PROGRAF^® is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies (14.1)], liver transplant [see Clinical Studies (14.2)], heart transplant [see Clinical Studies (14.3)], or lung transplant [see Clinical Studies (14.4)] in combination with other immunosuppressants.

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

PROGRAF capsules and PROGRAF Granules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended- release dosage forms must occur under physician supervision [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 PROGRAF is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions (5.9)].

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

Oral Formulations (Capsules and Oral Suspension)

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

General Administration Instructions

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

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

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

Capsules

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

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

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

Patient Population	PROGRAF Capsules African-American patients may require higher doses compared to Caucasians (see Table 2). Initial Oral Dosage	Whole Blood Trough Concentration Range
Kidney Transplant
With Azathioprine	0.2 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL
With MMF/IL-2 receptor antagonist In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL. during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies (14.1)].	0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 4-11 ng/mL
Liver Transplant
With corticosteroids only	0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL
Lung Transplant
With azathioprine or MMF	0.075 mg/kg/dayPatients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology (12.3)]. , divided in two doses, administered every 12 hours	Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL

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

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

Table 2. Comparative Dose and Trough Concentrations Based on Race

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

In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

Intravenous Injection

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

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

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

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

Oral formulations (capsules or oral suspension)

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

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

Patient Population	Initial PROGRAF Capsule and PROGRAF Granules Dosing	Whole Blood Trough Concentration Range
Pediatric kidney transplant patients See Clinical Pharmacology (12.3), PROGRAF Granules Pharmacokinetics in Pediatric Patients.	0.3 mg/kg/day capsules or oral suspension, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Pediatric liver transplant patients See Clinical Studies (14.2), Liver Transplantation.	0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Pediatric heart transplant patients	0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Pediatric lung transplant patients	0.3 mg/kg/day , Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology (12.3)]. capsules or oral suspension, divided in two doses, administered every 12 hours	Week 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL

In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

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

Intravenous Injection

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

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

In kidney transplant patients with post-operative oliguria, the initial dose of PROGRAF should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

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

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

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.

Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures¹ [see How Supplied/ Storage and Handling (16.4)].

PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Due to the chemical instability of tacrolimus in alkaline media, PROGRAF injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures¹ [see How Supplied/ Storage and Handling (16.4)].

The required dose for PROGRAF Granules is calculated based on the weight of the patient. Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose. Do not use tubing, syringes and other equipment (cups) containing PVC to prepare or administer tacrolimus products. Do not sprinkle PROGRAF Granules on food. Prepare and administer PROGRAF Granules as follows:

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

Patients receiving immunosuppressants, including PROGRAF, 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.

Patients receiving immunosuppressants, including PROGRAF, 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)].

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. PROGRAF 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 PROGRAF dosage forms [see Dosage Forms and Strengths (3)] and to confirm with the healthcare provider if a different product is dispensed.

PROGRAF was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, heart, or lung 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 PROGRAF [see Adverse Reactions (6.1)].

PROGRAF, 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 PROGRAF 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)].

PROGRAF 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 PROGRAF if neurotoxicity occurs.

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

Hypertension is a common adverse effect of PROGRAF 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 PROGRAF [see Drug Interactions (7.2)].

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

PROGRAF is not recommended for use with sirolimus:

           The use of sirolimus with PROGRAF in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended.

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

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

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

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

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

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

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

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 PROGRAF.

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

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with PROGRAF. 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.

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

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.

PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received PROGRAF-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on PROGRAF and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), 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 PROGRAF-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. 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 PROGRAF in conjunction with azathioprine are presented below:

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

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

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

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

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

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

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

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

	PROGRAF/MMF	Cyclosporine/MMF
	(N = 212)	(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 (≥ 40%) observed in PROGRAF-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of PROGRAF and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving PROGRAF in the U.S. and European randomized trials.

