Tacrolimus (tacrolimus 0.5 mg) Dailymed

Recent Major Changes Section

Warnings and Precautions ( 5.5, 5.10, 5.16)	11/2022
Warnings and Precautions, Cannabidiol Drug Interactions ( 5.17)	08/2023

1 Indications And Usage

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

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

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

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

2 Dosage And Administration

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

ADULT
Patient Population	Initial Oral Dosage (formulation)		Whole Blood Trough Concentration Range
Kidney Transplant
With azathioprine	0.2 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL
With MMF/IL-2 receptor antagonist	0.1 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 12: 4 to 11 ng/mL
Liver Transplant
With corticosteroids only	0.1 to 0.15 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 12: 5 to 20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL
PEDIATRIC
Patient Population	Initial Oral Dosage (formulation)		Whole Blood Trough Concentration Range
Liver Transplant
	0.15 to 0.2 mg/kg/day capsules divided in two doses, every 12 hours		Month 1 to 12: 5 to 20 ng/mL
MMF= Mycophenolate mofetil

2.1 Important Administration Instructions

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

Tacrolimus capsule is not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under-or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions (5.3)]

Intravenous Formulation -Administration Precautions due to Risk of Anaphylaxis

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

Patients receiving 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.

Oral Formulations (Capsules)

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

General Administration Instructions

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

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

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

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

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

The initial oral tacrolimus capsule dosage recommendations for adult patients with kidney, liver, or heart transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges uled in Table 1.

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

1. African-American patients may require higher doses compared to Caucasians (see Table 2) 2. In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 [see Clinical Studies (14.1)] .
Patient Population	Tacrolimus Capsules 1 Initial Oral Dosage	Whole Blood Trough Concentration Range
Kidney Transplant
With Azathioprine	0.2 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL
With MMF/IL-2 receptor antagonist 2	0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 12: 4 to 11 ng/mL
Liver Transplant
With corticosteroids only	0.10 to 0.15 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 12: 5 to 20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL

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

The data in kidney transplant patients indicate that the African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8)and Clinical Pharmacology (12.3)] .

Table 2. Comparative Dose and Trough Concentrations Based on Race

Time After Transplant	Caucasian N = 114		African-American N = 56
	Dose (mg/kg)	Trough Concentrations (ng/mL)	Dose (mg/kg)	Trough Concentrations (ng/mL)
Day 7	0.18	12.0	0.23	10.9
Month 1	0.17	12.8	0.26	12.9
Month 6	0.14	11.8	0.24	11.5
Month 12	0.13	10.1	0.19	11.0

Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of tacrolimus capsules should be given 8 to 12 hours after discontinuing the intravenous infusion.

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

The whole blood trough concentration range described in Table 1 pertains to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous intravenous infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

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

2.3 Dosage Recommendations for Pediatric Liver Transplant Patients

Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges uled in Table 3.

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

2. See Clinical Studies (14.2) , Liver Transplantation.
Patient Population	Initial Tacrolimus Capsule Dosing	Whole Blood Trough Concentration Range
Pediatric liver transplant patients 2	0.15 to 0.2 mg/kg/day capsules divided in two doses, administered every 12 hours	Month 1 to 12: 5 to 20 ng/mL

For conversion of pediatric patients from tacrolimus for oral suspension to tacrolimus capsules or from tacrolimus capsules to tacrolimus for oral suspension, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)] .

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

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

2.4 Dosage Modification for Patients with Renal Impairment

Due to its potential for nephrotoxicity, consider dosing tacrolimus 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 capsule should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)] .

2.5 Dosage Modification for Patients with Hepatic Impairment

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

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

2.6 Therapeutic Drug Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1.

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

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

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

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

• Not Interchangeable with Extended-Release Tacrolimus Products- Medication Errors. Instruct patients or caregivers to recognize the appearance of tacrolimus capsules. ( 5.3)
• New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4)
• Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5)
• Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES), monitor for neurologic abnormalities; reduce or discontinue tacrolimus. ( 5.6)
• Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7)
• Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8)
• Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis. ( 5.9)
• Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10)
• Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13)
• Immunizations: Avoid live vaccines. ( 5.14)
• Pure Red Cell Aplasia: Consider discontinuation of tacrolimus. ( 5.15)
• Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16)
• Therapeutic drug monitoring and dose reduction for tacrolimus should be considered when tacrolimus is co-administered with cannabidiol ( 5.17, 7.3).

5.1 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

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

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

5.2 Serious Infections

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

• Polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection
• JC virus-associated progressive multifocal leukoencephalopathy (PML)
• Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.

