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

Prograf is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus in 1 mL for administration by intravenous infusion only. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80.0% v/v. Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.

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

The chemical structure of tacrolimus is:

Tacrolimus has an empirical formula of C₄₄H₆₉NO₁₂•H₂O and a formula weight

of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids. Because of the risk of anaphylaxis, Prograf injection should be reserved for patients unable to take Prograf capsules orally. In heart transplant recipients, it is recommended that Prograf be used in conjunction with azathioprine or mycophenolate mofetil (MMF). The safety and efficacy of the use of Prograf with sirolimus has not been established (see Clinical Studies).

Prograf injection (tacrolimus injection)

For IV Infusion Only

NOTE: Anaphylactic reactions have occurred with injectables containing castor oil derivatives. See WARNINGS.

In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. The recommended starting dose of Prograf injection is 0.01 mg/kg/day (heart) or 0.03-0.05 mg/kg/day (liver, kidney) as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. Continuous IV infusion of Prograf injection should be continued only until the patient can tolerate oral administration of Prograf capsules.

Preparation for Administration/Stability

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 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).

Prograf capsules (tacrolimus capsules)

Summary of Initial Oral Dosage Recommendations and Typical Whole Blood Trough Concentrations

Patient Population	Recommended Initial Oral Dose*	Typical Whole Blood Trough Concentrations
Adult kidney transplant patients	0.2 mg/kg/day	month 1-3 : 7-20 ng/mL month 4-12 : 5-15 ng/mL
Adult liver transplant patients	0.10-0.15 mg/kg/day	month 1-12 : 5-20 ng/mL
Pediatric liver transplant patients	0.15-0.20 mg/kg/day	month 1-12 : 5-20 ng/mL
Adult heart transplant patients	0.075 mg/kg/day	month 1-3: 10-20 ng/mL month = 4: 5-15 ng/mL
*Note: two divided doses, q12h

Liver Transplantation

It is recommended that patients initiate oral therapy with Prograf capsules if possible. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of Prograf capsules is 0.10 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations).

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

Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

Kidney Transplantation

The recommended starting oral dose of Prograf is 0.2 mg/kg/day administered every 12 hours in two divided doses. The initial dose of Prograf may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.

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

Time After Transplant	Caucasian n=114		Black 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

Heart Transplantation

The recommended starting oral dose of Prograf is 0.075 mg/kg/day administered every 12 hours in two divided doses. If possible, initiating oral therapy with Prograf capsules is recommended. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

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

Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Heart Transplantation below.

Pediatric Patients

Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney and heart transplantation patients is limited.

Patients with Hepatic or Renal Dysfunction

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

Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended IV and oral dosing ranges. Further reductions in dose below these ranges may be required. Prograf therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

Conversion from One Immunosuppressive Regimen to Another

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.

Blood Concentration 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. 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 posttransplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.

Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for tacrolimus. 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 anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

Liver Transplantation

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range.

Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

Kidney Transplantation

Data from the Phase 3 study indicate that trough concentrations of tacrolimus in whole blood, as measured by IMxR were most variable during the first week of dosing. During the first three months, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

The relative risk of toxicity is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

Heart Transplantation

Data from a European Phase 3 study indicate that trough concentrations of tacrolimus in whole blood, as measured by IMxR were most variable during the first week of dosing. From 1 week to 3 months post transplant, approximately 80% of patients maintained trough concentrations between 8-20 ng/mL and, from 3 months through 18 months post transplant, approximately 80% of patients maintained trough concentrations between 6-18 ng/mL.

