can cause death. Call your doctor right away if you have symptoms of an infection such as:
      • fever
      • sweats or chills
      • cough or flu-like symptoms
      • muscle aches
      • warm, red, or painful areas on your skin

    What is Tacrolimus Capsules USP?

    Tacrolimus Capsules USP is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant and Tacrolimus Capsules USP is not for use with medicines called cyclosporines (Gengraf®, Neoral®, and Sandimune®).

    Tacrolimus Capsules USP is not for use with a medicine called sirolimus (Rapamune®) in people who have had a liver or heart transplants.

    It is not known if Tacrolimus is safe and effective when used with sirolimus in people who have had kidney transplants.

    It is not known if Tacrolimus is safe and effective in children who have had a kidney or heart transplants.

    Who should not take Tacrolimus Capsules USP?

    Do not take Tacrolimus Capsules USP if you are allergic to tacrolimus or any of the ingredients in Tacrolimus Capsules USP. See the end of this leaflet for a complete list of ingredients in Tacrolimus Capsules USP.

    What should I tell my doctor before taking Tacrolimus Capsules USP?

    Before you take Tacrolimus Capsules USP, tell your doctor if you:

    • plan to receive any live vaccines
    • have or have had liver, kidney or heart problems
    • are pregnant or plan to become pregnant. Tacrolimus Capsules USP may harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
    • are breastfeeding or plan to breastfeed. Tacrolimus can pass into your breast milk. You and your doctor should decide if you will take or breastfeed. You should not do both.

    Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and heral supplements.

    Especially tell your doctor if you take:

    • cyclosporine (Gengraf®, Neoral®, and Sandimune®)
    • sirolimus (Rapamune®)
    • nelfinavir (Viracept®)
    • telaprevir (Incivek™)
    • boceprevir (Victrelis™)
    • amiodarone (Cordarone™, Nexterone™, Pacerone™)

    Ask your doctor or pharmacist if you are not sure if you take any of the medicines listed above.Tacrolimus Capsules USP may affect the way other medicines work, and other medicines may affect how Tacrolimus Capsules USP works.

    Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

    How should I take Tacrolimus Capsules USP?

    • Take Tacrolimus Capsules USP exactly as your doctor tells you to take it.
    • Your doctor will tell you how many Tacrolimus Capsules USP to take and when to take them.
    • Your doctor may change your Tacrolimus Capsules USP dose if needed. Do not stop taking or change your dose of Tacrolimus Capsules USP without talking to your doctor.
    • Take Tacrolimus Capsules USP with or without food.
    • Take Tacrolimus Capsules USP the same way everyday. For example, if you choose to takeTacrolimus Capsules USP with food, you should always take Tacrolimus Capsules USP with food.
    • Take Tacrolimus Capsules USP 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 USP at the same time each day helps to keep enough medicine in your body to give your transplanted organ the around-the-clock medicine it needs.
    • Do not eat grapefruit or drink grapefruit juice while taking Tacrolimus Capsules USP.
    • If you take too much Tacrolimus Capsules USP, call your doctor or go to the nearest hospital emergency room right away.

    What should I avoid while taking Tacrolimus Capsules USP?

    While you take Tacrolimus Capsules USP you should not receive any live vaccines such as:

    • flu vaccine through your nose
    • measles
    • mumps
    • rubella
    • polio by mouth
    • BCG (TB vaccine)
    • yellow fever
    • chicken pox (varicella)
    • typhoid

    Avoid exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.

    What are the possible side effects of Tacrolimus Capsules USP?

    Tacrolimus Capsules USP may cause serious side effects, including:

    • See “What the most important information I should know about Tacrolimus Capsules USP?”
    • high blood sugar (diabetes). Your doctor may do certain tests to check for diabetes while you take Tacrolimus Capsules USP. Call your doctor right away if you have:
      • frequent urination
      • increased thirst or hunger
      • blurred vision
      • confusion
      • drowsiness
      • loss of appetite
      • fruity smell on your breath
      • nausea, vomiting, or stomach pain
    • kidney problems. Your doctor may do certain tests to check your kidney function while you take Tacrolimus Capsules USP.
    • nervous system problems. Call your doctor right away if you get any of these symptoms while taking Tacrolimus Capsules USP. These could be signs of a serious nervous system problem:
      • confusion
      • coma
      • muscle tremors
      • numbness and tingling
      • headache
      • seizures
      • vision changes
    • high levels of potassium in your blood. Your doctor may do certain tests to check your potassium level while you take Tacrolimus Capsules USP.
    • high blood pressure. Your doctor will monitor your blood pressure while you take Tacrolimus Capsules USP.
    • heart problems (myocardial hypertrophy). Tell your doctor right away if you get any of these symptoms of heart problems while taking Tacrolimus Capsules USP:
      • shortness of breath
      • chest pain
      • feel lightheaded
      • feel faint

    The most common side effects of Tacrolimus Capsules USP in people receiving kidney transplant are:

    • infection
    • tremors (shaking of the body)
    • high blood pressure
    • kidney problems
    • constipation
    • diarrhea
    • headache
    • stomach pain
    • trouble sleeping
    • nausea
    • low levels of phosphate in your blood
    • swelling of the hands, ankles, or legs
    • weakness
    • pain
    • high levels of fat in your blood
    • high levels of potassium in your blood
    • low red blood cell count (anemia)

    The most common side effects of Tacrolimus Capsules USP in people receiving liver transplants are:

    • shaking of the body tremors
    • headache
    • diarrhea
    • high blood pressure
    • nausea
    • kidney problems
    • stomach pain
    • trouble sleeping
    • numbness or tingling in your hands or feet
    • anemia
    • pain
    • fever
    • weakness
    • high levels of potassium in the blood
    • low levels of magnesium in the blood

    The most common side effects of Tacrolimus Capsules USP for heart transplant patients are:

    • kidney problems
    • high blood pressure

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

    These are not all the possible side effects of Tacrolimus Capsules USP. For more information, ask your doctor or pharmacist.

