Astellas Pharma Canada, Inc.

PRODUCT MONOGRAPH

^PrAdvagraf ^TM

Tacrolimus extended release capsules

0.5mg, 1mg and 5mg capsules

Immunosuppressant

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

Submission Control No: 116714

Date of Preparation:
October 9, 2007

^PrAdvagraf ^TM

(tacrolimus extended release capsules)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Oral

0.5mg, 1mg and 5mg capsules

lactose, magnesium stearate, gelatin (capsule shell).

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

INDICATIONS AND CLINICAL USE

Advagraf (tacrolimus extended release capsules) is indicated for prophylaxis of organ rejection in adult patients receiving allogeneic kidney transplants.

Advagraf is to be used concomitantly with adrenal corticosteroids and mycophenolate mofetil (MMF) in de novo renal transplant recipients. Antibody induction therapy should also be used in kidney transplant recipients.

Stable renal transplant patients may be converted from Prograf to Advagraf, in combination with adrenal corticosteroids and MMF based on equivalent tacrolimus blood concentrations.

Pediatrics (< 18 years of age): Experience with Advagraf in pediatric kidney transplant patients is limited.

Geriatrics (≥ 65 years of age): Experience with Advagraf in patients older than 65 years of age is limited.

CONTRAINDICATIONS

Advagraf (tacrolimus extended release capsules) is contraindicated in patients with 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.

WARNINGS AND PRECAUTIONS

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant should prescribe Advagraf (tacrolimus extended release capsules). 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.

General

In de novo kidney transplant patients AUC_0-24 of tacrolimus for Advagraf on day 1 is significantly lower in comparison with that for Prograf at equivalent doses. By day 3, tacrolimus exposure as measured by trough levels is similar for both formulations. All patients in the clinical studies received antibody induction therapy. Advagraf is only approved to be used in combination with adrenal corticosteroids and MMF.

In clinical studies for stable patients converted from Prograf to Advagraf on 1:1 (mg:mg) total daily dose basis, approximately one-third of patients required dose adjustment after conversion during the early conversion period due to dosing errors, adverse events, or levels outside the target range. Tacrolimus blood trough levels should be measured and closely monitored prior to and after conversion. Conversion to Advagraf has primarily been studied from Prograf in combination with adrenal corticosteroids and MMF based on equivalent tacrolimus blood concentrations.

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 Advagraf recipients may be higher than in the normal, healthy population.

Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen with tacrolimus. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.

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

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

Cardiovascular

Heart failure, myocardial hypertrophy and arrhythmia have been reported in association with the administration of Prograf.

Hypertension is a common adverse effect of tacrolimus therapy (see Adverse Reactions). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. Tacrolimus should be discontinued in patients in whom hypertension and hyperkalemia cannot be controlled.

While calcium-channel blocking agents can be effective in treating tacrolimus-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions).

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

In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered.

Hepatic/Biliary/Pancreatic

Tacrolimus has been associated with hyperglycemia and posttransplant diabetes mellitus. New onset glucose intolerance, defined as fasting plasma glucose ≥ 126 mg/dl, insulin use ≥ 30 days or oral hypoglycemic use, was determined in a 1-year prospective, comparative, phase III trial of Advagraf in de novo kidney transplant recipients (Tables 1- 2).

Table 1: New Onset Glucose Intolerance in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
	Advagraf/MMF (n=163)	Prograf/MMF (n=150)	Neoral/MMF (n=152)
Fasting Plasma Glucose ≥ 126 mg/dl	56.4%	64.0%	52.6%
Insulin Use ≥ 30 days	5.5%	6.0%	2.6%
Oral Hypoglycemic Use	14.1%	10.0%	3.3%

All regimens included corticosteroids. At risk population.

Table 2: New Onset Glucose Intolerance in De Novo Kidney Black Transplant Recipients at 1 Year Posttransplant
	Advagraf/MMF (n=35)	Prograf/MMF (n=33)	Neoral/MMF (n=25)
Fasting Plasma Glucose ≥ 126 mg/dl	54.3%	54.5%	36.0%
Insulin Use ≥ 30 days	8.6%	6.1%	4.0%
Oral Hypoglycemic Use	20.0%	12.1%	0

All regimens included corticosteroids. At risk population.

Immune

As in patients receiving other immunosuppressants, patients receiving Advagraf are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to Advagraf following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system, which can increase susceptibility to infection, combination immunosuppressant therapy other than corticosteroids and MMF is not recommended.

Neurologic

Tacrolimus can cause neurotoxicity, particularly when used in high doses.