The relative risk of toxicity; for example, nephrotoxicity and post-transplant diabetes mellitus, is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

Prograf capsules (tacrolimus capsules)

strength	0.5 mg (containing the equivalent of 0.5 mg an hydrous tacrolimus)		1 mg (containing the equivalento f 1 mg an hydrous tacrolimus)		5 mg (containing the equivalent of 5 mg an hydrous tacrolimus)
shape/color	oblong/light yellow		oblong/white		oblong/grayish red
branding on capsule cap/body	f	607	f	617	f	657
100 count bottle	NDC	0469-0607-73	NDC	0469-0617-73	NDC	0469-0657-73
10 blister cards of 10 capsules			NDC	0469-0617-11	NDC	0469-0657-11

Made in Japan

Store and Dispense

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

Prograf injection (tacrolimus injection) (for IV infusion only)

NDC 0469-3016-01...........................Product Code 301601

5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 ampules

Made in Ireland

Store and Dispense

Store between 5° C and 25° C (41° F and 77° F).

Marketed by: Astellas Pharma US, Inc. Deerfield, IL 60015-2548. Revised: April 2006. FDA Rev date: 04/27/06

Liver Transplantation

The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of Prograf and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Hyperkalemia and hypomagnesemia have occurred in patients receiving Prograf therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS).

The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month posttransplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ≥ 15% in tacrolimus patients (combined study results) are presented below for the two controlled trials in liver transplantation:

LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS

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

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

Kidney Transplantation

The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia.

Adverse events that occurred in ≥ 15% of Prograf-treated kidney transplant patients are presented below:

KIDNEY TRANSPLANTATION: ADVERS EEVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS

	Prograf (N=205)	CBIR (N=207)
Nervous System
Tremor (see WARNINGS)	54%	34%
Headache (see WARNINGS)	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(see PRECAUTIONS)	50%	52%
Chest pain	19%	13%
Urogenital
Creatinine Increased (see WARNINGS)	45%	42%
Urinary Tract Infection	34%	35%
Metabolic and Nutritional
Hypophosphatemia	49%	53%
Hypomagnesemia	34%	17%
Hyperlipemia	31%	38%
Hyperkalemia (see WARNINGS)	31%	32%
Diabetes Mellitus (see WARNINGS)	24%	9%
Hypokalemia	22%	25%
Hyperglycemia (see WARNINGS)	22%	16%
Edema	18%	19%
Hemic andLymphatic
Anemia	30%	24%
Leukopenia	15%	17%
Miscellaneous
Infection	45%	49%
PeripheralEdema	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%

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

Heart Transplantation

The more common adverse reactions in Prograf-treated heart transplant recipients were abnormal renal function , hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, and hyperlipemia.

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

HEART TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS

COSTART Body System COSTART Term	Prograf+Azathioprine (n=157)	CsA +Azathioprine (n=157)
Cardiovascular System
Hypertension (See PRECAUTIONS)	62%	69%
Pericardial effusion	15%	14%
Body as a Whole
CMV infection	32%	30%
Infection	24%	21%
Metabolic and Nutritional Disorders
Hyperlipemia	18%	27%
Diabetes Mellitus (See WARNINGS)	26%	16%
Hyperglycemia (See WARNINGS)	23%	17%
Hemic and Lymphatic System
Leukopenia	48%	39%
Anemia	50%	36%
Urogenital System
Kidney function abnormal (SeeWARNINGS)	56%	57%
Urinary tract infection	16%	12%
Respiratory System
Bronchitis	17%	18%
Nervous System
Tremor (See WARNINGS)	15%	6%

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

Only selected targeted treatment-emergent adverse events were collected in the US heart transplantation study. Those events that were reported at a rate of 15% or greater in patients treated with Prograf and mycophenolate mofetil include the following: any target adverse events (99.1%), hypertension (88.8%), hyperglycemia requiring antihyperglycemic therapy (70.1%) (see WARNINGS), hypertriglyceridemia (65.4%), anemia (hemoglobin < 10.0 g/dL) (65.4%), fasting blood glucose > 140 mg/dL (on two separate occasions) (60.7%) (see WARNINGS), hypercholesterolemia (57.0%), hyperlipidemia (33.6%), WBCs < 3000 cells/mcL (33.6%), serious bacterial infections (29.9%), magnesium < 1.2 mEq/L (24.3%), platelet count < 75,000 cells/mcL (18.7%), and other opportunistic infections (15.0%).

Other targeted treatment-emergent adverse events 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.

Less Frequently Reported Adverse Reactions

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

Nervous System

(see WARNINGS)

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

Special Senses

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

Gastrointestinal

Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting

Cardiovascular

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

Urogenital

(see WARNINGS)

Acute kidney failure, albuminuria, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, 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, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain

Endocrine

(see PRECAUTIONS) Cushing's syndrome, diabetes mellitus

Hemic/Lymphatic

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

Miscellaneous

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

Musculoskeletal

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

Respiratory

Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

Skin

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

Post Marketing

Post Marketing Adverse Events

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

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Prograf therapy (see PRECAUTIONS-Myocardial Hypertrophy).

Other events include:

Cardiovascular

Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation

Gastrointestinal

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

Hemic/Lymphatic

Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Metabolic/Nutritional

Glycosuria, increased amylase including pancreatitis, weight decreased

Miscellaneous

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

Nervous System

Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, quadriplegia, speech disorder, syncope

Respiratory

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

Skin

Stevens-Johnson syndrome, toxic epidermal necrolysis

Special Senses

Blindness, blindness cortical, hearing loss including deafness, photophobia

Urogenital

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

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Prograf with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with the co-administration of Prograf and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to Prograf should receive the first Prograf dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels.

Drugs that May Alter Tacrolimus Concentrations

Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.

*Drugs That May Increase Tacrolimus Blood Concentrations

Calcium Channel Blockers	Antifungal Agents	Macrolide Antibiotics
diltiazem	clotrimazole	clarithromycin
nicardipine	fluconazole	erythromycin
nifedipine	itraconazole	troleandomycin
verapamil	ketoconazole**
	voriconazole
Gastrointestinal Prokinetic Agents	Other Drugs
cisapride	bromocriptine
metoclopramide	chloramphenicol
	cimetidine
	cyclosporine
	danazol
	ethinyl estradiol
	methylprednisolone
	lansoprazole***
	omeprazole
	protease inhibitors
	nefazodone
	magnesium-aluminum-hydroxide
**In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients. *** Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.

*Drugs That May Decrease Tacrolimus Blood Concentrations

Anticonvulsants	Antimicrobials
carbamazepine	rifabutin
phenobarbital	caspofungin
phenytoin	rifampin
Herbal Preparations	Other Drugs
St. John's Wort	sirolimus
*This table is not all inclusive.

St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving Prograf could result in reduced tacrolimus levels.

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

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

Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with tacrolimus. Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are essential when nelfinavir is used concomitantly. Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (see DOSAGE AND ADMINISTRATION).

Following co-administration of tacrolimus and sirolimus (2 or 5 mg/day) in stable renal transplant patients, mean tacrolimus AUC_0-12 and Cmin decreased approximately by 30% relative to tacrolimus alone. Mean tacrolimus AUC_0-12 and Cmin following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and efficacy of tacrolimus used in combination with sirolimus for the prevention of graft rejection has not been established and is not recommended.

Other Drug Interactions

Immunosuppressants may affect vaccination. Therefore, during treatment with Prograf, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.¹

(See Boxed Warning.)

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of Prograf-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study (See Tables Below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in the Phase III study

Status of PTDM*	Prograf	CBIR
Patients without pretransplant 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%)
* 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.

Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group during First Year Post Kidney Transplantation in the Phase III study

PatientRace	Prograf		CBIR
	No. of Patients at Risk	Patients Who Developed PTDM*	No. of Patients At Risk	Patients Who Developed PTDM*
Black	41	15 (37%)	36	3 (8%)
Hispanic	17	5 (29%)	18	1 (6%)
Caucasian	82	10 (12%)	87	1 (1%)
Other	11	0 (0%)	10	1 (10%)
Total	151	30 (20%)	151	6 (4%)
*use of insulin for 30 or more consecutive days, with <5 day gap, without a prior history of nsulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.