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

    How should I store Tacrolimus Capsules USP?

    • Store Tacrolimus Capsules USP at 25°C (77°F); excursions permitted to 15ºC - 30ºC (59°F - 86ºF).
    • Safely throw away medicine that is out of date or no longer needed.

    Keep Tacrolimus Capsules USP and all medicines out of reach of children.

    General information about the safe and effective use of Tacrolimus Capsules USP

    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Tacrolimus Capsules USP for a condition for which it was not prescribed. Do not give Tacrolimus Capsules USP to other people, even if they have the same symptoms that you have. It may harm them.

    How Does Tacrolimus Capsules USP Protect My New Organ?

    The body’s immune system protects the body against anything that it does not recognize as part of the body. For example, when the immune system detects a virus or bacteria it tries to get rid of it to prevent infection. When a person has a liver, kidney or heart transplant, the immune system does not recognize the new organ as a part of the body and tries to get rid of it, too. This is called “rejection”. Tacrolimus Capsules USP protects your new organ by slowing down the body’s immune system.

    This Patient Information leaflet summarizes the most important information about Tacrolimus Capsules USP. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Tacrolimus Capsules USP that is written for health professionals.

    For more information, call Panacea Biotec Ltd at 1-877-687-4130.

    What are the ingredients in Tacrolimus Capsules USP?

    Active ingredient: tacrolimus USP

    Inactive ingredients: anhydrous lactose, hypromellose 2910, croscarmellose sodium, magnesium stearate, gelatin, titanium dioxide and ferric oxide.

  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    Panacea Biotec Ltd
    Malpur, Baddi,
    Distt. Solan (H.P.) – 173205, India

    Mfg.Lic.No: MB/05/203

    Distributed by:
    Bionpharma Inc., 600 Alexander Road,
    Princeton, NJ 08540, USA.

    Item Code: SRTP002

    Revised Date: July 2017

  • PRINCIPAL DISPLAY PANEL

    0.5 mg 100s Bottle Label

    0.5 mg 100s Bottle Label

  • PRINCIPAL DISPLAY PANEL

    0.5 mg 100s Carton Label

    0.5 mg 100s Carton Label

  • PRINCIPAL DISPLAY PANEL

    1 mg 100s Bottle Label

    1 mg 100s Bottle Label

  • PRINCIPAL DISPLAY PANEL

    1 mg 100s Carton Label

    1 mg 100s Carton Label

  • PRINCIPAL DISPLAY PANEL

    5 mg 100s Bottle Label

    5 mg 100s Bottle Label

  • PRINCIPAL DISPLAY PANEL

    5 mg 100s Carton Label

    5 mg 100s Carton Label

  • INGREDIENTS AND APPEARANCE
    TACROLIMUS 
    tacrolimus capsule, gelatin coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 43817-421
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TACROLIMUS (UNII: WM0HAQ4WNM) (TACROLIMUS ANHYDROUS - UNII:Y5L2157C4J) TACROLIMUS ANHYDROUS0.5 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
    HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    GELATIN (UNII: 2G86QN327L)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeCAPSULESize5mm
    FlavorImprint Code PBT;0;5
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 43817-421-01100 in 1 BOTTLE; Type 0: Not a Combination Product02/26/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09080202/26/2016
    TACROLIMUS 
    tacrolimus capsule, gelatin coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 43817-422
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TACROLIMUS (UNII: WM0HAQ4WNM) (TACROLIMUS ANHYDROUS - UNII:Y5L2157C4J) TACROLIMUS ANHYDROUS1 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
    HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    GELATIN (UNII: 2G86QN327L)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeCAPSULESize5mm
    FlavorImprint Code PBT;1;0
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 43817-422-01100 in 1 BOTTLE; Type 0: Not a Combination Product02/26/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09080202/26/2016
    TACROLIMUS 
    tacrolimus capsule, gelatin coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 43817-423
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TACROLIMUS (UNII: WM0HAQ4WNM) (TACROLIMUS ANHYDROUS - UNII:Y5L2157C4J) TACROLIMUS ANHYDROUS5 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
    HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    GELATIN (UNII: 2G86QN327L)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    ColorPINKScoreno score
    ShapeCAPSULESize4mm
    FlavorImprint Code PBT;5;0
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 43817-423-01100 in 1 BOTTLE; Type 0: Not a Combination Product02/26/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09080202/26/2016
    Labeler - Panacea Biotec Ltd (650090566)
    Registrant - Panacea Biotec Ltd (650090566)
    Establishment
    NameAddressID/FEIBusiness Operations
    Panacea Biotec Ltd677605923manufacture(43817-421, 43817-422, 43817-423)
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