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

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

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

5.4 New Onset Diabetes After Transplant

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

5.5 Nephrotoxicity due to Tacrolimus and Drug Interactions

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

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

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

Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1)]. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors) [see Drug Interactions (7.2)] . Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

5.6 Neurotoxicity

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

5.7 Hyperkalemia

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

5.8 Hypertension

Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)] . The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.7)] . Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.2)].

5.9 Anaphylactic Reactions with Tacrolimus Injection

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Dosage and Administration (2.1)].

5.10 Not Recommended for Use with Sirolimus

Tacrolimus is not recommended for use with sirolimus:

• The use of sirolimus with tacrolimus in studies of de novoliver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended.
• The use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)] .
• The use of sirolimus with tacrolimus may increase the risk of thrombotic microangiopathy [see Warnings and Precautions (5.16)].

5.11 Interactions with CYP3A4 Inhibitors and Inducers

When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].

5.12 QT Prolongation

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

When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7.2)] .

5.13 Myocardial Hypertrophy

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

5.14 Immunizations

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

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

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

5.15 Pure Red Cell Aplasia

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

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

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

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

5.17 Cannabidiol Drug Interactions

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

6 Adverse Reactions

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

• Lymphoma and Other Malignancies [see Warnings and Precautions (5.1)]
• Serious Infections [see Warnings and Precautions (5.2)]
• New Onset Diabetes After Transplant [see Warnings and Precautions (5.4)]
• Nephrotoxicity [see Warnings and Precautions (5.5)]
• Neurotoxicity [see Warnings and Precautions (5.6)]
• Hyperkalemia [see Warnings and Precautions (5.7)]
• Hypertension [see Warnings and Precautions (5.8)]
• Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions (5.9)]
• Myocardial Hypertrophy [see Warnings and Precautions (5.13)]
• Pure Red Cell Aplasia [see Warnings and Precautions (5.15)]

The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

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

Kidney Transplantation

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

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

	Tacrolimus / AZA (N = 205)	Cyclosporine / AZA (N = 207)
Nervous System
Tremor	54%	34%
Headache	44%	38%
Insomnia	32%	30%
Paresthesia	23%	16%
Dizziness	19%	16%
Gastrointestinal
Diarrhea	44%	41%
Nausea	38%	36%
Constipation	35%	43%
Vomiting	29%	23%
Dyspepsia	28%	20%
Cardiovascular
Hypertension	50%	52%
Chest Pain	19%	13%
Urogenital
Creatinine Increased	45%	42%
Urinary Tract Infection	34%	35%
Metabolic and Nutritional
Hypophosphatemia	49%	53%
Hypomagnesemia	34%	17%
Hyperlipemia	31%	38%
Hyperkalemia	31%	32%
Diabetes Mellitus	24%	9%
Hypokalemia	22%	25%
Hyperglycemia	22%	16%
Edema	18%	19%
Hemic and Lymphatic
Anemia	30%	24%
Leukopenia	15%	17%
Miscellaneous
Infection	45%	49%
Peripheral Edema	36%	48%
Asthenia	34%	30%
Abdominal Pain	33%	31%
Pain	32%	30%
Fever	29%	29%
Back Pain	24%	20%
Respiratory System
Dyspnea	22%	18%
Cough Increased	18%	15%
Musculoskeletal
Arthralgia	25%	24%
Skin
Rash	17%	12%
Pruritus	15%	7%

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

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

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

	Tacrolimus (Group C)	Cyclosporine (Group A)	Cyclosporine (Group B)
	(N = 403)	(N = 384)	(N = 408)
Diarrhea	25%	16%	13%
Urinary Tract Infection	24%	28%	24%
Anemia	17%	19%	17%
Hypertension	13%	14%	12%
Leukopenia	13%	10%	10%
Edema Peripheral	11%	12%	13%
Hyperlipidemia	10%	15%	13%
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.

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

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

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

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

Liver Transplantation

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%).

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

The most common adverse reactions (≥ 38%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.