Insulin-dependent post-transplant diabetes mellitus 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 studies, respectively (See Table below). Hyperglycemia was associated with the use of Prograf in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

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

Status of PTDM*	US Study		European Study
	Prograf	CBIR	Prograf	CBIR
Patients at risk**	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%)
* use of insulin for 30 ormore consecutive days, with < 5 day gap,without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus. **Patients without pretransplanthistory of diabetes mellitus.

Insulin-dependent post-transplant diabetes mellitus was reported in 13% and 22% of Prograf-treated heart transplant patients receiving mycophenolate mofetil or azathioprine and was reversible in 30% and 17% of these patients at one year post transplant, in the US and European randomized studies, respectively (See Table below). Hyperglycemia defined as two fasting plasma glucose levels 126 mg/dL was reported with the use of Prograf plus mycophenolate mofetil or azathioprine in 32% and 35% of heart transplant recipients in the US and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

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

Status of PTDM*	US Study			European Study
	Prograf/Sirolim us	Prograf/MMF	Cyclosporine/MMF	Prograf/AZA	Cyclosporine/AZA
Patients at risk**	85	75	83	132	138
New Onset PTDM*	21 (25%)	10 (13%)	6 (7%)	29 (22%)	5 (4%)
Patients still on insulin at 1 year***	10 (12%)	7 (9%)	1 (1%)	24 (18%)	4 (3%)
* 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 pretransplant history of diabetes mellitus. ***7-12 months for the US Study.

Prograf can cause neurotoxicity and nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Prograf in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial (see ADVERSE REACTIONS). Use of Prograf with sirolimus in heart transplantation patients in a US study was associated with increased risk of renal function impairment, and is not recommended (See Clinical Studies). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of Prograf may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, Prograf should not be used simultaneously with cyclosporine. Prograf or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated Prograf or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with Prograf in the U.S. and European randomized trials, respectively, and in 8% of heart transplant recipients in a European randomized trial and may require treatment (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during Prograf therapy (see PRECAUTIONS).

Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in Prograf-treated kidney transplant patients (54%) and heart transplant patients (15%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant and heart transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving Prograf (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

As in patients receiving other immunosuppressants, patients receiving 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. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to Prograf following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

A few patients receiving Prograf injection have experienced anaphylactic reactions. Although the exact cause of these reactions is not known, other drugs with castor oil derivatives in the formulation have been associated with anaphylaxis in a small percentage of patients. Because of this potential risk of anaphylaxis, Prograf injection should be reserved for patients who are unable to take Prograf capsules.

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.

General

Hypertension is a common adverse effect of Prograf therapy (see ADVERSE REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating Prograf-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see DRUG INTERACTIONS.

Renally and Hepatically Impaired Patients

For patients with renal insufficiency some evidence suggests that lower doses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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 levels 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).

Myocardial Hypertrophy

Myocardial hypertrophy has been reported in association with the administration of Prograf, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years).

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.

Laboratory Tests

Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted.

Carcinogenesis, Mutagenesis and Impairment of Fertility

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in Prograf recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.

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

Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area.

No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Pregnancy: Category C

In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

No reduction in male or female fertility was evident.

There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Prograf should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.

Nursing Mothers

Since tacrolimus is excreted in human milk, nursing should be avoided.

Pediatric Patients

Experience with Prograf in pediatric kidney and heart transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Prograf. Two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty- one patients were randomized to Prograf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).

REFERENCE

1. CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42(RR-4):1-18.

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

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

Prograf is contraindicated in patients with a hypersensitivity to tacrolimus. Prograf injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).

Mechanism of Action

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

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

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

Pharmacokinetics

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

Population	N	Route (Dose)	Parameters
			Cmax (ng/mL)	Tmax (hr)	AUC (ng•hr/mL)	t1/2 (hr)	CI (L/hr/kg)	V (L/kg)
Healthy Volunteers	8	IV (0.025 mg/kg/4hr)	--	--	598‡± 125	34.2± 7.7	0.040± 0.009	1.91±0.31
	16	PO (5 mg)	29.7 ± 7.2	1.6 ± 0.7	243§ ± 73	34.8 ± 11.4	0.041† ± 0.008	1.94† ± 0.53
Kidney Transplant Pts	26	IV (0.02 mg/kg/12 hr)			294¶ ± 262	18.8 ± 16.7	0.083 ± 0.050	1.41 ± 0.66
		PO (0.2 mg/kg/day)	19.2 ± 10.3	3.0	203¶ ± 42	#	#	#
		PO (0.3 mg/kg/day)	24.2 ± 15.8	1.5	288¶ ± 93	#	#	#
Liver Transplant Pts	17	IV (0.05 mg/kg/12 hr)			3300¶ ± 2130	11.7 ± 3.9	0.053 ± 0.017	0.85 ± 0.30
		PO (0.3 mg/kg/day)	68.5 ± 30.0	2.3 ± 1.5	519¶ ± 179	#	#	#
Heart Transplant Patients	11	IV (0.01 mg/kg/day as a continuous infusion)			954|| ± 334	23.6 ± 9.22	0.051 ± 0.015	#
	11	PO (0.075mg/kg/day)***	14.7 ± 7.79	2.1 [0.5-6.0]**	82.7* ± 63.2		#	#
	14	PO (0.15mg/kg/day)***	24.5 ±13.7	1.5 [0.4-4.0]**	142* ± 116		#	#
†Corrected for individual bioavailability; ‡AUC0-120; §AUC0-72; ¶AUC0-inf; ||AUC0-t; *AUC0-12; **:Median [range]; *** Determined after the first dose;--not applicable; #not available

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

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

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

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

Food Effects

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

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

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

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

Distribution

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

Metabolism

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

Excretion

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

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

Special Populations

Pediatric

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

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION).

Renal and Hepatic Insufficiency

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

Population (No. of Patients)	Dose	AUC0-t (ng·hr/mL)	t1/2 (hr)	V (L/kg)	CI (L/hr/kg)
Renal Impairment (n=12)	0.02 mg/kg/4hr IV	393±123 (t=60 hr)	26.3 ± 9.2	1.07 ± 0.20	0.038 ± 0.014
Mild Hepatic Impairment (n=6)	0.02 mg/kg/4hr IV	367 ± 107 (t=72 hr)	60.6 ± 43.8 Range: 27.8 -141	3.1±1.6	0.042 ± 0.02
	7.7 mg PO	488 ± 320 (t=72 hr)	66.1 ± 44.8 Range: 29.5 -138	3.7 ± 4.7*	0.034 ± 0.019*
Severe Hepatic Impairment (n=6, IV)	0.02 mg/kg/4hr IV (n=2)	762±204 (t=120hr)	198±158 Range: 81-436	3.9 ± 1.0	0.017 ± 0.013
	0.01 mg/kg/8hr IV (n=4)	289 ± 117 (t=144hr)
(n=5, PO)†	8 mg PO (n=1)	658 (t=120hr)	119 ± 35 Range: 85-178	3.1 ± 3.4*	0.016 ± 0.011*
	5 mg PO (n=4) 4 mg PO (n=1)	533 ±156 (t=144hr)
*corrected for bioavailability †1 patient didnot receive the PO dose

Renal Insufficiency: Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups.

The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (see previous table).

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

Race

A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION.)

Gender

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

Clinical Studies

Liver Transplantation

The safety and efficacy of Prograf-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The Prograf-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens.

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

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

One-year patient survival and graft survival in the Prograf-based treatment groups were equivalent to those in the CBIR treatment groups in both studies. The overall 1-year patient survival (CBIR and Prograf-based treatment groups combined) was 88% in the U.S. study and 78% in the European study. The overall 1-year graft survival (CBIR and Prograf-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral Prograf dosing was 2 days.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Kidney Transplantation

Prograf-based immunosuppression following kidney transplantation was assessed in a Phase 3 randomized, multicenter, non-blinded, prospective study. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

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

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Heart Transplantation

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

In the European Phase 3 study, patient/graft survival at 18 months posttransplant was similar between treatment arms, 91.7% in the tacrolimus group and 89.2% in the cyclosporine group. In the US study, patient and graft survival at 12 months was similar with 93.5% survival in the Prograf plus MMF group and 86.1% survival in the cyclosporine modified plus MMF group. In the European study, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100-200 ng/mL) at Day 122 and beyond in 32-68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5-15 ng/mL) in 74-86% of the patients in the tacrolimus treatment arm.

The US study contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose Prograf; however, this regimen was associated with increased risk of wound healing complications, renal function impairment, and insulin dependent post transplant diabetes mellitus, and is not recommended (see WARNINGS).

Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving Prograf. They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician.

Patients should be informed that Prograf can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger.

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

TACROLIMUS - ORAL

(tack-row-LEE-muss)

COMMON BRAND NAME(S): Prograf

WARNING: Tacrolimus lowers the body's ability to fight an infection/disease (immunosuppression). This may increase your risk of developing an infection or certain types of cancer (e.g., skin cancer, lymphoma). To reduce the risk of these serious side effects, take this medication at the lowest effective dose as directed by your doctor. Keep all medical and laboratory appointments.

Tell your doctor immediately if you develop any of the following: unusual skin changes, change in the appearance/size of moles, unusual growths/lumps, swollen glands, night sweats, unexplained weight loss, signs of infection (e.g., fever, persistent sore throat).

USES: Tacrolimus is used with other medications to prevent rejection of a kidney, heart, or liver transplant. This medication belongs to a class of drugs known as immunosuppressants. It works by weakening your body's defense system (immune system) to help your body accept the new organ as if it were your own.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat a certain type of bowel condition (fistulizing Crohn's disease) in patients who cannot take or have not been successfully treated by the usual treatment.

HOW TO USE: Take this medication by mouth with or without food, usually every 12 hours or as directed by your doctor. If you have nausea or an upset stomach, you may take this drug with food, although this may cause your body to absorb less of the drug. However, you must choose one way (with food or without food) and always take this medication the same way so that your body always absorbs the same amount of drug. Consult your doctor or pharmacist for more details.

Dosage is based on your weight, medical condition, blood test results (e.g., tacrolimus trough levels), and response to therapy.

Do not increase your dose or take this medication more often without your doctor's approval. Your condition will not improve any faster and the risk of serious side effects may be increased. Also, do not stop taking this medication without your doctor's approval.

Take this medication regularly in order to get the most benefit from it. It is important to take all doses on time to keep the amount of medicine in your body at a constant level. Remember to take it at the same times each day.

Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of certain medications in your bloodstream. Consult your doctor or pharmacist for more details.

Inform your doctor if your condition worsens.

SIDE EFFECTS: See also Warning section.

Shaking, headache, diarrhea, nausea/vomiting, upset stomach, loss of appetite, trouble sleeping, or tingling of the hands/feet may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes, seizures, dizziness, change in the amount of urine, tiredness/weakness, fast/pounding heartbeat, hearing problems (e.g., hearing loss, ringing in the ears), pain/redness/swelling of arms or legs, easy bruising/bleeding, muscle pain/cramp, yellowing skin/eyes, dark urine, persistent nausea/vomiting, stomach/abdominal pain, swelling ankles/feet.

Seek immediate medical attention if any of these rare but very s