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

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

Table 8. Pediatric Liver Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with PROGRAF Granules (STUDY 01-13)

	PROGRAF Granules (N = 91)	Cyclosporine (N = 90)
Body as a Whole
Fever	46%	51%
Infection	25%	29%
Sepsis	22%	20%
CMV Infection	15%	24%
EBV Infection	26%	11%
Ascites	17%	20%
Peritonitis	12%	7%
Cardiovascular System
Hypertension	39%	47%
Digestive System
Liver Function Tests Abnormal	37%	28%
Diarrhea	26%	26%
Vomiting	15%	13%
Gastrointestinal Hemorrhage	11%	12%
Bile Duct Disorder	12%	8%
Gastroenteritis	12%	4%
Hemic and Lymphatic System
Anemia	29%	19%
Metabolic and Nutritional Disorders
Hypomagnesemia	40%	29%
Acidosis	26%	17%
Hyperkalemia	12%	10%
Respiratory System
Pleural Effusion	22%	19%
Bronchitis	11%	8%
Urogenital System
Kidney Function Abnormal	13%	14%

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

Heart Transplantation

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

The most common adverse reactions (≥ 15%) observed in PROGRAF-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. 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 PROGRAF in Conjunction with Azathioprine (AZA)

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

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

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and PROGRAF in combination with sirolimus (n=109), PROGRAF in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), 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 PROGRAF and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%).

Other targeted treatment-emergent adverse reactions in PROGRAF-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. 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 PROGRAF-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
	PROGRAF/MMF (N = 212)	NEORAL/MMF (N = 212)
NODAT	112/150 (75%)	93/152 (61%)
Fasting Plasma Glucose ≥ 126 mg/dL	96/150 (64%)	80/152 (53%)
HbA1C ≥ 6%	59/150 (39%)	28/152 (18%)
Insulin Use ≥ 30 days	9/150 (6%)	4/152 (3%)
Oral Hypoglycemic Use	15/150 (10%)	5/152 (3%)

In early trials of PROGRAF, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited 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 PROGRAF/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)

Status of PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.	PROGRAF/AZA	CsA/AZA
Patients without pre-transplant history of diabetes mellitus	151	151
New onset PTDM , 1st Year	30/151 (20%)	6/151 (4%)
Still insulin-dependent at one year in those without prior history of diabetes	25/151 (17%)	5/151 (3%)
New onset PTDM post 1 year	1	0
Patients with PTDM at 2 years	16/151 (11%)	5/151 (3%)

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

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

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

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

Heart Transplantation

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

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

Status of PTDM Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.	US Trial		European Trial
	PROGRAF/MMF	Cyclosporine/MMF	PROGRAF/AZA	Cyclosporine/AZA
Patients at riskPatients without pre-transplant history of diabetes mellitus.	75	83	132	138
New Onset PTDM	10 (13%)	6 (7%)	29 (22%)	5 (4%)
Patients still on insulin at 1 year7-12 months for the U.S. trial.	7 (9%)	1 (1%)	24 (18%)	4 (3%)

Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies

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

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

Lung Transplantation

Adverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with PROGRAF [see Adverse Reactions (6.2)].

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

Postmarketing Adverse Reactions in Lung Transplantation

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

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

Table 15 displays the effects of other drugs on PROGRAF.

Table 15. Effects of Other Drugs/Substances on PROGRAFPROGRAF dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.

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

Direct Acting Antiviral (DAA) Therapy

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

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

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF during pregnancy.

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

Risk Summary

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

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m² basis).

Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m² basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m² basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data].

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

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

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

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

Maternal Adverse Reactions

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

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

Fetal/Neonatal Adverse Reactions

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

Labor or Delivery

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

Data

Human Data

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

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

Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus

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

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

Animal Data

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m² basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 to 6.9 times the recommended clinical dose range) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

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

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

Risk Summary

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

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

Contraception

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

Infertility

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

Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients.

Liver Transplantation

Safety and efficacy using PROGRAF Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received PROGRAF, and supported by two pharmacokinetic and safety studies in 151 children who received PROGRAF. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

Kidney and Heart Transplantation

Use of PROGRAF capsules and PROGRAF Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology (12.3)].

Lung Transplantation

The use of PROGRAF capsules and PROGRAF Granules in pediatric lung transplantation is supported by the experience in the U.S. Scientific Registry of Transplant Recipients (SRTR) including 450 pediatric patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil and 72 pediatric patients receiving tacrolimus immediate-release products in combination with azathioprine between 1999-2017.

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

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

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

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

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

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

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

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

Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients

Population	N	Route (Dose)	Parameters
			Cmax (ng/mL)	Tmax (hr)	AUC (nghr/mL)	t1/2 (hr)	CL (L/hr/kg)	V (L/kg)
Healthy  Volunteers	8	IV (0.025 mg/kg/4 hr)	Not applicable		652AUC0-inf ± 156	34.2 ± 7.7	0.040 ± 0.009	1.91 ± 0.31
	30