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

	U.S. TRIAL		EUROPEAN TRIAL
	Tacrolimus (N = 250)	Cyclosporine/AZA (N = 250)	Tacrolimus (N = 264)	Cyclosporine/AZA (N = 265)
Nervous System
Headache	64%	60%	37%	26%
Insomnia	64%	68%	32%	23%
Tremor	56%	46%	48%	32%
Paresthesia	40%	30%	17%	17%
Gastrointestinal
Diarrhea	72%	47%	37%	27%
Nausea	46%	37%	32%	27%
LFT Abnormal	36%	30%	6%	5%
Anorexia	34%	24%	7%	5%
Vomiting	27%	15%	14%	11%
Constipation	24%	27%	23%	21%
Cardiovascular
Hypertension	47%	56%	38%	43%
Urogenital
Kidney Function Abnormal	40%	27%	36%	23%
Creatinine Increased	39%	25%	24%	19%
BUN Increased	30%	22%	12%	9%
Oliguria	18%	15%	19%	12%
Urinary Tract Infection	16%	18%	21%	19%
Metabolic and Nutritional
Hypomagnesemia	48%	45%	16%	9%
Hyperglycemia	47%	38%	33%	22%
Hyperkalemia	45%	26%	13%	9%
Hypokalemia	29%	34%	13%	16%
Hemic and Lymphatic
Anemia	47%	38%	5%	1%
Leukocytosis	32%	26%	8%	8%
Thrombocytopenia	24%	20%	14%	19%
Miscellaneous
Pain	63%	57%	24%	22%
Abdominal Pain	59%	54%	29%	22%
Asthenia	52%	48%	11%	7%
Fever	48%	56%	19%	22%
Back Pain	30%	29%	17%	17%
Ascites	27%	22%	7%	8%
Peripheral Edema	26%	26%	12%	14%
Respiratory System
Pleural Effusion	30%	32%	36%	35%
Dyspnea	29%	23%	5%	4%
Atelectasis	28%	30%	5%	4%
Skin and Appendages
Pruritus	36%	20%	15%	7%
Rash	24%	19%	10%	4%

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

Heart Transplantation

The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with tacrolimus (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).

The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Adverse reactions in heart transplant patients in the European trial are presented below:

Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

	Tacrolimus/AZA (N = 157)	Cyclosporine/AZA (N = 157)
Cardiovascular System
Hypertension	62%	69%
Pericardial Effusion	15%	14%
Body as a Whole
CMV Infection	32%	30%
Infection	24%	21%
Metabolic and Nutritional Disorders
Diabetes Mellitus	26%	16%
Hyperglycemia	23%	17%
Hyperlipemia	18%	27%
Hemic and Lymphatic System
Anemia	50%	36%
Leukopenia	48%	39%
Urogenital System
Kidney Function Abnormal	56%	57%
Urinary Tract Infection	16%	12%
Respiratory System
Bronchitis	17%	18%
Nervous System
Tremor	15%	6%

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n = 109), tacrolimus in combination with MMF (n = 107) or cyclosporine modified in combination with MMF (n = 115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).

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

Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candidainfection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.”

New Onset Diabetes After Transplant

Kidney Transplantation

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA _1C≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1)] .

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

Parameter	Treatment Group
	Tacrolimus/MMF (n = 212)	NEORAL/MMF (n = 212)
NODAT	112/150 (75%)	93/152 (61%)
Fasting Plasma Glucose ≥ 126 mg/dL	96/150 (64%)	80/152 (53%)
HbA 1c≥ 6%	59/150 (39%)	28/152 (18%)
Insulin Use ≥ 30 days	9/150 (6%)	4/152 (3%)
Oral Hypoglycemic Use	15/150 (10%)	5/152 (3%)

In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)

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 1	Tacrolimus/AZA	CsA/AZA
Patients without pre-transplant history of diabetes mellitus	151	151
New onset PTDM 1 , 1 stYear	30/151 (20%)	6/151 (4%)
Still insulin-dependent at one year in those without prior history of diabetes	25/151 (17%)	5/151 (3%)
New onset PTDM 1 post 1 year	1	0
Patients with PTDM 1 at 2 years	16/151 (11%)	5/151 (3%)

Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

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 Race	Patients Who Developed PTDM 1
	Tacrolimus	Cyclosporine
African-American	15/41 (37%)	3 (8%)
Hispanic	5/17 (29%)	1 (6%)
Caucasian	10/82 (12%)	1 (1%)
Other	0/11 (0%)	1 (10%)
Total	30/151 (20%)	6 (4%)

Liver Transplantation

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

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

Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Patients without pre-transplant history of diabetes mellitus.
Status of PTDM 1	US Trial		European Trial
	Tacrolimus	Cyclosporine	Tacrolimus	Cyclosporine
Patients at risk 2	239	236	239	249
New Onset PTDM 1	42 (18%)	30 (13%)	26 (11%)	12 (5%)
Patients still on insulin at 1 year	23 (10%)	19 (8%)	18 (8%)	6 (2%)

Heart Transplantation

Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels ≥ 126 mg/dL was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

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

Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies: The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

• Nervous System: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired
• Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
• Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis
• Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
• Urogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis
• Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain
• Endocrine: Cushing’s syndrome
• Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased
• Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
• Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis
• Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration
• Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating

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

6.2 Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

Other reactions include:

• Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsades de pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy
• Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease
• Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy
• Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy, (PVAN) including graft loss
• Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased
• Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction
• Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)
• Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope
• Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure
• Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis
• Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia
• Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome