Astellas Pharma Canada, Inc.

PRODUCT MONOGRAPH

^Pr Prograf ^®

(Tacrolimus Injection and Capsule)

0.5mg, 1mg and 5mg hard gelatin capsules

5mg/mL in 1mL ampoules for infusion only

Immunosuppressant

Astellas Pharma Canada, Inc.
675 Cochrane Drive, Suite 500
West Tower
Markham, Ontario
L3R 0B8
Canada

® Registered Trademark

Date of Revision: October 27, 2006

Control Number: 101102

Prograf^®

Tacrolimus Injection and Capsule

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

(For a complete listing see Dosage Forms, Composition and Packaging section.)

oral

Capsules/ 0.5mg, 1mg and 5mg

Lactose Monohydrate, NF

Magnesium Stearate, NF

intravenous

Injection / 5mg/mL

Polyoxyl 60 hydrogenated Castor Oil (HCO-60)

INDICATIONS AND CLINICAL USE

Transplantation

Prograf (tacrolimus) is indicated for:

prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants.

treatment of refractory rejection in patients receiving allogeneic liver or kidney transplants.

Prograf is to be used concomitantly with adrenal corticosteroids and other immunosuppressive agents.

Only physicians experienced in immunosuppressive therapy and management of organ transplant should prescribe Prograf (tacrolimus). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Rheumatoid Arthritis

Prograf (tacrolimus), capsule monotherapy is indicated for:

treatment of active rheumatoid arthritis in adult patients for whom anti-rheumatic drug (DMARD) therapy is ineffective or inappropriate.

Prograf may be used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and/or steroids, although the possibility of increased toxicity has not been fully explored (See Warnings and Precautions and Drug Interactions).

Combined use of Prograf with gold, penicillamine, hydroxychloroquine, sulfasalazine or azathioprine has not been studied. There is currently insufficient data to support the concomitant use of Prograf and methotrexate.

Careful monitoring of Prograf treated patients is mandatory. Prograf should only be prescribed for rheumatoid arthritis by physicians experienced with the use of immunosuppressants.

Geriatrics (> 65 years of age): The safety and efficacy of Prograf in patients older than 65 years of age has not been established.

Pediatrics or (< 18 years of age): Experience with Prograf in pediatric kidney and heart transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages 4 months up to 16 years) using Prograf, with the majority of these patients under 5 years of age (See Warnings and Precautions).

Prograf is not indicated for the use of rheumatoid arthritis in children younger than 18 years of age.

CONTRAINDICATIONS

Prograf (tacrolimus) is contraindicated in patients with a hypersensitivity to tacrolimus or to any ingredient in the formulation or component of the capsules. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
Prograf Injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).
Prograf may interact with a number of drugs administered concomitantly with Prograf. Please refer to the Drug Interactions section.

WARNINGS AND PRECAUTIONS

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Transplant Patients

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Prograf (tacrolimus). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Rheumatoid Arthritis

Careful monitoring of Prograf treated patients is mandatory. Prograf should only be prescribed for rheumatoid arthritis by physicians experienced with the use of immunosuppressants. Prograf is indicated for the treatment of active rheumatoid arthritis in adult patients for whom disease modifying anti-rheumatic drug (DMARD) therapy is ineffective or inappropriate.

For Transplant Patients

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 1:1000 should be available at the bedside as well as a source of oxygen.

Carcinogenesis and Mutagenesis

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 (See Toxicology).

Cardiovascular

Hypertension is a common side effect of Prograf (tacrolimus) therapy (See Adverse Reactions). Mild or moderate hypertension is more frequently reported than severe hypertension. The incidence of hypertension decreases over time. 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 in the transplant patient (See Drug Interactions). Hypertension and hyperkalemia has also been noted in patients with rheumatoid arthritis. Tacrolimus should be discontinued in patients in whom hypertension and hyperkalemia cannot be controlled.

Heart failure, myocardial hypertrophy and arrhythmia have been reported in association with the administration of Prograf. Myocardial hypertrophy 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 transplant 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 - 46 ng/mL in children (n=7) age 2 - 15 years and 11 - 24 ng/mL in adults (N=3) age 37 - 53 years.

Hepatic/Biliary/Pancreatic

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 dose adjustments should be considered. Some evidence suggests that the use of lower doses may be warranted in these patients. (See Dosage And Administration.)

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% and 6% of Prograf-treated kidney transplant patients in the U.S. and European studies respectively. Since the development of PTDM is related to increased whole blood trough concentrations of tacrolimus and higher doses of corticosteroids, trough concentrations of tacrolimus and/or steroid doses may be decreased if the risk/benefit assessment permits. In the U.S. multicenter trial, Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM, regardless of randomized treatment. Insulin-dependence was reversible in some patients without discontinuation of Prograf or steroids, and therefore, the need for insulin therapy should be reassessed periodically. In the Phase IV kidney transplant study, PTDM was reported in 11.9% of patients. Insulin dependence was reversible in 40% of these PTDM patients at one year post-transplant.

Table 1: The Incidence of post-transplant Diabetes Mellitus and Insulin Use at One Year in the Kidney Transplant Phase IV Study

Status of PTDM*	Prograf + AZA	Prograf + MMF 1 gram	Prograf + MMF 2 grams
Patients without pretransplant history of diabetes mellitus	42	41	43
New onset insulin-dependent PTDM*	8 (19%)	5 (12%)	2 (5%)
Patients with PTDM* at one year	6 (14%)	2 (5%)	1 (2%)

*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.

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). Insulin dependent diabetes was associated with the use of Prograf. This may reverse with dose decrease, however, it may be irreversible after prolonged tacrolimus administration.

In de novo heart transplant recipients, new onset glucose intolerance (no history/no diabetes at baseline; fasting plasma glucose ≥126 mg/dL; oral hypoglycemic agent use; and/or insulin use ≥30 days) was observed in 63% (83/132) of transplant recipients in the tacrolimus group and 54% (74/138) in the cyclosporine group in the European trial (p=0.139, Fisher's exact test). In the US trial in de novo heart transplant recipients, new onset glucose intolerance was observed in 68% (58/85) of transplant recipients in the tacrolimus/sirolimus group, 61% (46/75) in the tacrolimus/MMF group and 58% (48/83) in the cyclosporine/MMF group.

Hyperglycemia, elevations in HgbA1c, and overt diabetes have also been noted in rheumatoid arthritis patients treated with tacrolimus. Tacrolimus should be discontinued in patients in whom blood sugars cannot be controlled.

Immune

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. 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. Experiences on combining Prograf with immunosuppressive drugs other than adrenal corticosteroids is limited because of the potency of Prograf and the risk of over immunosuppression and such combinations are not recommended.

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.

Neurologic

Prograf may cause neurotoxicity and the likelihood increases with higher blood levels.

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 in the U.S. and European studies (54 and 35%, respectively), and heart transplant patients (15%) compared with cyclosporine-treated patients. The incidence of other neurological events in the two treatment groups in both kidney studies and heart transplant patients was similar. 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 . Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

Renal

Prograf may cause nephrotoxicity, and the likelihood increases with higher blood levels.

Nephrotoxicity has been noted in approximately 52% and 57% 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). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Impaired renal function requires close monitoring and may necessitate Prograf dosage reduction. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to other immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, when switching patients from a cyclosporine-based regimen to a Prograf-based regimen, cyclosporine should be discontinued at least 24 hours prior to initiating Prograf. Prograf dosing may be further delayed in the presence of elevated cyclosporine levels (See Drug Interactions). When switching from tacrolimus to cyclosporine, tacrolimus should be discontinued for at least 24 hours.

For patients with renal insufficiency some evidence suggests that the use of lower doses may be warranted. (See Action and Clinical Pharmacology and Dosage and Administration.)

Mild to severe hyperkalemia was reported in 31% and 21% of kidney transplant patients 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 and Warnings Monitoring and Laboratory Tests).

Hyperkalemia has also been noted in patients with rheumatoid arthritis. Tacrolimus should be discontinued in patients in whom hypertension and hyperkalemia cannot be controlled. The adverse events associated with Prograf treatment in rheumatoid arthritis patients occurred at a lower rate of incidence than seen in transplant patients receiving Prograf. The majority of adverse events were mild or moderate in intensity, of limited duration and did not result in discontinuation of the study drug.

Sexual Function/Reproduction

No impairment of fertility was demonstrated in studies of male and female rats. In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. However, in female rats dosed during organogenesis, embryo toxicity (expressed as reduced pup weights) was seen at a dose which was one-third of the maternally toxic dose. At this same dose, when administered prior to mating and during gestation, tacrolimus was associated with adverse effects on female reproductive parameters and embryolethality. This dose was equivalent to 0.5X the clinical dose. (See Warnings and Precautions)

Special Populations

Pregnant Women:

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 0.33X and 1.0X (based on body surface area corrections) the recommended clinical dose (0.3 mg/kg). 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 0.5X and 1.5X), the recommended clinical dose based on body surface area corrections to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

Tacrolimus, given orally at 1.0 mg/kg (0.5X the recommended clinical dose 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 adverse effects on female reproduction and embryo lethality. Effects on female reproductive function (parturition) and embryo lethal 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 (1.5X the recommended clinical dose 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. Toxicities to parental rats were indicated by tremors and circling, as well as reduced weight gains and food consumption in males; and reduced food consumption during gestation and lactation in females. Adverse effects on reproductive parameters included: 1) increased copulatory intervals, 2) increased pre- and post-implantation loss of fetuses (resulting in smaller litter sizes), and 3) decreased numbers of dams delivering. No reduction in male or female fertility was evident. Adverse effects seen in pups were markedly reduced viability and a slight increase in the incidence of malformation (3 pups from 3 dams).

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.

In experience reported by the University of Pittsburgh, eleven female transplant patients maintained on tacrolimus therapy throughout pregnancy delivered twelve babies, with one patient conceiving twice. These patients received tacrolimus from week one to 20 months prior to conception. Ten of the pregnancies were successful, four with C-sections. The neonates showed no growth retardation or congenital anomalies. Hyperkalemia was observed in the majority of babies, but resolved within 24-48 hours without adverse effects. Two babies (both premature 22 and 24 weeks) died shortly after birth. One pregnancy was complicated by diabetes, hypertension and proteinuria, the other by CMV infection requiring ganciclovir therapy. Additional information includes a report of one newborn who had temporary anuria associated with high cord blood tacrolimus concentration, however, renal function was normal within one week. Another reference reports on the successful pregnancy (normal healthy male) in a 28 year old female with bolus steroids and increased doses of tacrolimus for liver graft rejection. In this case, the cord blood plasma concentration was approximately one half that noted in maternal plasma.

Nursing Women:

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

Pediatrics ( < 18 years of age):

Heart failure, cardiomegaly and increased thickness of the myocardium have been reported in patients taking Prograf. Patients at risk for these effects are primarily children younger than 5 years undergoing liver "rescue", small bowel or multivisceral transplantation with trough whole blood tacrolimus levels exceeding 25 ng/mL. Also, these patients at risk often have experienced fluid overload, renal and/or hepatic dysfunction, hypertension and are receiving large doses of corticosteroids and other concomitant medications. Cardiovascular function for such patients should be carefully monitored. In addition, tacrolimus trough whole blood levels should be maintained below 25 ng/mL. If cardiac abnormalities develop, dose reduction or discontinuation of Prograf should be considered in cases where the perceived risk to the patient outweighs the benefit.

The two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf and 25 to cyclosporine-based therapies. Additionally, a minimum of 120 pediatric patients (median age 22.5 months) who underwent 122 liver transplants were studied in an uncontrolled published 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). This is thought to be a result of age related differences in the oxidative capacity of the cytochrome P450 enzyme system (CYP3A) used to metabolize tacrolimus.

Geriatrics (> 65 years of age):

No formal studies have been performed to evaluate the effect of Prograf specifically in the geriatric patient population.

Monitoring and Laboratory Tests

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

Blood Level Monitoring in Transplant Patients

Monitoring of tacrolimus blood levels in conjunction with other laboratory and clinical parameters is considered an essential aid to transplant patient management. During the immediate post-operative period trough blood concentrations should be measured every 1-3 days. In patients with hepatic or renal dysfunction or in those receiving or discontinuing concomitant interacting medications, more intensive monitoring may be required, since tacrolimus clearance may be affected under each of these circumstances. More frequent monitoring may also be required in patients early after transplantation since it is at this time patients experience the highest risk of rejection. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Following discharge from the hospital, the frequency of patient monitoring will decrease with time post-transplant.

Although there is a lack of direct correlation between tacrolimus levels and drug efficacy, data from Phase II and III studies of kidney and liver transplant patients has shown an increasing incidence of adverse events with increasing trough blood concentrations. Most stable patients are maintained with 12 hour trough whole blood levels of 5 to 20 ng/mL. Long term post-transplant patients often are maintained at the low end of this target range.

Two methods are available for the assay of tacrolimus: 1) microparticle enzyme immuno assay (MEIA) and 2) enzyme linked immuno sorbent assay (ELISA). Both methods use the same monoclonal anti-body for the tacrolimus parent compound. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored in a refrigerator and assayed within 3 days; if samples are to be kept longer they should be deep frozen -20 ^oC for up to 12 months.

Kidney Transplantation:Data from the U.S. and European Phase III studies indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx®, 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 one 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.

Liver Transplantation: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.

Heart Transplantation

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

Blood Level Monitoring in Rheumatoid Arthritis Patients

Prograf used in the treatment of rheumatoid arthritis patients has resulted in a lower incidence rate of adverse events than previously seen in transplant patients. Trough blood levels of tacrolimus in this patient population have been demonstrated to be very close to the lower limit of quantitation in assays used to evaluate tacrolimus levels. The lower incidence rates of adverse events as well as the lower levels of tacrolimus detected in rheumatoid arthritis patients may be due to the lower daily dose of Prograf administered to this patient population. Consequently, monitoring tacrolimus trough levels in rheumatoid arthritis patients has not proven to be the most effective approach of managing this patient population. Management of these patients has proven to be effective based on the incidence of adverse events and monitoring serum creatinine levels. Current data further supports the fact that nephrotoxicity associated with Prograf is predictable and can be managed through the careful monitoring of serum creatinine, adjustments of concomitant medications and if necessary, withdrawal of treatment. Since Prograf can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment. Serum creatinine should be monitored every 2 weeks during the first month of therapy and every four weeks for the next three months, then quarterly thereafter.

If serum creatinine is increased by more than 40% above baseline, the serum creatinine should be repeated in one week. If the repeated serum creatinine remains increased by more than 40% from baseline, dosing of Prograf should be interrupted for 14 days and the serum creatinine measurement should again be repeated. If the serum creatinine returns to a value less than a 40% increase from baseline, dosing with Prograf may be resumed. If the serum creatinine remains elevated by more than 40% from baseline, Prograf should be discontinued. These recommendations apply even if the patient=s values still lie within the laboratory normal range.

ADVERSE REACTIONS

Kidney Transplantation

The most common adverse reactions reported were infection, tremor, hypertension, decreased renal function, constipation, diarrhea, headache, abdominal pain and insomnia. Many of these adverse reactions were mild and responded to a reduction in dosage. Insulin-dependent post-transplant diabetes mellitus (PTDM) was related to increased whole blood trough concentrations of tacrolimus and higher doses of corticosteroids. The median time to onset of PTDM was 68 days.

Liver Transplantation

The principal adverse reactions of Prograf (tacrolimus) are tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. These occur with oral and intravenous 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.

Heart Transplantation

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

Rheumatoid Arthritis

The adverse events associated with Prograf treatment in rheumatoid arthritis patients, occurred at a lower rate of incidence than seen in transplant patients receiving Prograf. The majority of adverse events were mild or moderate in intensity, of limited duration and did not result in discontinuation of the study drug.

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

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Kidney Transplantation

The incidence of adverse events was determined in two randomized Phase 3 comparative kidney transplant studies involving 508 patients receiving Prograf and 352 patients receiving cyclosporine. Adverse events that occurred in ≥ 15% of Prograf-treated patients (combined study results) are presented below for the two controlled trials in kidney transplantation:

Table 2 - Kidney transplantation: Adverse Events Occurring in ≥ 15% of Prograf-treated Patients
Body System	U.S. STUDY (%)		EUROPEAN STUDY (%)
Body System	Prograf N=205	CBIR N=207**	Prograf N=303	CBIR N=145**
Nervous System
Tremor * Headache * Insomnia	54 44 32	34 38 30	35 21 24	12 14 26
Gastrointestinal
Diarrhea Nausea Constipation Vomiting Dyspepsia	44 38 35 29 28	41 36 43 23 20	22 17 31 13 16	10 16 35 8 13
Cardiovascular
Hypertension *	50	52	37	39
Urogenital
Creatinine increased *	45	42	35	21
Metabolic and Nutritional
Hypophosphatemia Hypomagnesemia Hyperkalemia * Diabetes mellitus * Hyperglycemia *	49 34 31 24 22	53 17 32 9 16	3 4 21 12 16	5 1 16 2 7
Hemic and Lymphatic
Anemia Leukopenia	30 15	24 17	18 17	17 15
Body as a Whole
Infection Peripheral edema Asthenia Abdominal pain Pain Fever	45 36 34 33 32 29	49 48 30 31 30 29	76 16 7 27 21 8	75 16 4 23 23 9
Respiratory System
Dyspnea	22	18	12	11
Musculoskeletal
Arthralgia	25	24	9	10

*See Warnings and Precautions ** Cyclosporine-based immunosuppressive regimen.

Tacrolimus has been studied in combination with azathioprine and steroids (triple therapy) in recipients of kidney transplants. In a Phase II European trial, tacrolimus triple therapy was administered to 31 adults receiving deceased donor kidney transplants. Within six weeks post-transplant there were no deaths or graft losses. Six patients (19.4%) experienced acute rejection, with one patient experiencing corticosteroid resistant rejection. Three patients (9.7%) developed transient hyperglycemia, but no patient required long-term therapy for diabetes. Other adverse events reported frequently included infections (51.6%), minor neurological disorders (54.8%), and hypertension (48.8%) (Transpl Int 1995;8:86-90.). The University of Pittsburgh has studied double therapy (tacrolimus and steroids) compared to triple therapy in 204 adult recipients of kidney transplants between August 1991 and October 1992. (Clin Transplantation 1994;8:508-515). The one year actuarial patient and graft survival of double therapy were 95 and 90% versus 91 and 82% for triple therapy (p=NS). The incidence of rejection was significantly lower with triple therapy in deceased donor recipients (39% versus 58%) but not significantly different in recipients from living related donors. New onset diabetes was seen in 20.2% of double therapy patients versus 7.7% of triple therapy patients. A U.S. Phase II trial studied 92 adult recipients of deceased donor kidney transplants randomized to three target whole blood concentration ranges of tacrolimus. All patients received antilymphoblast globulin induction with azathioprine and steroids followed by tacrolimus triple therapy initiated within 2 weeks post-transplant. With follow-up to six weeks post-transplant there were no patient deaths, and one graft loss. The incidence of rejection was 14% combining all tacrolimus treatment groups. Adverse events requiring dose reduction were significantly associated with target tacrolimus blood concentrations (36%-62%).

Data on the safety and efficacy of tacrolimus in combination with immunosuppressants other than steroids in liver transplant patients is more limited. In the European multicentre liver transplant study, many patients received azathioprine or ATG/ALG when tacrolimus therapy was withheld. Seven patients received azathioprine in combination with tacrolimus and steroids. Of these 7 patients, one died and one lost their graft in the first year post-transplant.

Liver Transplantation

The incidence of adverse events reported in two randomized comparative liver transplant trials was determined in 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 post-transplant information from the U.S. study and from the European study is presented below. The two studies 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.

Table 3 - Liver Transplantation: Adverse Events Occurring in ≥ 15% of Prograf-treated Patients

Body System

U.S. STUDY (%)

EUROPEAN STUDY (%)

Prograf N=250

CBIR* N=250

Prograf N=264

CBIR* N=265

Nervous System

Headache

Tremor

Insomnia

Paresthesia

Gastrointestinal

Diarrhea

Nausea

Constipation

LFT Abnormal

Anorexia

Vomiting

Cardiovascular

Hypertension

Urogenital

Kidney Function Abnormal

Creatinine Increased

Hyperkalemia

Hypokalemia

BUN Increased

Urinary Tract Infection

Oliguria

Metabolic and Nutritional

Hyperglycemia

Hypomagnesemia

Peripheral Edema

Hemic and Lymphatic

Anemia

Leukocytosis

Thrombocytopenia

Body as a Whole

Abdominal pain

Pain

Fever

Asthenia

Back Pain

Ascites

Respiratory System

Pleural Effusion

Atelectasis

Dyspnea

Skin and Appendages

Pruritus

Rash

* Cyclosporine-based immunosuppressive regimen.

Heart Transplantation

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

Table 4: Heart Transplantation: Adverse Events Occurring ≥15% of Prograf-Treated Patients

COSTART Body System

COSTART Term

Prograf

(n=157)

CBIR

(n=157)

(%)

Cardiovascular System

Hypertension (See Precautions)

Pericardial effusion

Body as a Whole

CMV Infection

Infection

Metabolic and Nutritional Disorders

Hyperlipemia

Diabetes Mellitus (See Warnings)

Hyperglycemia (See Warnings)

Hemic and Lymphatic System

Leukopenia

Anemia

Urogenital System

Kidney Function Abnormal (See Warnings)

Urinary Tract Infection

Respiratory System

Bronchitis

Nervous System

Tremor (See Warnings)

The incidence of hyperlipidemia or hypercholesteremia as an adverse event at any time during the 18 month study was significantly lower in the tacrolimus group (45/157, 28.7%) than in the cyclosporine group (63/157, 40.1%) (p=0.043, Fisher's exact test).

In the US study, mean serum creatinine levels at 1 year post-transplant were significantly lower in the tacrolimus/MMF group compared with those in either the cyclosporine/MMF group (p=0.002, one-way ANOVA) or the tacrolimus/sirolimus group (p=0.020, one-way ANOVA).

Rheumatoid Arthritis

In a long-term study of rheumatoid arthritis patients receiving Prograf treatment, the adverse events seen in this patient population were similar in nature to those previously reported for patients receiving liver or kidney transplants. In this study, as well as two other studies, the incidence of treatment emergent adverse events seen in the rheumatoid arthritis patient, has a lower incidence of occurrence than seen in the transplant patient.

A summary of treatment-emergent adverse events experienced by at least 5% of patients in any treatment group is presented in the following tables.

Table 5: Summary of Common Treatment-Emergent Adverse Events (%) in Rheumatoid Arthritis Patients
Body System	Phase II Study FK506RA-001
Body System	Placebo N=71	Prograf 1mg N=69	Prograf 3mg N=64	Prograf 5mg N=64
Body as a Whole
Flu Syndrome Accidental Injury Abdominal Pain Asthenia Allergic Reaction Infection	19.7 1.4 4.2 4.2 2.8 2.8	26.1 10.1 7.2 2.9 5.8 1.4	20.3 3.1 9.4 4.7 6.3 6.3	15.6 7.8 9.4 6.3 1.6 1.6
Digestive System
Diarrhea Nausea Dyspepsia Vomiting Gastroenteritis	11.3 5.6 7.0 1.4 1.4	11.6 15.9 17.4 7.2 4.3	15.6 18.8 20.3 6.3 7.8	28.1 14.1 9.4 6.3 7.8
Nervous System
Headache Tremor Paresthesia Anxiety	11.3 0 1.4 1.4	10.1 4.3 2.9 1.4	20.3 3.1 3.1 1.6	15.6 21.9 9.4 10.9
Cardiovascular
Hypertension Mygraine Vasodilatation	4.2 2.8 0	5.8 1.4 2.9	3.1 6.3 1.6	4.7 3.1 6.3
Respiratory System
Pharyngitis Sinusitis Dyspnea	2.8 0 0	10.1 4.3 5.8	3.1 7.8 0	3.1 3.1 1.6
Metabolic and Nutritional Disorders
Creatinine Increased	0	2.9	3.1	6.3
Musculoskeletal System
Arthralgia	5.6	5.8	4.7	4.7
Urogenital System
Urinary Tract Infection	1.4	0	12.5	9.4

Table 6: Phase III Studies: Summary of Common Treatment-Emergent Adverse Events (%) in Rheumatoid Arthritis Patients
Body System	Study 98-0-049			Study 98-0-51
Body System	Placebo N=157	Prograf 2mg N=154	Prograf 3mg N=153	Prograf 3mg N=896
Body as a Whole
Flu Syndrome Accidental Injury Abdominal Pain Asthenia Back Pain Insomnia	16.6 5.1 4.5 3.2 2.5 5.1	16.2 7.8 6.5 4.5 3.2 3.9	16.3 6.5 7.8 8.5 4.6 2.6	26.2 8.7 13.5 8.5 6.4 4.2
Digestive System
Diarrhea Nausea Dyspepsia Vomiting	5.1 6.4 3.2 1.3	13.0 11.7 11.0 2.6	13.7 10.5 6.5 5.2	19.9 14.6 13.1 6.6
Nervous System
Headache Dizziness Tremor	8.9 3.8 1.9	8.4 4.5 4.5	9.2 7.2 8.5	15.1 7.1 10.5
Cardiovascular
Hypertension	4.5	5.8	7.8	8.5
Respiratory System
Pharyngitis Sinusitis	2.5 3.2	6.5 4.5	2.0 3.9	5.5 6.0
Skin and Appendages
Rash	6.4	7.1	3.3	6.8
Metabolic and Nutritional Disorders
Creatinine Increased	1.9	1.9	6.5	6.7
Musculoskeletal System
Cramps	0	2.6	5.2	5.6
Urogenital System
Urinary Tract Infection	2.5	3.2	4.6	5.9

The overall incidence of treatment-emergent adverse events for any treatment group for the three studies (RA-001, 049, and 051) ranged from 72.0% to 90.6%. In the placebo-controlled studies (RA-001 and 049), the overall incidence of treatment-emergent adverse events for the tacrolimus-treated groups was significantly different from placebo. In the tacrolimus-treated groups, the most common adverse events seen across the three studies were flu syndrome, diarrhea, nausea, abdominal pain, dyspepsia, and tremor.

In the case of gastrointestinal events, the incidence of diarrhea in the tacrolimus-treated groups in the three studies varied from 13.0% to 28.1%, with incidence increasing with dose. Tacrolimus 5mg/day in the RA-001 study elicited the highest incidence of diarrhea (28.1%); the next highest incidence of diarrhea was 19.9% in the 3mg/day group in the 051 study. The incidences of diarrhea in the tacrolimus 5 mg/day group in the RA-001 study, and in the 2mg and 3mg groups in the 049 study were significantly different from placebo. Nausea was seen in the tacrolimus-treated groups with incidences of 10.5% to 18.8%. Only the incidence of nausea in the tacrolimus 3mg/day group in the RA-001 study was significantly different from placebo, and the incidence did not increase with an increasing dose. Dyspepsia was observed in the tacrolimus-treated groups with incidences of 6.5% to 20.3%. In the three studies, the incidence of dyspepsia in patients taking 3mg tacrolimus/day were 6.5% (049), 13.1% (051), and 20.3% (RA-001). The incidences of dyspepsia in the 2mg tacrolimus/day group in the 049 study and in the tacrolimus 3mg/day group in the RA-001 study were significantly different from placebo. No increase in incidence was seen with increasing dose in any study. Abdominal pain was reported in the tacrolimus-treated groups with incidences of 6.5% to 13.5%. There was no increase in incidence with increasing doses, and there was no significant difference from placebo in either placebo-controlled study.

The incidence of vasodilatation in the tacrolimus-treated groups varied from 1.6% to 6.3%. There was an increased incidence of vasodilatation with higher doses of tacrolimus. The incidences of vasodilatation in the tacrolimus 3 mg/day group in the 049 study and in the tacrolimus 5 mg/day group in the RA-001 study were significantly different from placebo.

Tremor occurred in the tacrolimus-treated groups with incidences of 3.1% to 21.9%. The incidence of tremor increased with an increasing dose, and in the tacrolimus 5mg/day group in the RA-001 study, the incidence of tremor (21.9%) was more than twice the incidence of tremor seen with tacrolimus 3mg/day in any of the three studies. The incidences of tremor in the tacrolimus 3mg/day group in the 049 study and in the tacrolimus 5 mg/day group in the RA-001 study were significantly different from placebo. Paresthesia was seen in the tacrolimus-treated groups with incidences of 2.6% to 9.4%. The incidence of paresthesia increased with increasing dose, and in the tacrolimus 5 mg/day group in the RA-001 study, the incidence of paresthesia (9.4%) was more than twice the incidence of tremor seen with tacrolimus 3 mg/day in any of the three studies. The incidence of paresthesia in the tacrolimus 5 mg/day group in the RA-001 study was significantly different from placebo.

The incidence of urinary tract infections in the tacrolimus-treated groups varied from 3.2% to 12.5%. The incidence of urinary tract infection in the tacrolimus 3 mg/day group in the RA-001 study was significantly different from placebo; however, the incidence did not increase with increasing doses. The incidence of flu-like syndrome in the tacrolimus-treated groups ranged from 15.6% to 26.2%. There was no increase in incidence with larger doses, and no difference from placebo in any tacrolimus-treated group. The incidence of other infections was between 1.6% and 3.3% in the tacrolimus-treated groups. Increasing dose did not influence the incidence of infection, and there was no difference seen from placebo.

Comparisons of patient subpopulations were performed on data from patients in the 051 study, all of whom received tacrolimus 3 mg/day. In general, the incidence of adverse events was similar in patients < 65 years of age and ≥ 65 years of age, in patients with and without hypertension, in patients with and without hyperlipidemia, and in patients with and without diabetes.

A total of 213 patients (23.8%) were at least 65 years of age at study entry. The overall incidence of adverse events for patients ≥ 65 years of age (86.9%) was similar to that for patients <65 years of age (88.7%). There were no notable differences between patients ≥ 65 years of age and those <65 years of age for the incidence of any specific adverse events. The more common adverse events occurring in at least 10% of patients ≥ 65 years of age were flu syndrome (18.3%), diarrhea (16.9%), tremor (15.0%), nausea (13.6%), headache (12.7%), accidental injury (12.2%), hypertension (12.2%), dyspepsia (11.7%), and abdominal pain (11.3%). For patients <65 years of age, the more common adverse events were occurring in at least 10% of patients were flu syndrome (28.7%), diarrhea (20.8%), headache (15.8%), nausea (14.9%), abdominal pain (14.2%), and dyspepsia (13.5%). The incidences of tremor, accidental injury, and hypertension among these patients were 9.1%, 7.6%, and 7.3%, respectively.

Three hundred fifty patients (39.1%) had a history of hypertension at the time they entered the study. The overall incidence of adverse events for patients with a history of hypertension (91.1%) was similar to that for patients without a history of hypertension (86.4%). Among adverse events reported for at least 5% of patients with a history of hypertension, the incidences of bronchitis (6.9%) and peripheral edema (6.0%) were more than twice the incidences (3.1% and 2.4%, respectively) reported for patients without a history of hypertension. The more common adverse events occurring in at least 10% of patients with a history of hypertension were flu syndrome (26.9%), diarrhea (18.3%), nausea (15.7%), headache (13.4%), dyspepsia (13.1%), tremor (13.1%), abdominal pain (13.1%), and hypertension (11.7%). For patients without a history of hypertension, the more common adverse events occurring in at least 10% of patients were flu syndrome (25.8%), diarrhea (20.9%), headache (16.1%), nausea (13.9%), abdominal pain (13.7%), and dyspepsia (13.0%). The incidences of tremor and hypertension among these patients were 8.8% and 6.4%, respectively.

A total of 271 patients (30.2%) had a history of hyperlipidemia at the time they entered the study. The overall incidence of adverse events for patients with a history of hyperlipidemia (92.6%) was similar to that for patients without a history of hyperlipidemia (86.4%). There were no notable differences between patients with a history of hyperlipidemia and those without a history of hyperlipidemia for the incidence of any specific adverse events. The more common adverse events occurring in at least 10% of patients with a history of hyperlipidemia were flu syndrome (26.2%), diarrhea (18.1%), nausea (15.9%), dyspepsia (14.0%), headache (12.9%), tremor (12.2%), abdominal pain (11.8%), and asthenia (10.3%). For patients without a history of hyperlipidemia, the more common adverse events occurring in at least 10% of patients were flu syndrome (26.2%), diarrhea (20.6%), headache (16.0%), abdominal pain (14.2%), nausea (14.1%), and dyspepsia (12.6%). The incidences of tremor and asthenia among these patients were 9.8% and 7.7%, respectively. Hypercholesterolemia and hyperlipemia were reported as adverse events in 3.0% and 2.2%, respectively, of patients with a history of hyperlipidemia, and in 1.4% and 1.0%, respectively, of patients without a history of hyperlipidemia.

Seventy-five patients (8.4%) had a history of diabetes at the time of study entry. The overall incidence of adverse events for patients with a history of diabetes (89.3%) was similar to that for patients without a history of diabetes (88.2%). Among adverse events reported for at least 5% of patients with a history of diabetes, the incidences of urinary tract infection (13.3%), hyperglycemia (9.3%), and infection (8.0%) were more than twice the incidences (5.2%, 1.8%, and 2.9%, respectively) reported for patients without a history of diabetes, and the incidence of headache (6.7%) in patients with a history of diabetes was less than half the incidence (15.8%) reported for patients without a history of diabetes. The more common adverse events occurring in at least 10% of patients with a history of diabetes were flu syndrome (26.7%), diarrhea (18.7%), tremor (17.3%), dyspepsia (16.0%), urinary tract infection (13.3%), nausea (13.3%), and hypertension (12.0%). The incidences of headache and abdominal pain among these patients were 6.7% and 8.0% respectively. For patients without a history of diabetes, the more common adverse events occurring in at least 10% of patients were flu syndrome (26.2%), diarrhea (20.0%), headache (15.8%), nausea (14.7%), abdominal pain (14.0%), and dyspepsia (12.8%). The incidences of tremor and urinary tract infection among these patients were 9.9% and 5.2%, respectively.

In some Rheumatoid Arthritis patients, an increase in serum creatinine levels has been detected. In the long-term safety study (98-0-051), in which patients were treated with Prograf for up to 18 months, 65.5% of all patients who had increases in serum creatinine ≥ 30% to < 40% above baseline had levels return to baseline during the study. For the remaining patients, creatinine levels either did not return to baseline or no documentation of follow-up levels was available. Patients with increases in serum creatinine levels, ≥ 40%above baseline, had their levels return to baseline in 56.3% of all patients. These included patients who continued study drug therapy and patients who discontinued study drug therapy during the recovery period. For those patients whose creatinine levels returned to baseline, the median time to return to baseline creatinine levels was 40.5 days for patients with ≥ 30% to < 40% increase from baseline and 32.0 days for patient with ≥ 40% increases from baseline.

In Study FK506RA-001, patients who experienced an increase from baseline in serum creatinine levels of ≥ 30% and < 40%, 50% of the patients in the placebo group, 80% of patients in the 1 mg Prograf treatment group, 89% in the 3mg Prograf treatment group and 78% patients in the 5mg Prograf treatment group experienced a return to baseline serum creatinine levels within 56 days for placebo treated patients, 33 days for patients treated with 1 mg Prograf, 29 days for those treated with 3mg and 57 days for those treated with 5mg.

In those patients experiencing a serum creatinine increase of ≥ 40%, above baseline, 50% of placebo treated patients, 20% of the 1 mg treated patents, 75% of the patients treated with 3mg Prograf and 31% of patients treated with 5mg Prograf experienced a subsequent return to baseline creatinine levels. The duration of time for serum creatinine levels to return to baseline for this patient population occurred sooner than those patients experiencing a serum creatinine increase of ≥ 30% and < 40%. Patients treated with placebo demonstrated a return to baseline of serum creatinine levels within 28 days, an average of 6 days for patients treated with 1mg, 20 days for those treated with 3 mg and 38 days for those treated with 5 mg. There were however, eight of nine patients with elevated creatinine levels (>40%) who discontinued the study. These patients had creatinine values return to below a 40% increase from baseline and within normal limits (0.7-1.4mg/dL) post discontinuation, with one patient lost to follow-up.

In study 98-0-049, of those patients who experienced an increase from baseline in creatinine of ≥ 30% to < 40%, 63.6% of these patients in the placebo treatment group, 50.0% of patients in the 2 mg Prograf treatment group, and 77. 8% of patients in the 3mg Prograf treatment group, experienced a documented subsequent return to baseline creatinine values, within 36 days for placebo treated patients, 43 days for 2 mg treated patients and 41 days for 3 mg patients treated with Prograf. For those patients with a ≥ 40% increase from baseline, 33.3% of patients in the placebo treatment group, 53.3% of patients in the 2mg Prograf treatment group, and 45.5% of patients in the 3mg Prograf treatment group experienced a documented subsequent return to baseline creatinine values. Serum creatinine levels in this patient population returned to baseline levels sooner, than patients who experienced an increase from baseline of ≥ 30% to <40%. Patients with a serum creatinine increase > 40% demonstrated a return to baseline at 20 days for placebo treated patients, 33 days for patients treated with 2 mg and 38 days for those patients treated with 3mg Prograf per day. The remaining patients either had creatinine levels that did not return to baseline during the follow-up period or were not monitored for return to baseline values.

For 88.5% (139/157) of placebo-treated patients, 87.0% (134/154) of patients treated with 2 mg/day Prograf and 86.3% (132/153) of patients treated with 3 mg/day Prograf, creatinine levels were within the normal range at baseline, and remained within the normal range throughout the study. In total, four patients all treated with 3mg Prograf, discontinued treatment as a result of a reported adverse event of increased serum creatinine.

Table 7: Number of Patients with at Least a 30% Baseline Increase in Serum Creatinine That Returned to Baseline
Evaluated Study Groups	Increase in Serum Creatinine Levels Above Baseline
Evaluated Study Groups	≥ 30% to < 40%††	≥ 40%††
Study 98-0-051
Combined De Novo† (n=685)	46/78 (59.0%)	90/177 (50.8%)
2mg‡ (n=103)	8/11 (72.7%)	20/37 (54.1%)
3mg* (n=108)	20/24 (83.3%)	37/47 (78.7%)
Total (n=896)	74/113 (65.5%)	147/261 (56.3%)
Study FK506RA-001
Placebo (n=71)	1/2 (50%)	2/4 (50%)
1 mg (n=69)	4/5 (80%)	1/5 (20%)
3 mg (n=64)	8/9 (88.9%)	9/12 (75%)
5 mg (n=64)	7/9 (77.8%)	4/13 (30.8%)
Study 98-0-049
Placebo (n=157)	7/11 (63.6%)	5/15 (33.3%)
2 mg (n=154)	4/8 (50%)	16/30 (53.3%)
3 mg (n=153)	7/9 (77.8%)	20/44 (45.5%)

Patient base: Full analysis set; all patients who received at least one dose of the study drug in study 98-0-051.

†† Percent increase from baseline during treatment. A patient could have been represented in both percentage increase groups if their creatinine increased, returned to baseline levels, and subsequently increased into the other percentage increase group. †All de novo patients for study 98-0-051, all patient from study FK506RA-001, and all placebo rollover patients from study 98-0-049. ‡All 2mg tacrolimus rollover patient from study 98-0-049. *All 3 mg tacrolimus rollover patients from study 98-0-049.

Less Common Clinical Trial Adverse Drug 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 and Precautions) abnormal dreams, agitation, amnesia, anxiety, confusion, crying, convulsion, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, paresthesia, 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, dyspepsia, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, gastroesophagitis, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis,;

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

Urogenital: (See Warnings and Precautions) acute kidney failure, albuminuria, bladder spasms cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary tract infection,

urinary incontinence, urinary retention, vaginitis;

Metabolic/Nutritional: acidosis, alkaline phosphatase increased, alkalosis, AST (SGOT) increased, ALT (SGPT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypocalcemia, hypervolemia, hypoglycemia, hypokalemia, hypophosphatemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain;

Endocrine System: (See Warnings and Precautions) diabetes mellitus, cushing's syndrome;

Hemic/Lymphatic: coagulation disorder, ecchymosis, haemotocrit increased, haemoglobin abnormal, hypochromic anemia, leukopenia, prothrombin decreased, leukocytosis, polycythemia, serum iron decreased, thrombocytopenia;

Body as a Whole: abdomen enlarged, abscess, accidental injury, allergic reaction, back pain, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer;

Musculoskeletal: arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis;

Respiratory System: asthma, bronchitis, cough increased, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumothorax, pneumonia, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration;

Skin & Appendages: acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, pruritus, rash, neoplasm skin benign, skin discolouration, skin disorder, skin ulcer, sweating.

The following nervous system adverse events were also reported at a frequency (<3%): acute brain syndrome (0.2%), coma (2.1%), delirium (1.2%), dysarthria (0.4%), dystonia (0.4%), encephalopathy (2.5%), flaccid paralysis (0.4%), hemiplegia (0.8%), nystagmus (0.8%), paralysis (0.4%) and stupor (0.2%).

Abnormal Hematologic and Clinical Chemistry Findings

Refer to Warnings and Precautions (Hepatic and Renal) and Monitoring and Laboratory Tests

Post-Market Adverse Drug Reactions

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:

Cardiovascular:atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram t wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation with or without 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.

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Prograf therapy (see Warnings and Precautions).

There has been a report of pure red cell aplasia in a renal transplant recipient who was receiving tacrolimus. This condition was reversed upon termination of the administration of tacrolimus.

DRUG INTERACTIONS

Overview

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, and are not limited to, aminoglycosides, amphotericin B, and cisplatin. NSAIDs may interact with Prograf causing deteriorations in blood pressure (BP) control and serum creatinine levels. Initial clinical experience with Prograf and cyclosporine resulted in additive/synergistic nephrotoxicity when both agents were co-administered. 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.

Since tacrolimus is metabolized mainly by the cytochrome P450 IIIA enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus with resultant increases in whole blood or plasma levels. 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 levels. Monitoring of blood levels and appropriate dosage adjustments in transplant patients are essential when such drugs are used concomitantly.

Drug-Drug Interactions

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 clearance of oral 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, clearance of IV tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients.

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

*Table 8: Drugs that may Increase Tacrolimus Blood Concentrations

Antifungal Agents

Calcium Channel Blockers

clotrimazole

fluconazole

ketoconazole

itraconazole

voriconazole

diltiazem

nicardipine

nifedipine

verapamil

Gastrointestinal Prokinetic Agents

Macrolide Antibiotics

cisapride

metoclopramide

erythromycin

clarithromycin

troleandomycin

Others

bromocriptine

cimetidine

chloramphenicol

cyclosporine

danazol

ethinyl estradiol

magnesium aluminum hydroxide methylprednisolone

nefazodone

omeprazole

protease inhibitors

*this table is not all inclusive.

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. In a study of 9 normal volunteers, concomitantly administered 10 mL doses of aluminum hydroxide or milk of magnesia antacids did not affect the rate and extent of absorption of orally administered tacrolimus, as indicated by C_max, T_max and AUC _0-t.

Following 14 days co-administration of tacrolimus and sirolimus (2mg/day or 5mg/day) in stable renal transplant patients, tacrolimus AUC and C_min decreased approximately 30% relative to tacrolimus alone.

*Table 9: Drugs that may Decrease Tacrolimus Blood Concentrations

Anticonvulsants	Antimicrobials
carbamazepine phenobarbital phenytoin	caspofungin rifabutin rifampin
Herbal Preparations	Others
St. John's Wort	sirolimus

*this table is not all inclusive.

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.

Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration.

Drug-Food Interactions

Grapefruit juice affects P450 IIIA-mediated metabolism and should be avoided.

Drug-Herb Interactions

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.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

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 sunscreen with a high protection factor.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Due to intersubject variability following dosing with tacrolimus, individualization of the dosing regimen is necessary for optimal therapy.

Additional factors that may impact dosing include, pre-existing conditions, such as renal or hepatic impairment, race, pediatric use and the concomitant use of other medications.

Prograf has been used in combination with azathioprine. Prograf has been used in combination with mycophenolate mofetil (MMF) in patients receiving deceased donor kidney transplants and heart transplants. Because of the risk of anaphylaxis, Prograf injection should be reserved for patients unable to take Prograf capsules orally.

Recommended Dose and Dosage Adjustment

Prograf Injection 5mg/mL (tacrolimus injection) for transplantation only. For Intravenous Infusion only. Anaphylactic reactions have occurred with injectables containing castor oil derivatives (See Warnings and Precautions).

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 0.01mg/kg/day (heart) or 0.03 - 0.05 mg/kg/day (liver, kidney) as a continuous intravenous infusion (see Table 11). Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. Continuous intravenous infusion of Prograf injection should be continued until the patient can tolerate oral administration of Prograf capsules.

Kidney Transplantation

The recommended starting oral dose of Prograf is 0.2 - 0.3 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 < 4mg/dL). Black patients may require higher doses to achieve comparable blood levels. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table below; blood concentration details are described under Warnings and Precautions.

Table 10: Recommended Tacrolimus Oral Dosing in Kidney Transplant Patients

Dosage
Initial Oral Dose	0.2 - 0.3 mg/kg/day
Dosing Regimen	two divided doses, q12h
Typical tacrolimus whole blood trough concentrations
Month 1-3 Month 4-12	7 - 20 ng/mL 5 - 15 ng/mL

Liver Transplantation

It is recommended that patients be converted from intravenous to oral Prograf capsules as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. 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 0.1-0.15 mg/kg/day administered in two divided daily doses every 12 hours. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. Adult patients should receive doses at the lower end of the dosing range.

Some centres use lower Prograf doses during maintenance therapy post-transplantation. Dosing should be titrated based on clinical assessment of rejection and tolerability. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

Heart Transplantation

The recommended starting oral dose of Prograf is 0.075 mg/kg/day administered every 12 hours in two divided doses. 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.

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.

Rheumatoid Arthritis

The recommended adult oral dose of Prograf is 3mg, administered once a day.

Regular monitoring of Prograf treated patients for occurrence of adverse events is mandatory.

Patients with Hepatic or Renal Dysfunction

Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended intravenous and oral dosing ranges. Further reductions in dose below these ranges may be required.

Conversion to Prograf from Cyclosporine

Patients converted 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. Patients converted from Prograf to cyclosporine should receive the first cyclosporine dose no sooner than 24 hours after the last Prograf dose. Dosing may be further delayed in the presence of elevated tacrolimus levels.

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.

Race

Although a formal study to evaluate the pharmacokinetics of tacrolimus in Black transplant patients has not been conducted, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations.

Missed Dose

Transplant and Rheumatoid Arthritis

If a dose is missed, contact your physician or pharmacist immediately.

Administration

Prograf Injection

Reconstitution:

Table 11: Reconstitution of Prograf Injection 5mg/ml
Vial Size	Diluent to be Added to Vial	Approximate Available Volume in Ampoule	Nominal Concentration per mL
1mL (2mL capacity)	0.9% Sodium Chloride or 5% Dextrose Injection	1 mL	Dilute to between 0.004mg/mL and 0.02mg/mL

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 poor 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 coinfused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir). Prograf Injection is administered as a continuous intravenous infusion.

Prograf Capsules

Prograf capsules should be administered whole and should not be cut, crushed or chewed. Prograf can be administered with or without food however doses should be administeredin a consistent manner, with doses spaced evenly throughout the day.

OVERDOSAGE

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. All patients recovered with no sequelae. Acute overdosage has been followed by adverse reactions consistent with those listed in the Adverse Reactions Section, including mild elevations of renal function markers (creatinine), nausea, headache, hyperreflexia, oliguria, hypotension, tremor and elevations in liver enzymes. In one case transient urticaria and lethargy were observed and in another case acute anuric renal insufficiency developed. 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 intravenous 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 intravenous dose (all based on body surface area corrections).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action / Pharmacodynamics

Tacrolimus, the active ingredient in Prograf, is a macrolide immunosuppressant produced by Streptomyces tsukubaensis.

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.

Tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, Freund's adjuvant arthritis, experimental allergic encephalomyelitis and graft versus host disease in several animal species.

Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. The minimum inhibitory tissue culture level of tacrolimus that prevents antigen stimulation of T-lymphocytes is 0.1 nM - 0.3 nM. 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 generation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate the gene transcription for the formation of lymphokines (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. After oral administration, absorption of tacrolimus into the systemic circulation from the gastrointestinal tract is incomplete and can be variable. Elimination of tacrolimus is via hepatic metabolism with a mean terminal elimination half-life of 18.8 hours in kidney transplant patients, 11.7 hours in liver transplant patients, 23.6 hours in heart transplant patients receiving a single intravenous dose of Prograf and 34.2 hours in healthy volunteers following intravenous administration. In rheumatoid arthritis patients the administration of a single intravenous and oral dose of Prograf, produced a mean terminal elimination half-life of 34.9 and 35.2 hrs respectively.

In transplant patients the intersubject variability in tacrolimus pharmacokinetics, has resulted in the need for the dosing regimen to be individualized . Dosing individualization can be achieved by therapeutic drug monitoring of tacrolimus blood concentrations and evaluation of clinical status (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 in- complete and can be variable. Mean (±S.D.) pharmacokinetic parameters of tacrolimus in whole blood after oral administration to volunteers in two studies are presented in the following table.

Table 12: Mean (±S.D.) Pharmacokinetic Parameters of Tacrolimus in Whole Blood after Oral Administration
Parameter	Bioequivalence Study		Pharmacokinetic Study
Age	19-53 yrs		19-50 yrs
Number	62	59	16
Dose	5 x 1 mg single dose	1 x 5 mg single dose	5 x 1 mg single dose
Absolute Bioavailability (%)	---	---	17.8 ± 5.0
C_max (ng/mL)	25.2 ± 9.7	26.5 ± 10.8	29.7 ± 7.2
T_max (hr)	1.2 ± 0.4	1.4 ± 0.6	1.6 ± 0.7
AUC _0-t (ng•hr/mL)	196 ± 93†	209 ± 97†	243 ± 73††
†AUC (0-72) †† AUC (0-120)

The 1mg and 5mg dose strengths of tacrolimus capsules are bioequivalent as indicated in the table above.

Bioequivalence Study 0.5 mg Capsule

An open label, four period, four sequence, randomized crossover study was done to determine the bioequivalence of the 0.5 mg Prograf capsule to the 1 mg Prograf capsule. In two periods of the study, a single dose of 6 x 0.5 mg capsules were consumed by healthy volunteers. In the two other periods of the study, 3 x 1 mg capsules were consumed in a single dose. The pharmaceutical parameters derived from this bioequivalence study are outlined in the table below.

Table 13: Bioequivalence of the 0.5 mg Prograf (tacrolimus) Capsule to the 1 mg Prograf (tacrolimus) Capsule in Healthy Volunteers: From Measured and Log Transformed Data, Uncorrected for Potency, Geometric Mean, Arithmetic Mean (CV %)
Parameter	Test (6 X 0.5 mg capsules)		Reference (3 x 1 mg capsules)		% Ratio of Geometric Means
Parameter	A1	A2	B1	B2	% Ratio of Geometric Means
AUC_T (ng•h/mL)	140 ± 52.4	122 ± 40.1	133 ± 53.9	125 ± 46.5	102.6
AUC_I (ng•h/mL)	168 ± 66.3	148 ± 50.4	160 ± 70.9	152 ± 62.1	102.9
C_max (ng/mL)	20.3 ± 6.94	18.7 ± 6.55	19.0 ± 6.91	18.7 ± 6.43	103.4
T_max *(h)	1.4 ± 0.61	1.3 ± 0.44	1.4 ± 0.51	1.5 ± 0.50	92.5
T_1/2*(h)	34.4 ± 9.12	35.4 ± 11.1	32.6 ± 7.86	35.8 ± 9.10	102.2

*expressed as arithmetic mean (CV%) only. A1 and A2 refer to data from two different study periods for test drug. B1 and B2 refer to data from two different study periods for reference drug.

Table 14: Bioequivalence of the 0.5 mg Prograf (tacrolimus) capsule to the 1 mg Prograf (tacrolimus) capsule in healthy volunteers: Corrected for Potency, Geometric Mean
Parameter	Test	Reference	% Ratio of Geometric Means
AUC_T (ngCh/mL)	121.1^a	116.3^a	104.2
AUC_I (ngCh/mL)	145.5^a	139.2^a	104.5
C_max (ng/mL)	18.1^a	17.3^a	105.0

Potency corrections made using potencies of 100.8% for the 0.5 mg capsule and 102.3% for the 1.0 mg capsule.

^aValues calculated using LS Means of log-transformed data.

In 26 kidney transplant patients, peak concentrations (C_max) were achieved at approximately 1-3 hours. The absorption half-life of tacrolimus in 17 liver transplant patients averaged 0.6 hour (S.D. 1.0 hour) with peak concentrations (C_max) in blood and plasma being achieved at approximately 1.5-3.5 hours. In rheumatoid arthritis patients peak concentrations (C_max) were achieved within 1.3 hours. Mean (± S.D.) pharmacokinetic parameters of tacrolimus in whole blood after initial dose in adult kidney and liver transplant patients and in rheumatoid arthritis patients are presented in the table below:

Table 15: Mean (±S.D.) Pharmacokinetic Parameters of Tacrolimus in Whole Blood after Initial Dose in Adult Transplant and Rheumatoid Arthritis Patients

Population	N		Pharmacokinetic Parameters
Population	N	Route(Dose)	C_max (ng/ml)	T_max (hr)	AUC (ng!hr/ml)
Kidney Transplant Patients	26	IV (0.02 mg/kg/12hr)	---	---	294§±262
		PO (0.2 mg/kg/day)	19.2±10.3	3.0	203§±42
		PO (0.3mg/kg/day)	24.2±15.8	1.5	288§±93
Liver Transplant Patients	17	IV (0.05 mg/kg/12hr)	---
Liver Transplant Patients	17	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
Heart Transplant Patients	11	PO (0.075 mg/kg/day)	24.9±7.72	1.0	175††±49.8
Rheumatoid Arthritis Patients	12	PO (3 X 1mg single dose)	19.64±6.32	1.3±0.58	192.88±86.42

PO: oral; IV: intravenous; ---: not applicable; NA: not available. † AUC0-120; ‡ AUC0-72; §AUC_o-inf ; ¶AUC _0-t ;

††AUC_0-12

The absolute bioavailability of tacrolimus is approximately 17% in kidney transplant patients, 22% in adult liver transplant patients, 34% in pediatric liver transplant patients, and approximately 25% in rheumatoid arthritis patients. In healthy volunteers the absolute bioavailability of tacrolimus was found to be approximately 18% (previous table).

Food Effects: The rate and extent of tacrolimus absorption is greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to healthy volunteers:

Table 16: Food Effects on the Rate and Extent of Tacrolimus Absorption in Healthy Volunteers
Parameter	Fasted (n=15)	*High Carbohydrate (n=15)**	High Fat (n=15)**
C_max (ng/mL)	25.6 ± 11.4	9.0 ± 3.8	5.9 ± 2.3
T_max (hr)	1.4 ± 0.6	3.2 ± 1.1	6.5 ± 3.0
AUC _0-t (ng•hr/mL)	233 ± 121†	168 ± 59†	147 ± 56 †

* 668 kcal (4% fat; 85% carbohydrate) ** 848 kcal (46% fat, 39% carbohydrate) † AUC (0-96)

The effect was most pronounced with the high-fat meal: mean area under the curve (AUC _0-96) and C_max were decreased 37% and 77%, respectively; T_max was lengthened 5-fold. The high-carbohydrate meal decreased AUC_0-96 and C_max by 28% and 65%, respectively.

The effect of food was also studied in 11 liver transplant patients. Prograf was administered in the fasted state or 15 minutes after a breakfast of known fat content (34% of 400 total calories). The results indicate that the presence of food reduces the absorption of tacrolimus in these patients (decrease in AUC and C_max and increase in T_max). The relative oral bioavailability (whole blood) was reduced by 27.0 (±18.2)% compared to administration in the fasting state.

In healthy volunteers, the time of the meal also affected tacrolimus bioavailability. Relative to the fasted state, there was little effect on tacrolimus bioavailability when administered one hour prior to a high-fat breakfast, whereas bioavailability (both extent and rate of absorption) was greatly reduced when the drug was administered immediately or 1.5 hours after the meal. When given immediately following the meal, C_max was reduced 71%, AUC_0-96 was reduced by 39%, and T_max was delayed 1.6 hours relative to the fasting condition. When administered 1.5 hours following the meal, C_max was reduced 63%, AUC_0-96 was reduced 39%, and T_max was delayed 1.4 hours relative to the fasted condition.

In fasted healthy volunteers given a single dose, the absorption of tacrolimus was proportional to dose; see table below.

Table 17: Absorption of Tacrolimus in Fasted Healthy Volunteers
Parameter	Dose
Parameter	3mg n = 18	7mg n = 18	10mg n = 18
C_max (ng/mL)	14.5 ± 5.8	31.2 ± 10.1	45.1 ±15.0
C_max (ng/mL)	14.5 ± 5.8*	13.4 ± 4.3*	13.5 ± 4.5*
T_max (hr)	1.4 ± 0.4	1.4 ± 0.5	1.3 ± 0.4
AUC _0-96 (ng•hr/mL)	131 ± 77	303 ± 138	420 ± 166
AUC _0-96 (ng•hr/mL)	131 ± 77*	130 ± 59*	126 ± 50*

*Adjusted to 3mg dose

Distribution:

The apparent volume of distribution (based on whole blood concentrations) of tacrolimus is approximately 1.41, 1.91 , 0.85 and 2.37 L/kg in kidney transplant patients, healthy volunteers, adult liver transplant patients and adult rheumatoid arthritis patients, respectively (refer to table below).

Table 18: Volume of Distribution and Clearance in Transplant and Rheumatoid Arthritis Patients
Parameter	Volunteers (n=8)	Kidney Transplant Patients (n=26)	Liver Transplant Patients (Adults, n=17)	Heart Transplant Patients (n=11)	Rheumatoid Arthritis Patients (Adults, n=12)
Mean IV Dose	0.025 mg/kg/4 hr	0.02 mg/kg/4 hr	0.05 mg/kg/12hr	0.01mg/kg/day as a continuous infusion	0.015mg/kg/4hr
V (L/kg)	1.91 ± 0.31	1.41 ± 0.66	0.85 ± 0.3	NA	2.37 ± 0.45
Cl (L/hr/kg)	0.040 ± 0.009	0.083 ± 0.050	0.053 ± 0.017	0.051±0.015	0.049 ± 0.014

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 to proteins, mainly 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 ranged from 12 to 67 (mean 35).

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post dose (C_min) correlated well with the AUC_0-12 (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, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

Metabolism:

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 enzyme 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; the 13-demethyl, 15-demethyl and 15- and 31- double-demethylated metabolites were shown to retain an activity of less than 10%.

Excretion:

The clearance of tacrolimus is 0.040, 0.083, 0.042 and 0.049 L/hr/kg in healthy volunteers, adult kidney transplant patients , adult liver transplant patients, and adult rheumatoid arthritis patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

Special Populations and Conditions

Pediatrics:

A study in liver transplantation has been conducted in sixteen pediatric patients (age range: 0.7-13.2 years). A mean terminal elimination half-life of 11.5 hours was determined following an intravenous dose of 0.037 mg/kg/day in twelve patients; the volume of distribution was 2.6 L/kg, whereas clearance was 0.135 L/hr/kg. In nine patients receiving capsule formulation, a mean C_max of 48.4 ng/mL was attained at a mean T_max of 2.7 hours following an oral dose of 0.152 mg/kg as Prograf capsules. The AUC (0-72hr) was 337 ng•hr/mL. The absolute bioavailability was 31%.

Whole blood trough concentrations from 31 pediatric patients (less than 12 years old) showed that pediatric patients need higher doses than adults to achieve similar tacrolimus trough concentrations, suggesting that the pharmacokinetic characteristics of tacrolimus are different in pediatric patients compared to adults (See Dosage and Administration).

Geriatrics:

The pharmacokinetics of tacrolimus has not been established in the geriatric population.

Gender:

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

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.)

Hepatic Insufficiency:

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single intravenous and oral administrations. The pharmacokinetic parameters obtained were as follows:

Table 19: Tacrolimus Pharmacokinetics in Patients with Mild Hepatic Impairment
Parameter (N = 6)	Dose and Route
Parameter (N = 6)	7.7mg P.O.	1.3mg IV
Age Range (yrs)	52-63
Absolute Bioavailability (%)	22.3 ± 11.4	-
C_max (ng/mL)	48.2 ± 17.9	-
T_max (hr)	1.5 ± 0.6	-
AUC 0-72 (ng•hr/mL)	488 ± 320	367 ± 107
V (L/kg)	3.7 ± 4.7*	3.1 ± 1.6
Cl (L/hr/kg)	0.034 ± 0.019*	0.042 ± 0.020
t_1/2 (hr)	66.1 ± 44.8	60.6 ± 43.8

*Corrected for bioavailability

The disposition of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous tables). In general, tacrolimus elimination half-life was longer and volume of distribution larger in patients with mild hepatic dysfunction compared to normal volunteers. The clearance in both populations was similar and since tacrolimus is extensively metabolized at multiple sites, patients with mild hepatic dysfunction may not require lower maintenance doses of tacrolimus than patients with normal hepatic function.

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.

Table 20: Tacrolimus Pharmacokinetics in Patients with Severe Hepatic Impairment
Route, N	Dose	AUC ng•hr/mL (0-t)	T_1/2(hr)	V (L/kg)	Cl (L/hr/kg)
IV, n=6	0.02mg/kg/4hr IV (n=2)	762 (t=120 hr)	198 ± 158 Range: 81-436	-	-
IV, n=6	0.01 mg/kg/8hr IV (n=4)	289±117 (t=144 hr)	198 ± 158 Range: 81-436	3.9 ± 1.0	0.017 ± 0.013
PO, n=5†	8 mg PO (n=1)	658 (t=120 hr)	119 ± 35 Range: 85-178	3.1 ± 3.4	0.016 ± 0.011
	5 mg PO (n=4)	533 ± 156 (t=144 hr)
	4 mg PO (n=1)	-

† 1 patient did not receive the PO dose.

Renal Insufficiency:

Tacrolimus pharmacokinetics following a single intravenous administration have been determined in 12 patients (7 not on dialysis and 5 on dialysis) prior to their kidney transplant. The pharmacokinetic parameters obtained are presented in the table below:

Table 21: Tacrolimus Pharmacokinetics in Patients with Renal Insufficiency

Serum Creatinine (mg/dL)	3.9 ± 1.6 (not on dialysis) 12.0 ± 2.4 (on dialysis)
Age range (yrs)	25-65
Route	IV
Dose (mg)	1.17 ± 0.28
AUC 0-60 (ng•hr/mL)	393 ± 123
AUC 0-inf (ng•hr/mL)	499 ± 155
V (L/kg)	1.07 ± 0.20
Cl (L/hr/kg)	0.038 ± 0.014
t_1/2(hr)	26.3 ± 9.2

The disposition of tacrolimus in patients with renal dysfunction was not different from that in normal volunteers (see previous tables). The clearance was similar whereas volume of distribution was smaller and the mean terminal elimination half-life shorter than that of normal volunteers.

STORAGE AND STABILITY

Prograf Capsules: Store and dispense at controlled room temperature, 15 ^oC - 30 ^oC.

Prograf Injection: Store in the carton and protect from light. Dispense Prograf ampoules between 15 ^oC and 25^oC.

Prograf Injection must be diluted to a concentration between 0.004 mg/mL and 0.02 mg/mL with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. The diluted infusion solution should be stored at 15-25^oC 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 poor stability and the potential for extraction of phthalates. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

SPECIAL HANDLING INSTRUCTIONS

None required.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Prograf (tacrolimus) is available for oral administration as capsules (tacrolimus capsules) containing the equivalent of 0.5mg, 1 mg or 5 mg of anhydrous tacrolimus. Excipients include croscarmellose sodium, hydroxypropylmethylcellulose 2910, lactose and magnesium stearate. The 1 mg capsule shell contains gelatin and titanium dioxide and the 0.5mg and 5 mg capsule shells contain 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, 83% v/v. Prograf injection must be diluted to a concentration between 0.004 mg/mL and 0.02 mg/mL with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. Diluted infusion solution should be stored at 15-25EC 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 poor stability and the potential for extraction of phthalates. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Prograf capsules (tacrolimus capsules) 0.5 mg

Oblong, light yellow, capsules imprinted with red "0.5mg", on the capsule cap and " f 607" on the capsule body supplied in 100-count bottles or in blister packs of 100 capsules (10 capsules per card).

Prograf capsules (tacrolimus capsules) 1 mg

Oblong, white, capsules imprinted with red " lmg", on the capsule cap and " f 617" on the capsule body supplied in 100-count bottles or in blister packs of 100 capsules (10 capsules per card).

Prograf capsules (tacrolimus capsules) 5 mg

Oblong, grayish/red, capsules imprinted with white "5mg", on the capsule cap and " f 657" on the capsule body supplied in 100-count bottles or in blister packs of 100 capsules (10 capsules per card).

Prograf injection (tacrolimus injection) 5 mg (for intravenous infusion)

Supplied as a sterile colourless solution in l mL ampoules containing the equivalent of 5 mg of anhydrous tacrolimus per mL, in boxes of 10 ampoules.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: tacrolimus

Chemical name: [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.

Molecular formula and molecular mass: C₄₄H₆₉NO₁₂•H₂O

Molecular mass: 822.03

Structural formula:

Physicochemical properties: 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.

Melting Point: 124.9 - 126.8 ^oC by thermal analysis

Partition Coefficient: > 1000 (in n-octanol/water)

CLINICAL TRIALS

Kidney Transplantation

Efficacy and Safety Studies

Study demographics and trial design

Table 22: Summary of Patient Demographics for Prograf (tacrolimus) Kidney Transplantation Trials
Study #	Trial design	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender	Race (Caucasian/Black/Other)
93-0006 (U.S)	Randomized, multi-centre, open label, comparative	0.2 mg/kg per day tacrolimus BID orally ( IV dose is 20% of oral dose), 1 year	N = 205	43.4 ± 13.1 (9-71 years)	M = 123 F = 82	114/56/35
93-0006 (U.S)	Randomized, multi-centre, open label, comparative	Initial Dose: 10 mg/kg per day cyclosporine A BID orally (IV dose is 33% of oral dose), 1 year	N = 207	43.6 ± 12.4 (10-74 years)	M =129 F = 78	123/48/36
FG-02-02 (Europe)	Multicentre, open, parallel-group study, randomized	Initial dose 0.3 mg/kg per day BID to target whole blood trough concentrations of 10-20ng/mL, oral, 1 year	N = 303	46.6 ± 13.5 (18-72 years)	M = 196 F = 107	300/1/2
FG-02-02 (Europe)	Multicentre, open, parallel-group study, randomized	Initial dose 8.0 mg/kg per day to target blood level 100-300ng/mL, oral, 1 year	N = 145	45.8 ± 12.5 (20-70 years)	M = 92 F = 53	143/0/2

Study results

The safety and efficacy of Prograf-based immunosuppression following kidney transplantation was assessed in two, Phase III randomized, multicentre, non-blinded, prospective studies. The active control groups were treated with cyclosporine-based immunosuppression. These studies were designed to evaluate whether the two regimens were therapeutically equivalent for one-year patient and graft survival. Based on the results from these two studies, the Prograf-based regimen was found to be therapeutically equivalent to the cyclosporine-based regimen.

In one trial, (Study 93-0006), 412 kidney transplant patients were enrolled at 19 clinical sites in the United States; 205 patients were 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. Prograf was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (353.6 µmol/L). Prograf was initiated a median of 4 days after transplantation. Patients less than 6 years of age were excluded.

In the second trial, (Study FG-02-02), 448 kidney transplant patients were enrolled at 15 clinical sites in Europe; 303 patients were randomized to Prograf-based immunosuppression and 145 patients were randomized to cyclosporine-based immunosuppression. Prograf was initiated within 24 hours of transplantation and was administered with corticosteroids and azathioprine. Patients less than 18 years of age were excluded.

One-year patient and graft survival in the Prograf-based treatment groups were equivalent to those in the cyclosporine-based treatment groups. The overall one-year patient survival (Prograf and cyclosporine combined) was 96.1% in the U.S. study and 94.2% in the European study. The overall one-year graft survival was 89.6% in the U.S. study and 83.7% in the European study.

The two large, randomized clinical trials demonstrated that significantly fewer tacrolimus - treated patients (approximately 16% fewer) experienced an episode of acute rejection during the one-year treatment period compared with cyclosporine-treated patients (p < 0.001).

Significantly fewer tacrolimus-treated patients crossed over to cyclosporine therapy due to adverse events and acute rejection episodes compared to cyclosporine-treated patients transferring to tacrolimus therapy (p = 0.007). The majority of patients who crossed over from the cyclosporine therapy to tacrolimus therapy were due to rejection (n = 27). The majority of patients who crossed over from tacrolimus therapy to cyclosporine therapy were due to adverse reactions (n = 13) and rarely for rejection (n = 2). Of 27 cyclosporine-treated patients demonstrating acute rejection episodes and transferred to tacrolimus, 21 of these patient rejection episodes resolved (77.8%). Of the 2 tacrolimus patients transferred to cyclosporine due to acute rejection, one of the rejection episodes resolved.

An open label, rescue study, 93-0003, assessed the effect of tacrolimus on 73 kidney transplant patients with biopsy-proven, corticosteroid-resistant acute rejection. Responses to tacrolimus therapy included improvement in 78% of patients, stabilization in 11% and progressive deterioration in 11%. Patient and graft survival one year-post conversion to tacrolimus was 93% and 75% respectively.

The use of Prograf-based immunosuppression in combination with mycophenolate mofetil or azathioprine was evaluated in a Phase IV, randomized, 3-arm, multicenter, non-blinded, prospective study. A total of 176 deceased donor kidney transplant recipients were randomized to one of three treatment groups; azathioprine, mycophenolate mofetil 1 gram per day or mycophenolate mofetil 2 grams per day in two divided doses. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation and corticosteroids. The respective one year patient survival rates were 98.3%, 94.9% and 94.8% for the three treatment groups of azathioprine, mycophenolate mofetil 1 gram per day and mycophenolate mofetil 2 grams per day in two divided doses. Corresponding one year graft survival rates were 94.9%, 93.2% and 94.8%.

A long-term comparison study of tacrolimus (n = 205) and cyclosporine (n = 207) in kidney transplantation was conducted as a 5-year follow-up to study 93-0006. The study focussed on the long-term impact of tacrolimus therapy. Patient and graft survival rates over the follow-up period were equivalent between tacrolimus and cyclosporine treatment arms (79.1% vs. 81.4% and 64.3% vs. 61.6%, respectively). The estimated graft half-life was 13.3 years for tacrolimus and 11.9 years for cyclosporine. However, the incidence of crossover from cyclosporine to tacrolimus was significantly greater than the crossover from tacrolimus to cyclosporine (27.5% vs. 9.3%).

Kidney function tests showed mean serum creatinine levels were higher among patients treated with cyclosporine than those treated with tacrolimus. Significantly fewer patients in the tacrolimus treatment arm developed serum creatinine levels >1.5 mg/dL (40.4% vs. 62.0%).

The risk of treatment failure (defined as the occurrence of graft loss or discontinuation of randomized drug) was significantly lower among patients treated with tacrolimus compared to those treated with cyclosporine (43.8% vs. 56.3%; p=0.008). Graft failure due to rejection occurred more frequently among cyclosporine-treated patients (22.1% vs. 17.0%). At 5 years, fewer patients receiving tacrolimus-based therapy were treated with antihypertensive and antihyperlipidemia medications. It was found that significantly fewer patients maintained on tacrolimus-based therapy developed hypercholesterolemia compared to those receiving cyclosporine (4.7% vs. 17.4%).

Liver Transplantation

Study demographics and trial design

Table 23: Summary of Patient Demographics for Prograf (tacrolimus) Liver Transplantation Trials
Study #	Trial design	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender	Race (Caucasian/Black/Other)
FPC-FK506-7	Open label, randomized, multicenter, active comparator, parallel study	Tacrolimus: 0.075mg/kg then 0.15 mg/kg PO BID or 0.05 mg/kg IV BID, 360 days	N = 263	44.0	M = 136 F = 127	208/13/42
FPC-FK506-7		CyA*: 1- 2mg/kg IV BID, 5mg/kg PO, 360 days	N = 266	44.0	M = 140 F = 126	203/14/49
GHBA-157	Randomized, multicenter, active comparator, open label, parallel study	0.075mg/kg then 0.03 -0.05 IV BID, 360 days	N = 270	45.7	M = 136 F = 134	260/2/8
GHBA-157		CyA*: 1-15mg/kg/day, 360days	N = 275	45.6	M = 158 F = 117	260/2/13
FPC-FK506-9	Open label, multicenter, rescue use of FK506 (tacrolimus)	0.075mg/kg then 0.15 mg/kg PO BID or 0.05 mg/kg IV BID, 360 days	N = 125	34.7	M = 56 F = 69	79/18/28

*CyA: Cyclosporine A

Study results

The safety and efficacy of Prograf (tacrolimus) administered in combination with adrenal corticosteroids was compared with cyclosporine-based immunosuppressive regimens in two randomized, prospective, open-labelled, multicentre studies after orthotopic liver transplantation. In addition, the efficacy of Prograf as rescue therapy in patients with liver allograft rejection refractory to standard therapy was examined in an open-labelled, nonrandomized, multicentre, historically controlled trial.

In one controlled trial, (Study FPC-FK506-7), 529 patients were randomized to receive immunosuppression with Prograf (N=263) or cyclosporine-based regimens (N=266). Patient survival was equivalent with Kaplan-Meier actuarial one-year estimates of 88% for both Prograf and cyclosporine-based regimens. Actuarial one-year graft survival estimates were 82% for the Prograf group and 79% for the cyclosporine-based group. The incidences of acute rejection (68% vs. 76%), steroid-resistant rejection requiring treatment with OKT3 (19% vs. 36%), and refractory rejection (3% vs. 15%) were lower in recipients of the Prograf regimen compared with cyclosporine-based regimens (see table below). Cumulative adrenal corticosteroid use was lower in the Prograf group, however, equivalent doses of corticosteroids were not mandated for induction or maintenance in the two arms of the study. Other measures of efficacy, such as liver function tests and Karnofsky scores, showed similar improvement over time in both groups.

Table 24: Results for the Liver Transplantation Study FPC-FK506-7
Efficacy Parameters	Prograf (%)	*CBIR(%)**	95% Confidence Intervals (%) **
Actuarial One Year Patient Survival Estimates	88	88	-5, 7
Actuarial One Year Graft Survival Estimates	82	79	-5, 10
Incidence of Acute Rejection	68	76	-17,1
Incidence of Steroid-Resistant Rejection Requiring Orthoclone OKT3 Treatment	19	36	-25, -8
Incidence of Refractory Rejection	3	15	-18, -6

* Cyclosporine-Based Immunosuppressive Regimens ** Prograf minus CBIR

In the second controlled study, (Study GHBA-157) 545 patients were randomized to receive Prograf combined with adrenal corticosteroids (N=270) as a treatment for prevention of rejection of primary liver allograft patients, compared with cyclosporine-based therapy (N=275).

The estimated one-year Kaplan-Meier patient survival rates were 81% for the Prograf treatment group and 75% for the cyclosporine-based treatment group. One-year estimated Kaplan-Meier graft survival rates were 76% for the Prograf group and 70% for the cyclosporine-based group. The acute rejection rate was 42% for the Prograf group compared with 55% for the cyclosporine-based group. The incidence of refractory rejection was also less in the Prograf group (3%) compared with the cyclosporine-based group (10%). (See table below.) The cumulative amount of adrenal corticosteroids administered to patients in the Prograf group was less than in the cyclosporine-based group.

Table 25: Results for the Liver Transplantation Study GHBA-157
Efficacy Parameters	Prograf (%)	*CBIR (%)**	95% Confidence Intervals (%) **
Actuarial One Year Patient Survival Estimates	81	75	-1, 13
Actuarial One Year Graft Survival Estimates	76	70	-1, 14
Incidence of Acute Rejection	42	54.7	-23, -4
Incidence of Refractory Rejection	2.6	9.2	-12, -3

* Cyclosporine-Based Immunosuppressive Regimens ** Prograf minus CBIR

In a non-randomized historically controlled trial, (Study FPC-FK506-9) 125 patients previously treated with cyclosporine-based regimens with refractory acute or chronic liver allograft rejection were treated with Prograf plus adrenal corticosteroids as rescue therapy. Actuarial Kaplan-Meier estimates of survival at one year post-conversion to Prograf were 71% for patient survival and 56% for graft survival. Other measures of efficacy such as clinical response scores, liver function test, and Karnofsky performance status showed improvement over time after conversion to Prograf.

Study 91-0045 was conducted in the United States to establish a safe and effective reduced dosage regimen for adult liver transplant patients. Patients were randomized to an initial low dose (0.15 mg/kg/day) or an initial high dose (0.30 mg/kg/day) of oral Prograf and all patients received the same initial dose of corticosteroids. Azathioprine was not allowed during the first 42 days of the study. Prograf doses were adjusted upward or downward in the event of rejection or toxicity, respectively. The mean dose in the higher group shifted downward while the mean dose in the lower group shifted upward over time. By study day 42 both groups were receiving similar Prograf doses (0.13 mg/kg/day). At one year post-transplant, patient results based on the two initial dosing groups were as follows:

Table 26: Results for the Liver Transplantation Study 91-0045
12 Month Results	Low Dose (n=100)	High Dose (n=98)
Patient Survival	91.9%	89.7%
Graft Survival	88.9%	85.6%
Acute Rejection	65.1%	49.7%
Mean Whole Blood Trough Levels of Tacrolimus	9.6 ng/mL (n=76)	10.6 ng/mL (n=67)

Two of 100 patients in the low dose group and 8 of 98 patients in the high dose group discontinued the study due to an adverse event during the first 6 weeks of therapy.

A long-term (5-year) comparison study of tacrolimus (n=263) versus cyclosporine (n=266) in primary liver transplantation was conducted in a 1-year randomized, multicenter trial (FPC-FK506-7) with a 4-year follow-up period.

The 5-year patient and graft survival rates were comparable among tacrolimus (79.0%, 71.8%) and cyclosporine (73.1%, 66.4%) treatment groups. However, patient half-life survival was significantly longer for tacrolimus-treated patients (25.1 ± 5.1 years vs. 15.2 ± 2.5 years), a similar trend occurred with graft half-life. Patient survival of hepatitis C-positive patients was also significantly longer with tacrolimus treatment (78.9% vs. 60.5%).

During the first year after transplant, patients in the tacrolimus group had a statistically significant lower incidence of acute rejection ( 68% vs. 76%) and steroid-resistant rejection (19% vs. 36%). There was no significant difference between treatment groups in the following years. The incidence of death or graft loss due to rejection was 3% in both treatment groups over the 5-year follow-up period. The incidence of malignancies, lymphoproliferative disorders, and late infections were low and comparable between treatment groups.

Heart Transplantation

Study demographics and trial design

Table 26 - Summary of patient demographics for Prograf (tacrolimus) Heart Transplantation Trials
Study #	Trial design	Dosage, route of administration and duration	Study subjects (N))	Mean age (Range)	Gender	Race (Caucasian/ Black/ Other)
FG-506-05-02	Open-label, randomized, parallel-group study	Antibody induction therapy; azathioprine, corticosteroids and tacrolimus. Tacrolimus initial oral dose, 0.075mg/kg/day. At ≤ 3months post-transplant, tacrolimus blood trough concentrations between 10-20 ng/ml. At > 3 months post-transplant, tacrolimus blood trough concentrations at 15ng/ml.	157	50.8 ±11.0 (18-65)	Female: 30 Male: 127	153/1/3
FG-506-05-02	Open-label, randomized, parallel-group study	Antibody induction therapy; azathioprine , corticosteroids and cyclosporine. Cyclosporine microemulsion: Initial oral dose at 4-6 mg/kg/day. At ≤ 3months post-transplant, cyclosporine blood trough concentrations between 200-350ng/ml. At > 3 months post-transplant, cyclosporine blood trough concentrations between 100-200ng/ml thereafter.	157	50.7±9.9 (18-65)	Female: 28 Male: 129	151/4/2
20-01-003	Randomized, Prospective, Multi-center Comparison	Tacrolimus, MMF and steroid treatment therapy Tacrolimus: 2-4mg/kg per day, in two divided oral doses, within 12 hours of transplant. Dosing was adjusted to achieve whole blood concentrations of 200-400ng/ml in the first 3 months and 100 to 300ng/ml thereafter.	113	54.34±10.9 (20-75)	M=86 F=21	95/9/3
20-01-003	Randomized, Prospective, Multi-center Comparison	Cyclosporine, MMF and steroids Cyclosporine: 3 to 5mg/kg per day, as two divided oral doses, within 12 hours of transplant. Dosing was adjusted to achieve whole blood concentrations of 200-400ng/ml in the first 3 months and 100 to 300ng/ml thereafter.	117	51.89±11.5 (22-72)	M=84 F=31	91/20/4

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 III 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 the US study, all patients received corticosteroids in addition to Prograf plus mycophenolate (MMF) (113 patients) or cyclosporine modified plus MMF (117 patients) for 1 year.

In the European Phase III study, patient/graft survival at 18 months post-transplant was similar between treatment arms, 91.7% in the tacrolimus group and 89.2% in the cyclosporine group (treatment difference 2.4%; 95% CI: -4.0%, 8.9%). In the US study, patient and graft survival at 12 months was comparable between the treatment groups with 93.5% survival in the Prograf plus MMF group and 86.1% survival in the cyclosporine modified plus MMF group.

In the European Phase III study, the incidence of biopsy-verified acute rejection standardized grade ≥1B at 6 months post-transplantation was significantly lower (p=0.029, Cochran-Mantel- Haenszel) in the tacrolimus group (54%) compared with the cyclosporine group (66.4%) based on blinded central assessments. The incidence of biopsy-verified acute rejection standardized grade ≥3A at 6 months post-transplantation was significantly lower with tacrolimus-based immunosuppression (29.3%) compared with cyclosporine-based immunosuppression (42%; p=0.018, chi-square) based on blinded central assessments. The incidence of biopsy-verified acute rejection grade ≥3A with hemodynamic compromise was similar (Prograf: 0.6% vs cyclosporine modified 0%; treatment difference 0.6%; 95% CI: - 0.6%, 1.9%).

In the US comparative study, biopsy-verified acute rejection grade ≥3A and biopsy-verified acute rejection grade ≥3A with hemodynamic compromise at 1 year were similar between the treatment groups (Prograf/MMF: 24.3% and 3.7%; cyclosporine/MMF: 35.7% and 7.8%)

Rheumatoid Arthritis

Study demographics and trial design

Table 27- Summary of Patient Demographics for Prograf (tacrolimus) Clinical Trials in Rheumatoid Arthritis

Study #	Trial design	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender	Race (Caucasian/ Black/ Other)
FK-506-RA-001	Randomized, double-blind parallel group	Placebo, 1, 3 or 5 mg tacrolimus as a single daily oral dose for 24 weeks	N= 268	52.0 ± 10.4	M = 59 F = 209	253/11/4
98-0-049	Randomized, double-blind parallel group	Placebo, 2 mg tacrolimus, or 3 mg tacrolimus as a single daily dose for 6 months	N=464	55.8±12.25	M = 38 F = 119	421/25/18
98-0-051	Open label, long term safety study	3 mg tacrolimus single daily oral dose for 12 months (roll-over from 98-0-049 in total patient received up to 18 months of treatment.)	N= 896	55.7 ± 11.84	M = 242 F = 654	835/36/25

Study results

Safety and efficacy of Prograf-based treatment in rheumatoid arthritis patients was evaluated in one Phase II study and two Phase III studies.

The results for the Phase II study, FK506RA-001 and a Phase III study, 98-0-049 depicting the ACR response rates and change from baseline to the end of treatment for individual component scores are depicted below;

Table 28: ACR Response Rates and Change from Baseline to End of Treatment for Individual Component Scores

Variable	FK506RA-001¹				98-0-049¹
Variable	placebo	1mg	3mg	5mg	Placebo	2mg	3mg
ACR20 Response Rate	15.5%	29.9%#	34.4%*	50.0%***	13.4%	21.4%#	32.0%***
ACR20 Success Rate	11.3%	29.0%#	23.4%#	40.6%***	10.2%	18.8%*	26.8%***
ACR50 Response Rate	1.4%	14.5%*	17.2%*	14.1%*	4.5%	11.7%	11.8%*
ACR70 Response Rate	NA	NA	NA	NA	0.6%	5.2%*	3.3%
Swollen Joint Count² (LS Mean)	-1.8	-3.8	-5.4*	-6.8**	-1.47	-4.02*	-5.3***
Tender Joint Count² (LS Mean)	-0.9	-6.3*	-7.9**	-12.9***	-1.87	-3.09	-7.25***
Patient's Assessment of Pain²	-5.4	-11.4	-16.2*	-23.7***	-2.13	-11.3**	-10.6**
Patient's Global Assessment of Disease Activity ² (mm)	-3.4	-11.0	-13.5#	-21.1***	2.5	-7.2**	-6.6**
Physician's Global Assessment of Disease Activity ² (mm)	-10.2	-13.4	-18.5#	-27.8***	-9.0	-15.8*	-18.2**
Patient's Assessment of Physical Function (MHAQ)²	0.0	-0.1	-0.3*	-0.4***	0.09	-0.13***	-0.03*
CRP² (mg/dL)	0.5	-0.3#	-0.8**	-1.7***	0.01	-0.8**	-0.6*
ESR² (mm/hr)	5.1	-4.0*	-4.3*	-11.4*	2.6	-4.3**	-8.6

¹Patients who were randomized and received at least one dose of study medication.

²Mean change from baseline. ACR20, ACR50 and ACR 70: ≥ 20%, ≥ 50% and ≥ 70%, respectively, improvement in tender or painful joint count and swollen joint count and ≥ 20%, ≥ 50% and ≥ 70% respectively, improvement in 3 of the 5 following parameters: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function (based on the modified health assessment questionnaire), and an acute-phase reactant (erythrocyte sedimentation rate or C-reactive protein). LS Mean: Least square means are based on general linear model analysis with treatment group and DMARD strata included in the model. #p ≤ 0.10, *p ≤ 0.05, **p ≤ 0.01,*** p ≤ 0.001

Phase II Study

In the randomized, double-blind, placebo-controlled study, (Study FK-506-RA-001), patients intolerant or resistant to methotrexate were enrolled and were also being treated with corticosteroids, such as prednisone or its equivalent and/or nonsteroidal anti-inflammatory drugs (NSAIDS) and /or analgesics. Patients were randomized to receive one of the following oral doses of study medication capsules: 1 mg FK506, 3 mg FK506, 5 mg FK506 or placebo once a day, for 6 months.

The primary and secondary efficacy endpoints evaluated in this patient population included the ACR20, 50 and 70 responses, as defined by the American College of Rheumatology, for improvement assessment in rheumatoid arthritis at the end of treatment. These criteria are based in corresponding increase of 20, 50 or 70% improvement in tender or painful joint counts and swollen joint counts and a 20%, 50% or 70% improvement in 3 of 5 of the following parameters: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function (based on the modified health assessment questionnaire), and an acute-phase reactant (ESR or C-reactive protein (CRP)).

The ACR20 response rate at the end of treatment was higher in all 3 dose groups, (29.0%) 1mg, 34.4% (3mg), 50.0% (5mg) compared to placebo (15.5%). The response rates in the 3 mg and 5 mg groups were statistically significantly higher than placebo (p=0.013 and <0.001, respectively), while the rate for the 1 mg group were not statistically significant (p=0.058). A difference in ACR20 response rates between placebo and active dose groups was first observed at Week 8, with substantial increases seen in the proportion of patients in the 5mg group who achieved ACR20 responses during Weeks 12 and 16.

While there were no differences in swollen and tender joint counts in all 3 dose groups at baseline, there was a definite dose response with the greatest improvement occurring in the 5mg dose group. Improvement in swollen joint count was significantly higher in the 3 mg and 5 mg groups than in the placebo group (p=0.029 and 0.002, respectively). Improvement in tender joint counts was significantly greater for the 1, 3 and 5 mg dose groups versus placebo (p=0.022, 0.004 and<0.001, respectively).

There was a statistically significant linear dose relationship over the 4 groups with respect to ACR20 at the end of treatment (p<0.001), swollen joint counts at end of treatment (p=0.001) and tender joint counts at the end of treatment (p<0.001). The primary efficacy measure indicated a dose response among the Prograf groups, with statistically significantly greater efficacy at the 3 and 5 mg dose levels versus placebo for all primary measures.

Phase III Studies

In a randomized, double-blind, placebo-controlled study, (Study 98-0-049), 465 patients who were concomitantly using prednisone (or its equivalent) and/or NSAIDS and had previously demonstrated resistance or intolerance to one or more disease-modifying antirheumatic drugs (DMARDS), were enrolled to receive either placebo, 2mg/day or 3mg/day Prograf, for a duration of 6 months.

Patients treated with Prograf generally experienced notable improvements in the ACR components of tender or painful joint counts, swollen joint counts as well as the physicians global assessment while experiencing either no change or a slight improvement in the other ACR components. The median time required for the first ACR20 response to be detected in the tacrolimus dose group (2mg/day and 3mg/day) was approximately 8 weeks and was achieved by approximately 42% of the patient population.

The ACR20 response rate at the end of treatment for the full analysis set was significantly greater in the 2mg and 3mg tacrolimus treatment groups as well as the combined treatment groups compared with placebo. The differences between the ACR20 response rates at the end of treatment for the 2mg tacrolimus treatment group and the placebo treatment group were not statistically significant (p=0.0595), while that for the 3mg tacrolimus treatment group and placebo were statistically significant (p=0.0001). The ACR20 response at the end of treatment demonstrated a dose-response relationship.

Based on the median percent change from baseline to the end of treatment, patients in the 2mg and 3mg tacrolimus treatment groups also generally experienced notable improvements in tender or painful joint counts, 10.5% (2mg) and 30.0% (3mg) versus 2.2% (placebo) as well as improvements in the swollen joint counts 16.7% (2mg) and 30.0% (3mg) verus 5.9% (placebo). With the exception of tender or painful joint counts for the 2mg tacrolimus treatment group, statistically significantly greater improvements from baseline to the end of treatment in each of the ACR component scores were observed in the 2mg tacrolimus treatment group, the 3mg tacrolimus treatment group and the combined tacrolimus treatment group as compared to placebo.

Among DMARD intolerant patients (those patients unable to continue on methotrexate therapy as determined by documented adverse events as judged by the investigator), significantly greater proportions of patients in the combined, 2mg and 3 mg tacrolimus treatment groups achieved ACR20 and ACR50 responses at the end of treatment compared with patients in the placebo treatment group. Among DMARD resistant patients ( a patient on 15mg/wk or more of methotrexate for at least 8 weeks who still presented with active disease), the proportion of patients achieving an ACR20 response at the end of treatment was not significantly different for the 2 mg tacrolimus treatment group or the combined tacrolimus treatment group compared with the placebo treatment group. However, a significantly greater proportion of DMARD resistant patients treated with 3 mg tacrolimus achieved an ACR20 response at the end of treatment compared with placebo. Among tacrolimus treated patients, ACR20, 50 and 70 response rates at the end of treatment were greater for DMARD intolerant patients compared with DMARD resistant patients.

In the long-term safety study, (Study 98-0-051), an extension of study 98-0-049, patients were treated for a 12 to 18 month duration. These patients demonstrated continued improvement in the ACR20 response rates with an overall response rate at the end of treatment of 37.6%. Approximately 30% of patients experienced an ACR 20 response within 3 months of receiving Prograf treatment. The ACR20 response rate was higher among patients who had previously received tacrolimus therapy in 98-0-049, at 45.5% (96/211) than among de novo patients enrolled in this study 35.2% (241/685), thereby indicating that those patients receiving a longer duration of treatment experienced a greater rate of response. Two of the greatest improvements in the median percent change from baseline were the ACR component scores at the end of treatment observed for swollen joint counts (47.5%) and tender or painful joint counts (50.0%)

DETAILED PHARMACOLOGY

Animal Studies

The primary mechanism of rejection following transplantation involves activation of T-lymphocytes and the subsequent formation of factors such as interleukin-2 (IL-2). Tacrolimus inhibits the activation of T-lymphocytes in both animals and humans, especially the activation that is calcium-dependent. The minimum inhibitory tissue culture level of tacrolimus that prevents antigen stimulation of T-lymphocytes is 0.1 nM - 0.3 nM. Tacrolimus interferes with the formation of active transcription factor NF-AT (nuclear factor of activated T-cells) and inhibits the formation of lymphokines such as IL-2, IL-3, IL-4, and interferon-γ. The net result is immunosuppression.

Tacrolimus significantly prolonged host survival and/or graft viability in animal transplant models involving the liver, kidney, heart, small bowel, lung, pancreas, pancreatic islet, bone marrow, skin, limb, cornea, and trachea. A dose range of 0.1 to 1 mg/kg/day PO or IM was used in most studies in various dosing regimens: (pre- and post-surgery, short- and long-term administration).

At intravenous doses of 0.32 to 3.2 mg/kg, and at oral doses of 3.2 to 32 mg/kg, tacrolimus showed little effect on general activity and the central nervous system; little or no effect on somatic and autonomic nervous systems and smooth muscle.

Most of the effects shown by IV tacrolimus in dogs and cats were also shown by the tacrolimus-placebo IV formulation. Intravenous tacrolimus at ≥ 0.1 mg/kg increased the respiration rate in dogs only; blood pressure was decreased by IV tacrolimus at ≥ 0.1 mg/kg in dogs, to a lesser extent at 3.2 mg/kg in cats, and by PO tacrolimus at 32 mg/kg in rats; heart rate was decreased by IV tacrolimus at ≥ 0.1mg/kg in dogs, at ≥ 0.32 mg/kg in cats, at 3.2 mg/kg in rats, and by PO tacrolimus at 10 and 32 mg/kg in rats; blood flow in femoral artery of dogs was decreased by IV tacrolimus at ≥ 0.1 mg/kg; carotid artery blood flow was increased at 3.2 mg/kg IV in cats.

Intravenous tacrolimus at ≥ 1.0 mg/kg increased pilocarpine-induced salivary secretion in rabbits and decreased gastric fluid secretion in rats; and, at 3.2 mg/kg, increased accumulation of intestinal fluid and slightly inhibited gastrointestinal transit rate in rats. Intravenous tacrolimus did not affect bile secretion nor produce irritation to gastric mucosa in rats. Gastrointestinal transit rate and accumulation of intestinal fluid in rats were not affected by PO tacrolimus. Bleeding time in mice and prothrombin time and activated partial thromboplastin time in rats were not affected by IV or PO tacrolimus. Tacrolimus did not affect ADP- or collagen-induced aggregation of rabbit platelets, or produce hemolysis in rabbit blood. Oral tacrolimus at 32 mg/kg slightly increased urine volume and Na⁺ excretion, but not excretion of K⁺, Cl^-, or uric acid, in rats; IV tacrolimus at 3.2 mg/kg had no effect. Oral tacrolimus had no effect on carrageenin-induced paw edema in rats.

When ¹⁴C-tacrolimus was dosed orally to pregnant or lactating rats, trace amounts of tacrolimus were found in fetal liver and in breast milk, respectively.

When ¹⁴C-tacrolimus was administered to rats, either intravenously or orally, total recovery of radioactivity in urine and feces was over 95%. Trace amounts of unchanged tacrolimus, as well as small amounts of numerous metabolites, were detected in urine, feces, and bile, indicating that the drug is extensively metabolized. In vitro studies identified the main metabolite as 13-demethylated-tacrolimus in animals and humans.

Human Studies

In vitro, several drugs have been shown to inhibit the metabolism of tacrolimus by human liver microsomes. Conversely, tacrolimus has been shown to inhibit the metabolism of other drugs (e.g., CyA). In vivo, the metabolism of tacrolimus is presumably by hepatic P450IIIA4. Therefore, there is a potential for a drug-drug interaction between tacrolimus and other drugs that are substrates for this P450 isozyme.

Five healthy volunteers received a single IV infusion of 0.03 mg/kg of tacrolimus. The mean (SD) pharmacokinetic parameters for whole blood concentrations were: half-life, 17.6 (4.6) h; volume of distribution, 0.63 (0.15) L/kg; and clearance, 0.032 (0.008) L/h/kg. The mean pharmacokinetic parameters for plasma concentrations were: half-life, 43.4 (14.7) h; volume of distribution, 16.9 (6.7) L/kg; and clearance, 0.43 (0.15) L/h/kg.

Table 29: Mean Pharmacokinetic Parameters for Tacrolimus Whole Blood Concentrations in Healthy Volunteers

Component	T_1/2 (h)	V_d (L)	V_d (L/kg)	Cl (L/h)	Cl (L/h/kg)
Blood	17.6	47.6	0.63	2.4	0.032
Plasma	43.4	1303	16.9	33.6	0.43

The administration of tacrolimus did not result in clinically significant immunosuppression in the subjects. Four of the 5 subjects experienced decreases in creatinine clearance that returned to normal within 2-9 days post-dose. The average creatinine clearance decreased from 110 mL/min at baseline to 90 mL/min between 12-48 hours post-dose. There were no clinically significant changes observed during 24-hour electrocardiogram monitoring.

The following pharmacokinetic parameters were calculated following the first IV dose of FK506 in kidney transplant patients: Elimination half-life (T_½), area under the concentration-time curve from 0 to 12 hours (AUC_0-12), area under the concentration-time curve from 0 to infinity

(AUC_0-∞), total body clearance (Cl), and volume of distribution at steady-state (V_ss).

Table 30: Mean Pharmacokinetic Parameters for Tacrolimus Whole Blood Concentrations following the Initial IV Dose of FK506 in Kidney Transplant Patients

Component

T_1/2

(h)

(L/h/kg)

V_ss

(L/kg)

AUC_0-12

(ng.h/mL)

AUC_0-∞

(ng.h/mL)

Blood

8.04 ± 4.88

0.12 ± 0.05

1.0 ± 0.36

481.0 ± 129

755.0 ± 297

Plasma

6.86 ± 2.92

4.29 ± 2.1

29.2 ± 15.8

20.0 ± 19.5

25.3 ± 20.9

The following pharmacokinetic parameters were calculated following maintenance oral dosing with FK506 in kidney transplant patients: bioavailability (BA), time to maximum concentration (T_max), maximum blood/plasma concentration (C_max), plasma/blood concentration before dosing (C_0h), and plasma/blood concentration 12 hours after dosing (C_12h).

Table 31: Mean Pharmacokinetic Parameters for Tacrolimus Whole Blood Concentrations following the Maintenance Oral Dosing of FK506 in Kidney Transplant Patients

Component

(%)

T_max

(h)

C_max

(ng/mL)

C_0h

(ng/mL)

C_12h

(ng/mL)

Blood

20.0 ± 17.8

4.2 ± 2.9

44.0 ± 4.2

15.0 ± 10

16.0 ± 12

Plasma

17.3 ± 12.0

3.1 ± 2.4

1.4 ± 1.7

0.4 ± 0.1

0.4 ± 0.2

There were great individual differences among the IV and oral pharmacokinetic parameters. However, C_0h and C_12h in whole blood and plasma from each patient following oral dosing were almost identical. It was suggested that steady-state was obtained upon repeated dosing.

In a prospective, multicentre study, 37 kidney transplant patients received 0.075 mg/kg IV infused over 4 hours twice daily, and were converted to oral tacrolimus at a dose of 0.3 mg/kg/day in two divided doses when they were able to tolerate oral medication. The results of this study suggested that if the range of trough whole blood tacrolimus levels is maintained between 15 and 20 ng/mL, the incidence of adverse events is decreased. Maintaining optimal therapeutic levels may also decrease the incidence of rejection. Results suggested that tacrolimus is better monitored with whole blood than with plasma, and that patient's trough tacrolimus levels in whole blood be maintained at 20 ng/mL for the initial 2 weeks following transplantation, then decreased to trough blood levels of 15 ng/mL for the next 12 weeks.

In an open-labelled study to evaluate the effect of hepatic dysfunction on the pharmacokinetics of tacrolimus, patients with and without liver impairment received 0.15 mg/kg IV tacrolimus over 1 to 2 hours and 0.15 mg/kg oral tacrolimus. The effect of T-tube clamping on the oral absorption of tacrolimus at 0.15 mg/kg was studied in 5 liver transplant patients, who had a duct to duct biliary reconstruction with a T-tube stent. In patients with moderate to severe hepatic dysfunction, the elimination half-life of tacrolimus was increased and the total body clearance was decreased, resulting in higher daily trough plasma concentrations. The bioavailability increased following oral administration of tacrolimus to hepatically impaired patients. Bile did not alter the absorption of tacrolimus. Dosage adjustments may be necessary for patients with severe hepatic impairment, but not for those patients with mild impairment.

The clearance of tacrolimus is independent of renal function; less than 1% is recovered unchanged in the urine. However, reducing the dose of tacrolimus may be necessary with deterioration of renal function in order to reduce the potential nephrotoxic effects of the drug.

Studies showed that as the dose of tacrolimus increased, a dose-proportional increase in AUC and C_max resulted. However, a large interpatient variability was observed. Whole blood and plasma trough concentrations taken 10-12 hours after oral administration of tacrolimus (C_min) correlated well with the AUC_0-12h r = 0.93-0.98, demonstrating that C_min is an accurate indicator of overall patient exposure to drug.

Children ≤ 12 years of age required approximately twice the adult IV and oral doses to attain similar tacrolimus plasma trough concentrations following liver transplantation.

Tacrolimus concentrations measured by EIA have been shown to correlate well with those determined by HDLC-MS assay specific for the parent compound, (r = 0.86 - 0.93), indicating that EIA provides a reliable measure of tacrolimus concentrations.

MICROBIOLOGY

Not Applicable.

TOXICOLOGY

Acute Toxicology

Table 32: Acute Toxicology Studies of Tacrolimus in Rats and Baboon
Species	No./ Group (M/F)	Route	Dose Range (mg/kg)	Overt Signs of Toxicology	LD₅₀ (mg/kg)
Rat, Sprague-Dawley	5/5	Gavage	32-320	Tremor, ptosis, salivation, hyperreactivity, decreased spontaneous motility	134 (M) 194 (F)
Rat, Sprague-Dawley	5/5	IV	10-100	Bloody urine, prone position, ptosis, hyper- reactivity, salivation, decreased motility	57.0 (M) 23.6 (F)
Rat, Sprague-Dawley (21 days old)	5/5	Gavage	10-320	Hyperreactivity, salivation, decreased motility	70 (M) 32-100 (F)
Baboon	1/1	Gavage	5-250	Huddled posture, emesis	ND*
Baboon	1/1	IV	2-50	Debility and exhaustion: 1 of 2	ND*

*Not determined

Subchronic and Chronic Toxicity

Both rats and baboons showed a similar toxicologic profile following oral or intravenous administration of tacrolimus. Toxicity following intravenous administration was evident at lower doses than after oral administration for both rats and baboons. Toxicity was seen at lower doses in rats than in baboons. The primary target organs of toxicity were the kidney, pancreatic islets of Langerhans and exocrine pancreas, spleen, thymus, gastrointestinal tract, and lymph nodes. In addition, decreases in erythrocyte parameters were seen. Effects such as atrophy of the spleen, lymph nodes, and thymus may be a reflection of the immunosuppressant actions of tacrolimus. In rats, chronic oral administration of tacrolimus at high doses resulted in changes in sex organs, and glaucoma/eye changes.

Rats receiving oral doses greater than 1 mg/kg/day for two and 13 weeks experienced decreased body weight gain, hypersalivation, hematology changes, elevated BUN, atrophy of the thymus and kidney, mineralization of the kidney, vacuolation of the islets of Langerhans, lenticular opacity and degeneration, and prostate contraction. In a 52-week study, the no-observable effect level was 0.15 mg/kg/day PO.

A 4-week oral toxicity study of tacrolimus in immature rats showed a similar toxicological profile; however, the severity of the changes noted appeared to be increased relative to mature animals. The no-observable effect level in immature rats was 0.32 mg/kg/day PO.

Rats receiving intravenous doses showed a dose-dependent decrease in weight gain. Micropathological changes were similar to those seen after oral administration of higher doses, and consisted of thymic, lymph node, and splenic atrophy, vacuolation of the pancreatic islets, reduced colloid and contraction of the prostate and seminal vesicles, uterine wall narrowing, and corticomedullary mineralization in the kidney. The no-observable effect level was 0.032 mg/kg/day IV.

Baboons receiving 10 mg/kg/day PO for 4 weeks, showed body weight loss, quiet behavior, huddled behavior, pelleted feces, and piloerection. There were no abnormal laboratory findings or lesions.

In a 13-week oral study, body weight gain increased after the first 4 weeks in a manner parallel to that of controls. There were incidences of drowsiness and 4 huddled and/or unnatural posture. Histopathological examination indicated atrophy of the thymus and spleen. The no-observable effect level was 1 mg/kg/day PO.

A second 13-week oral study additionally produced intermittent tremors, unsteadiness, gingivitis, and emesis. There was a slight reduction in packed cell volume and hemoglobin, and a slight increase in clotting time in the high-dosage group animals. Elevations in BUN and blood glucose levels and a reduction in serum cholesterol concentration were dose related. There were increased levels of total reducing substances and glucose, and significant reductions in absolute thymus and pancreas weight in both dosage groups. There were dose-related pathological changes in the thymus (atrophy), spleen (atrophy), lymph nodes (atrophy), pancreas (exocrine cell degranulation or increased eosinophilic islet cells), intestinal tract (lymphoid infiltration, ulceration), and kidneys (interstitial inflammation).

Oral administration to baboons for 52 weeks at doses of 0, 1, 3.2, or 10 mg/kg/day resulted in an initial decreased weight gain, increase in urinary glucose and reducing substances, and pathological changes in the thymus, lymph nodes, and pancreas. The no-observable effect level was 1 mg/kg/day PO.

IV administration of tacrolimus to baboons for 4 weeks at doses of 0.5, 1, or 2 mg/kg/day resulted in overt signs of toxicity in all animals. Body weight gain was reduced and animals displayed quiet behavior, huddled posture, sleepiness, and piloerection. One out of 3 female animals at 2 mg/kg was sacrificed because of overt toxicity. BUN and serum potassium were elevated in animals dosed at 1 and 2 mg/kg. Glucose and total reducing substances were present in urine samples from one animal in each of the treatment groups. Pathological changes were noted in the thymus (atrophy), lymph nodes (atrophy), spleen (atrophy), and pancreatic islets (angiectasis of islets).

Carcinogenicity

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

An 80 week study in mice administered tacrolimus at oral doses of 0.3, 1.0 and 3.0 mg/kg/day showed no evidence of tumorigenicity. The 104 week studies in rats administered tacrolimus at oral doses of 0.2, 0.5, 1.25, 2.5 and 5.0 mg/kg/day demonstrated no evidence of tumorigenicity.

The carcinogenicity potential of FK506 has been evaluated in mice and rats. Mice (56/sex) were administered FK506 as a dietary admix at doses of 0 (control), 0 (placebo), 0.3, 1 and 3 mg/kg/day. There was no evidence of any tumorigenic potential of FK506 in this study. Signs of toxicity were evident in the form of reduced bodyweight gain in both sexes receiving 3.0 mg/kg/day and for males receiving 1 mg/kg/day. For males receiving 3.0 mg/kg/day, there was a reduction in the efficiency of food utilization. An increase in mortality for males at 3.0 mg/kg/day was accompanied by pathological findings of minimal adipose tissue and fur staining, evidence of dysfunctional testes/epididymides, prostate glands and seminal vesicles. Males and females at 3.0 mg/kg/day also demonstrated reduced islets of Langerhans and increased basophilia and cellularity of islets. The no-effect level was considered to be 0.3 mg/kg/day in both sexes. In addition, 1 mg/kg/day was a no-effect level for females only.

Rats (55/sex/group) were administered FK506 as a dietary admix at doses of 0 (basal diet), 0 (placebo), 0.2, 0.5 and 1.25 mg/kg/day. There was no evidence of any tumorigenic potential for FK506 in this study, nor were there any FK506 administration-related effects on factors contributory to death. Evidence of toxicity were reduced body weight gain in both sexes at 1.25 mg/kg/day and in males at 0.5 mg/kg/day. The non-toxic dose level in the study was 0.2 mg/kg/day for males and 0.5 mg/kg/day for females.

FK506 was administered to rats as a dietary admix in the supplementary study, at doses of 0 (placebo) to 50/sex, and 2.5 mg/kg/day (100/sex). In the absence of clear toxicity, at the end of week 26, the FK506-treated group was divided into two groups (50/sex/group). One group received a dose of 2.5 mg/kg/day whereas the dose in the other group was increased to 5.0 mg/kg/day. There was no evidence of tumorigenic potential at either dose level. Evidence of toxicity were dose-related mortality rates, reduced body weight gain and histopathological changes; toxicity was more pronounced in males. There was no non-toxic dose in this study.

Reproductive and Developmental Toxicity

Oral doses of tacrolimus at 1 and 3.2 mg/kg/day produced overt signs of parental toxicity and changes in the fertility and general reproductive performance study (Segment I) of rats. Effects on reproduction included some embryo lethality, reduced number of implantations, increased incidence of post-implantation loss, and reduced embryo and offspring viability. In this study, the no-observable effect level of tacrolimus in the rat was considered to be 0.32 mg/kg/day (1 to 2 times the recommended human dose).

In a rat teratology study (Segment II), increased post-implantation loss was observed at 3.2 mg/kg/day PO. Maternal doses of 1 mg/kg/day decreased the body weight of F₁ offspring. Decreased body weight, reduced survival number, and some skeletal alterations were seen in F₁ offspring at maternal doses of 3.2 mg/kg/day. The maternal and developmental no-observable effect level was 1 mg/kg/day (3 to 6 times the recommended human dose).

In a rabbit teratology study (Segment II), signs of maternal toxicity including reduced body weight were produced at all oral doses of tacrolimus administered (0.1, 0.32, or 1 mg/kg/day). Doses of 0.32 and 1 mg/kg/day produced signs of developmental toxicity, such as increased incidence of post-implantation losses, reduced number of viable fetuses, and increased incidences of morphological variations. The incidence of toxicity relative to that in controls suggests that the no-observable-effect dose of tacrolimus may be 0.32 mg/kg/day (1 to 2 times the recommended human dose).

In a Segment III study, oral doses of 3.2 mg/kg/day produced a decrease in body weight and food consumption in F₀ dams during gestation and lactation. The no-observable effect level with respect to maternal and developmental toxicity was 1 mg/kg/day (3 times the recommended human dose) and greater than 3.2 mg/kg/day with respect to reproductive potential.

Special Studies

The toxicity of tacrolimus degradation products and a dosage form excipient were studied for antigenicity, effects on morphology and function of pancreas, and local irritation in several species. The acute IV toxicity of known heat- and light-degradation products of tacrolimus, a tacrolimus tautomer, related compounds, and a tacrolimus metabolite was assessed in mice. The acute toxicity of these compounds was not greater than that of tacrolimus as bulk drug or as the IV formulation.

Antigenicity studies produced no antibody formation in mice, and no skin reactions, sensitization, or delayed hypersensitivity reactions.

Tacrolimus produced a reversible, dose-dependent, pancreatic islet cell toxicity in rats; there were no effects on pancreatic exocrine function.

The irritation potential of the IV formulation of tacrolimus was similar to that of 0.425% acetic acid.

REFERENCES

Fung JJ, Alessiani M, Abu-Elmagd, et al. Adverse effects associated with the use of FK506. Transplant Proc. 1991;23:3105-3108.

Ali Shah I, Whiting PH, Omar G, Thomson A, Burke MD. Effects on FK506 on human hepatic microsomal cytochrome P450-dependent drug metabolism in vitro. Transplant Proc. 1991;23:2783-2785.

Bumgardner GL, Matas AJ. Transplantation and pregnancy. Transplant Rev. 1992;6:139-162.

Jain A, Venkataramanan R, Fung J, Warty V, Tzakis A, Starzl T. Pregnancy in liver transplant patients under FK506. Am Soc Transplant Physicians. 1993, abstract.

Pichard L, Fabre I, Domergue J, Joyeux H, Maurel P. Effect on FK506 on human hepatic cytochrome P450: interaction with CyA. Transplant Proc. 1991;23:2791-2793.

Moochhala SM, Lee EJD, Ernest L, Wong JYY, Ngoi SS. Inhibition of drug metabolism in rat and human liver microsomes by FK506 and cyclosporine. Transplant Proc. 1991;23:2786-2788.

Jain AB, Venkataramanan R, Fung J, et al. Pharmacokinetics of cyclosporine and nephrotoxicity in orthotopic liver transplant patients rescued with FK506. Transplant Proc. 1991;23:2777-2779.

Pichard L, Fabre I, Fabre G, et al. Cyclosporine A drug interactions; screening for inducers and inhibitors of cytochrome P450 (cyclosporine A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos. 1990;18:595-606.

Iwasaki K, Matsuda H. Effect of co-dosing drugs on metabolism of FK506 by human liver microsomes. Report R92-0069-506-P5-E. Fujisawa USA, Inc., Deerfield, Il. 1992.

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.

Suranyi MG, Hall BM. Current status of renal transplantation. West Med J. 1990;152:687-696.

Keeffe EB. Liver transplantation and surgery. Curr Opin Gastroenterol. 1992;8:433-438.

Fung J, Abu-Elmagd, Jain A, et al. A randomized trial of primary liver transplantation under immunosuppression with FK506 vs. cyclosporine. Transplant Proc. 1991;23:2977-2983.

Todo S, Fung JJ, Tzsaki A, et al. One hundred-ten consecutive primary orthotopic liver transplants under FK506 in adults. Transplant Proc. 1991;23:1397-1402.

Jain AB, Fung JJ, Todo S. Incidence and treatment of rejection episodes in primary orthotropic liver transplantation under FK506. Transplant Proc. 1991;23:928-930.

Tzakis, AG, Reyes J, Todo S, et al. FK506 versus cyclosporine in pediatric liver transplantation. Transplant Proc. 1991;23:3010-3015.

Takaya S, Brosthner O, Todo S, et al. Retransplantation of liver: a comparison of FK506 and cyclosporine-treated patients. Transplant Proc. 1991;23(6):3026-3028.

Venkataramanan R, Jain A, Cadoff E, et al. Effect of hepatic dysfunction and T-tube clamping on FK506 pharmacokinetics and trough concentrations. Transplant Proc. 1990;22(1, Supplement 1):57-59.

Piekoszewski W, Jusko WJ. Plasma protein binding of tacrolimus in humans. J of Pharm Sci. 1993;82:340-341.

Lhoest G, Wallemacq P, Verbeeck R. Isolation and mass spectrometric identification of five metabolites of FK506, a novel macrolide immunosuppressive agent, from human plasma. Pharm Acta Helv. 1991;66:302-306.

Christians U, Radeke H, Kownatzki R, et al. Isolation of an immunosuppressive metabolite of FK506 generated by human microsome preparations. Clinical Biochemistry. 1991;24:271-275.

Iwaskai KA, Nagase K, and Matsuda H. Metabolism of C-FK506 by rat and human liver microsomes. Fujisawa Pharmaceutical Co., Ltd. Report CRR920238, 1992.

Nagase K, Iwaska K, and Noda K. Binding of FK506 to plasma and plasma proteins. Fujisawa Pharmaceutical Co., Ltd. Report CRR920219, 1992.

Christians V, Braun F, Kosian N, Schmidt M, Schiebel HM, Ernst L, Kruse C, Winkler M, Holze I, Linck A, and Sewing K-FR. High performance liquid chromatography/mass spectrometry of FK506 and its metabolites in blood, bile and urine of liver grafted patients. Transplant Proc. 1991;23:2741-2744.

McCauley J, Fung J, Jain A, et al. The effects of FK506 on renal function after liver transplantation. Transplant Proc. 1990;22(Supplement 1):17-20.

Todo S, Fung JJ, Demetris AJ, Jain A, Venkataramanan R, Starzl T. Early trials with FK506 as primary treatment in liver transplantation. Transplant Proc. 1990;22:13-16.

Alessiani M, Cillo U, Fung JJ, et al. Adverse effects on FK506 overdosage after liver transplantation. Transplant Proc. 1993;25:628-634.

Schleibner S, Krauss M, Wagner E, Erhard J, Christiaans M, Van Hooff J, Buist L, Mayer D. FK506 versus cyclosporine in the prevention of renal allograft rejection - European pilot study: Six week results. Transplant International. 1995;8(2):86-90.

Shapiro R, Jordan M, Scantlebury V, Vivas C, Fung J, McCauley J, Tzakis A, Randhawa P, Demetris AJ, Irish W, et al. A prospective, randomized trial of FK-506 in renal transplantation -- a comparison between double- and triple-drug therapy. Clin Transplant. 1994;8(4):508-515.

Jordan ML, Shapiro R, Vivas CA, et al. FK506 "rescue" for resistant rejection of renal allografts under primary cyclosporine immunosuppression. Transplantation 1994;57:860-865

Kitamura M, Hiraga S, Kobayashi D, et al. Clinical experience of FK 506 for renal allograft transplantation. Transplant Proc 1994;26:1924-1926.

Shapiro P, Scantlebury VP, Jordan ML, et al. FK506 in pediatric kidney transplantation: Primary and rescue experience. Pediatric Nephrol. 1995;9:S43-S48.

Inomata Y, Tanaka K, Egawa H, et al. The evolution of immunosuppression with FK506 in pediatric living-related liver transplantation. Transplantation 1996; 61:247-252.

Wiesner RH, et al. Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology, 1998 Sep;28(3):638-45.

Dunn SP, et al. Rejection after pediatric liver transplantation is not the limiting factor to survival. J Pediatr Surg. 1994 Aug;29(8):1141-4.

Esquivel CO, et al. Suggested guidelines for the use of tacrolimus in pediatric liver transplant patients. Transplantation. 1996 Mar 15;61(5):847-8.

Busuttil RW, et al. General guidelines for the use of tacrolimus in adult liver transplant patients. Transplantation. 1996 Mar 15;61(5):845-7.

Vincenti F., et al. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation. 2002 Mar 15;73(5):775-782

Wiesner Russell H., A long term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation. Transplantation. 1998 Aug 27;66(4):493-9

Wood N., et al., Antimicrobial Pharmacokinetics, Pharmacodynamics and General Pharmacology, "Effect of voriconazole on the pharmacokinetics of tacrolimus". 41^st ICAAC Abstracts. 2001 September 22-25, A-20.

Venkataramanan Raman, et al., Antimicrobial Pharmacokinetics, Pharmacodynamics and General Pharmacology, "Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes". 41^st ICAAC Abstracts. 2001 September 22-25, A-21.

Schulam Seth. et al., Interaction between tacrolimus and chloramphenicol in a renal transplant recipient. Transplantation. 1998 May 27;65(10):1397-8

Taber D.J., et al., Drug-drug interaction between chloramphenicol and tacrolimus in a liver transplant recipient. Transplantation Proceedings. 2000;32:660-662

Mathis A.S., et al., Interaction of chloramphenicol and the calcineurin inhibitors in renal transplant recipients. Transplant Infectious Disease. 2002;4:169-174

Austin Stephen and Bekersky Ihor, Effects of magnesia and alumina liquid antacid (Maalox®) on the absorption of tacrolimus (Prograf®) in healthy volunteers. Report No. 2001019581-1. Fujisawa Healthcare Inc., Deerfield Illinois. 2001.

Cancidas® (caspofungin acetate) for injection. Prescribing Information, Merck and Co. Inc. 2001.

Sundaram Hariharan et al., Pharmacokinetics (PK) and tolerability of tacrolimus and sirolimus combination therapy in stable renal transplant recipients. American Journal of Transplantation. 2001;406 (Supplement 1):Abstract no. 1074

Pirsch John, et al. Coadministration of tacrolimus and Mycophenolate in stable kidney transplant patients: pharmacokinetics and tolerability. J. Clin. Pharmacol. 2000;40(5):527-532.

Brown Nigel W., et al. Mycophenolic acid and Mycophenolic acid glucuronide pharmacokinetics in pediatric liver transplant recipients: effect of cyclosporine and tacrolimus comedication. Therapeutic Drug Monitoring. 2002;24:598-606

Gelder Teun van, et al., Coadministration of tacrolimus (FK) and Mycophenolate Mofetil (MMF) does not increase Mycophenolic acid ( MPA) exposure, but coadministration of cyclosporine (CsA) and MMF inhibits the enterohepatic recirculation of MPA, thereby decreasing its exposure. The Journal of the Heart and Lung Transplantation. 2001 Februrary;20(2):160-1

Hodak Stephen P., et al. QT prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration. Transplantation. 1998 Aug 27;66(4):535-7

Johnson Mark C. et al., QT prolongation and torsades de pointes after administration of FK506. Transplantation. 1992 April;53(4):929-930.

PART III: CONSUMER INFORMATION

TRANSPLANTATION

PROGRAF®

(tacrolimus injection and capsule)

This leaflet is part III of a three-part "Product Monograph" published when Prograf was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Prograf. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

You have received a prescription for Prograf capsules from your doctor. As you know, you need special medication, every day, to help keep your transplanted organ healthy and functioning. Prograf is a drug that is used to help your body accept your transplanted organ.

IT IS VERY IMPORTANT that you read the following information carefully. Your doctor, nurse, and pharmacist have explained Prograf to you, and this information will answer some of the questions you may have about your new medication. The success of treatment with this drug depends on how carefully you follow your doctor's instructions. As you review this information, write down any questions that you may have. Then, talk with your doctor, nurse or pharmacist. This information should not replace your doctor's or pharmacist's advice.

What the medication is used for:

Prograf is the brand name for tacrolimus. You may have also heard it called FK506. Prograf is an immunosuppressant that is used concomitantly with adrenal corticosteroids to prevent or treat rejection of your transplanted organ.

What it does:

Your body's immune system is your defence system. Immunity is the way your body protects itself from infections and other foreign material. When you receive a transplant, your immune system recognizes the transplanted organ as foreign and will try to reject it. Prograf is an anti-rejection drug that helps your body accept your transplanted organ(s).

When it should not be used:

Prograf may cause fetal abnormalities and malformations. For this reason it is recommended that you do not take Prograf if you are, or become, pregnant. You must use a reliable method of birth control before, during your treatment and for 6 weeks after stopping your treatment with Prograf. Should you become pregnant during the time you are taking Prograf, you should inform your doctor at once. However, never stop taking Prograf without first consulting your doctor.

Breast-feeding is not recommended while taking Prograf.

What the medicinal ingredient is: tacrolimus

What the important nonmedicinal ingredients are:

Lactose Monohydrate, NF
Magnesium Stearate, NF

For a full listing of nonmedicinal ingredients see Part 1 of the product monograph.

What dosage forms it comes in:

Prograf is available in one-half milligram capsules, 1 milligram capsules and 5 milligram capsules. The 0.5 mg capsules are light yellow and oblong with "0.5 mg" written on the capsule top. The 1 mg capsules are white and oblong, with "1 mg" written on the capsule top. The 5 milligram capsules are grayish/red, oblong, and have "5 mg" written on the capsule top.

WARNINGS AND PRECAUTIONS

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

BEFORE you use Prograf be sure you have told your doctor the following:

If you have taken Prograf, FK506 or tacrolimus before and had a bad, unusual or allergic reaction;
About all other medicines or treatments you use, including any products you buy off the shelf such as over-the-counter drugs and herbal or home remedies;
About all other health conditions you have now, or have had in the past;
If you are pregnant, plan to become pregnant, or are breastfeeding a baby: Pregnancy should be avoided while taking Prograf because its effect on pregnancy or on an unborn baby is not known. Breast-feeding is not recommended while taking Prograf. It is important to notify your doctor right away if you become pregnant or father a child while taking Prograf.
It is not known what effect Prograf has on the effectiveness of vaccinations and on the risk of getting an illness from vaccination with a live vaccine. Do discuss this with your doctor before you get any vaccinations or immunizations.

Precautions

Prograf is often given with other medications. Make sure you know if you are to stop, or continue, other immunosuppressive drugs you had been taking.

Be sure that you are taking the correct dose of Prograf prescribed by your doctor.

Be sure to keep all appointments at your transplant clinic. This is very important to help ensure that you receive the maximum benefit from your medications.
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 sunscreen with a high protection factor.
Tell all health professionals you see that you are taking Prograf. It is also a good idea to wear a Medic-Alert bracelet.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor, dentist, nurse, and pharmacist about all the drugs that you are taking. Other drugs may affect the way Prograf works for you and it is important that your doctor and pharmacist knows all the medications you are taking. Do not take any other drugs without asking your doctor first. This includes anything you can buy off the shelf such as over-the-counter drugs and herbal or home remedies.

Prograf should not be taken with grapefruit or grapefruit juice.

PROPER USE OF THIS MEDICATION

Usual dose:

Your doctor will give you specific instructions about how much Prograf you should take each day. Your doctor has decided the dose you should take based on your medical condition and response to the drug. It is very important to take the exact amount of Prograf that your doctor has told you.

Once your doctor has told you when and how many times a day to take Prograf.

Try to take your doses at the same time every day. This will help keep the same amount of Prograf in your body so it can continue to protect your transplanted organ.

Space your doses of Prograf as evenly as you can throughout the day. For example, if you take Prograf twice a day, doses should be 12 hours apart. Ask your transplant nurse or pharmacist about a dosing schedule that best fits your lifestyle.

Prograf may be taken with or without food. But it is best to be consistent. Once you decide when you are going to take it in relation to food, do it the same way each time.

Swallow the capsules whole. Do not cut, crush, or chew the Prograf capsule.

Blood tests are one of the ways your doctor decides how much Prograf you need. Based on these tests and your response to Prograf, your doctor may change your dose from time to time. Do not change your dose on your own.

Overdose:

Limited experience with overdosages is available. Overdosages of up to 30 times the intended dose have been reported. Almost all cases have had no symptoms and all patients have recovered. On occasion, an overdoseage has been followed by adverse reactions consistent with those listed

in the section entitled Side Effects And What To Do About Them.

Missed Dose:

Missing even a few doses of Prograf may cause your body to reject your transplanted organ. That is why it is very important to take each dose as your doctor prescribed. If you have trouble remembering doses, or if you are uncertain about how to take them, talk to your doctor, nurse or pharmacist and be sure to discuss any concerns you have about taking Prograf as prescribed.

If you do miss a dose of Prograf do not try to catch up on your own; instead call your doctor or pharmacist right away for advice. It is also a good idea to ask your doctor ahead of time what to do about missed doses.

Never allow your medication to run out between refills and be sure to take enough medication with you when you will be away from home for any extended period of time.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like other medicines, Prograf may cause side effects in some people. If you think that you are having side effects, talk to your doctor right away. DO NOT stop taking Prograf on your own.

Because Prograf decreases the function of your immune system you may be more likely to get an infection. Tell your doctor right away about any cold or flu-like symptoms (such as fever or sore throat), any mouth sores or burning discomfort with urination.

Be sure to tell your doctor right away if you notice any of these symptoms, and especially if they continue, bother you in any way, or seem to increase in intensity:
- diarrhea, nausea, constipation, vomiting, loss of appetite, stomach pain
- headache, tremors, convulsions, tiredness or fatigue, difficulty sleeping, nightmares
- urinary tract infection, weakness
- decreased or increased urine volumes, kidney or liver problems
- diabetes/increased blood sugar, swelling or tingling in your hands and feet
- palpitations, abnormal heart rhythms, chest pain, high blood pressure;
- fever, back pain, changes in mood or emotions, difficulty in breathing.

Immunosuppressive drugs including Prograf may also increase your chances of developing certain types of cancer. The following are possible warning signs of cancer and should be reported to your doctor as soon as possible:
- any sore that does not heal;
- unusual bleeding or discharge;
- the appearance of a lump or thickened areas in your breast or anywhere else on your body;
- unexplained stomach upset or any trouble with swallowing;
- any noticeable change in a wart or a mole;
- a nagging cough or hoarseness;
- night sweats:
- persistent and severe headaches;
- swollen lymph nodes;
- a change in your bowel or bladder habits.

It is important to regularly tell your doctor how you are feeling and if you have developed any new symptoms while taking Prograf.

This is not a complete list of side effects. For any unexpected effects while taking Prograf, contact your doctor or pharmacist.

HOW TO STORE IT

Keep Prograf out of the reach and away from children. A child who accidentally takes Prograf may be seriously harmed. All drugs should be kept in a locked drawer or cupboard if there are children who may accidentally take your drugs. Should anyone accidentally or mistakenly take Prograf, contact your physician immediately.

Always store Prograf at room temperature (15EC to 30EC) in the container or package that was dispensed by your pharmacist

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax: 866-678-6789

By email: cadrmp@hc-sc.gc.ca

By regular mail:
National AR Centre
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

If you have additional questions or would like to talk with someone to explain something you are worried about, ask your doctor, nurse, pharmacist, or other members of the Transplant Team. They are your best resource for guidance and information.

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.astellas.com/ca

or by contacting the sponsor, Astellas Pharma Canada, Inc., at:

1-800-668-8641

This leaflet was prepared by Astellas Pharma Canada, Inc.

Last revised: October 31, 2006.

PART III: CONSUMER INFORMATION

RHEUMATOID ARTHRITIS

PROGRAF^®

(tacrolimus capsules)

This leaflet is part III of a three-part "Product Monograph" published when Prograf ^® was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Prograf^®. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Prograf is the brand name for tacrolimus. You may have also heard it called FK506. Prograf is an immunosuppressant that is used alone or in combination with other drugs to reduce the symptoms experienced by patients with rheumatoid arthritis.

What it does:

Rheumatoid arthritis is an autoimmune disorder of unknown cause in which the bone joint lining (synovium) is attacked by the immune system. The mechanism of action of tacrolimus in rheumatoid arthritis is not known. Approximately 8 weeks of treatment with Prograf may be required before any significant improvement is noted in your symptoms of rheumatoid arthritis.

When it should not be used:

Breast-feeding is not recommended while taking Prograf.

What the medicinal ingredient is: tacrolimus

What the important nonmedicinal ingredients are:

Lactose Monohydrate, NF
Magnesium Stearate, NF

For a full listing of nonmedicinal ingredients see Part 1 of the product monograph.

What dosage forms it comes in:

Prograf is available in one-half milligram capsules and 1 milligram capsules and 5 milligram capsules. The 0.5 mg capsules are light yellow and oblong with "0.5 mg" written on the capsule top. The 1 mg capsules are white and oblong, with "1 mg" written on the capsule top. The 5 milligram capsules are grayish/red, oblong, and have "5 mg" written on the capsule top.

WARNINGS AND PRECAUTIONS

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

BEFORE you use Prograf be sure you have told your doctor the following:

If you have taken Prograf, FK506 or tacrolimus before and had a bad, unusual or allergic reaction;
About all other medicines or treatments you use, including any products you buy off the shelf such as over-the-counter drugs and herbal or home remedies;
About all other health conditions you have now, or have had in the past;
If you are pregnant, plan to become pregnant, or are breastfeeding a baby: Pregnancy should be avoided while taking Prograf because its effect on pregnancy or on an unborn baby is not known. Breast-feeding is not recommended while taking Prograf. It is important to notify your doctor right away if you become pregnant or father a child while taking Prograf.
It is not known what effect Prograf has on the effectiveness of vaccinations and on the risk of getting an illness from vaccination with a live vaccine. Do discuss this with your doctor before you get any vaccinations or immunizations.

Precautions

Prograf is often given with other medications. Make sure you know if you are to stop, or continue, other drugs you had been taking.
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 sunscreen with a high protection factor.
Be sure that you are taking the correct dose of Prograf prescribed by your doctor.
Tell all health professionals you see that you are taking Prograf. It is also a good idea to wear a Medic-Alert bracelet.

INTERACTIONS WITH THIS MEDICATION

Prograf should not be taken with grapefruit or grapefruit juice.

PROPER USE OF THIS MEDICATION

Usual dose:

Your doctor will decide the dosage. The usual adult dosage is 3mg taken once daily.

Prograf may be taken with or without food. But it is best to be consistent. Once you decide when you are going to take it in relation to food, do it the same way each time.

Swallow the capsules whole. Do not cut, crush, or chew the Prograf capsule.

Try to take your doses at the same time every day.

Overdose:

Missed Dose:

If you do miss a dose of Prograf, skip this dose and take the next one at the regular scheduled time. Call your doctor or pharmacist right away for advice. It is also a good idea to ask your doctor ahead of time what to do about missed doses.

Do not allow your medication to run out between refills and be sure to take enough medication with you when you will be away from home for any extended period of time.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like other medicines, Prograf may cause side effects in some people. If you think that you are having side effects, talk to your doctor right away.

Because Prograf decreases the function of your immune system you may be more likely to get an infection. Tell your doctor right away about any cold or flu-like symptoms (such as fever or sore throat), any mouth sores or burning discomfort with urination.
Be sure to tell your doctor right away if you notice any of these symptoms, and especially if they continue, bother you in any way, or seem to increase in intensity:
- diarrhea, nausea, vomiting, stomach pain;
- headache, tremors, convulsions, difficulty sleeping,
- pain and /or burning during urination which may be signs of a urinary tract infection;
- decreased or increased urine volumes, dark coloured urine which may be a sign of kidney problems or yellowing of the skin or eyes or back pain which may be a sign of liver problems.
- diabetes/increased blood sugar, swelling or tingling in your hands and feet;
- palpitations, abnormal heart rhythms, chest pain, high blood pressure, fever.

Immunosuppressive drugs including Prograf may also increase your chances of developing certain types of cancer. The following are possible warning signs of cancer and should be reported to your doctor as soon as possible:
- any sore that does not heal;
- unusual bleeding or discharge;
- the appearance of a lump or thickened areas in your breast or anywhere else on your body;
- unexplained stomach upset or any trouble with swallowing;
- any noticeable change in a wart or a mole;
- a nagging cough or hoarseness;
- night sweats:
- persistent and severe headaches;
- swollen lymph nodes;
- a change in your bowel or bladder habits.

It is important to regularly tell your doctor how you are feeling and if you have developed any new symptoms while taking Prograf.

This is not a complete list of side effects. For any unexpected effects while taking Prograf, contact your doctor or pharmacist.

HOW TO STORE IT

Always store Prograf at room temperature (15EC to 30EC) in the container or package that was dispensed by your pharmacist.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax: 866-678-6789

By email: cadrmp@hc-sc.gc.ca

By regular mail:
National AR Centre
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

If you have additional questions or would like to talk with someone to explain something you are worried about, ask your doctor, nurse, pharmacist. They are your best resource for guidance and information.

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.astellas.com/ca/

or by contacting the sponsor, Astellas Pharma Canada, Inc., at:

1-800-668-8641

This leaflet was prepared by Astellas Pharma Canada, Inc.

Last revised: October 31, 2006.

Immunology Prograf®

Immunology Prograf^®