Nervous system disorders, including tremor, headache and other changes in motor function, mental status and sensory function were reported in 63.1% of de novo kidney transplant recipients. Tremor occurred in 35.0% of Advagraf-treated kidney transplant patients compared to 19.8% of Neoral-treated kidney transplant patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see Adverse Reactions). Tremor and headache have been associated with high whole blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus as Prograf. Coma and delirium also have been associated with high plasma concentrations of tacrolimus received as Prograf.

Renal

Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Renal and urinary disorders were reported in 36.9% of de novo kidney transplantation patients receiving Advagraf. In de novo kidney transplant recipients, increased creatinine was reported in 18.7% of Advagraf-treated patients and 22.6% of Neoral-treated patients (see Adverse Reactions). More overt toxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus should not be used simultaneously with cyclosporine.

Mild to severe hyperkalemia was reported in 22.0% of kidney de novo transplant recipients treated with Advagraf and may require treatment (see Adverse Reactions). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during Advagraf therapy (see Warnings and Precautions - Cardiovascular, Monitoring and Laboratory Tests).

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).

Special Populations

Pregnant Women: 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. Advagraf should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus (Please see DETAILED PHARMACOLOGY - Human studies and TOXICOLOGY - Reproduction and Developmental Toxicity).

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 tacrolimus.

Geriatrics (≥ 65 years of age): No formal studies have been performed to evaluate the effect of tacrolimus specifically in the geriatric population.

Forty-three patients have been treated with Advagraf in phase II and III studies in solid organ transplantation; there were no patient deaths or graft failures in these patients. Two of these 43 elderly patients experienced acute rejection. No overall differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Monitoring and Laboratory Tests

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

Blood Concentration Monitoring

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.

Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS), enzyme immunoassay (EIA), microparticle enzyme immunoassay (MEIA) and enzyme linked immunosorbent assay (ELISA). Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer, they should be deep frozen at -20°C for up to 12 months.

Data from kidney transplant recipients receiving tacrolimus administered as Prograf indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx®† MEIA (kidney), were most variable during the first week of dosing and 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. Long-term posttransplant patients often are maintained at the low end of the recommended target range. For stable transplant recipients converted from Prograf to Advagraf, the same type of therapeutic monitoring can be used.

Data from the phase III Advagraf study indicate that trough concentrations of tacrolimus in whole bloodwere most variable during the first week of dosing. By month 2, 76% of the patients had trough concentrations between 7 - 16 ng/mL and greater than 78% maintained concentrations between 5 - 15 ng/mL, from month 4 through 1 year.

ADVERSE REACTIONS

Overview

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.

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.

In a large (n=668), phase III, randomized, comparative trial, de novo kidney transplant recipients received either Advagraf plus mycophenolate mofetil (MMF) or Prograf plus MMF or Neoral plus MMF. All three regimens included corticosteroids and basiliximab induction. The incidence of adverse events that occurred in ≥15% of Advagraf-treated de novo kidney transplant recipients is shown in table 3 below.

Table 3: De Novo Kidney Transplantation: Adverse Events Occurring in 15% of Advagraf + MMF Treated Patients
	Prograf + MMF N =212	Advagraf + MMF N =214	Neoral + MMF N =212
Gastrointestinal Disorders
Diarrhea Nausea Constipation Vomiting Dyspepsia	44.3% 38.7% 35.8% 25.5% 17.9%	45.3% 42.1% 41.6% 26.2% 15.0%	25.5% 46.7% 41.0% 24.5% 15.1%
Injury, Poisoning and Procedural Complications
Post procedural pain Incision site complication	28.8% 28.3%	29.4% 20.6%	27.4% 23.1%
Metabolism and Nutritional Disorders
Hypomagnesemia Hypophosphatemia Hyperkalemia Hyperglycemia Hyperlipidemia Hypokalemia	28.3% 27.8% 25.5% 21.2% 17.5% 16.0%	25.7% 23.8% 22.0% 19.2% 16.4% 15.9%	22.2% 21.2% 19.3% 15.1% 24.5% 17.5%
Infections and Infestations
Urinary tract infection	25.5%	15.9%	22.2%
General Disorders and Administration Site Conditions
Edema peripheral Fatigue	34.9% 10.8%	35.5% 15.9%	45.8% 12.3%
Nervous System Disorder
Tremor Headache	34.4% 24.1%	35.0% 21.5%	19.8% 24.5%
Investigations
Blood creatinine increased	23.1%	18.7%	22.6%
Blood and Lymphatic System Disorders
Anemia Leukopenia	30.2% 15.6%	33.6% 16.4%	27.8% 11.8%
Vascular Disorders
Hypertension	32.1%	29.9%	34.9%
Musculoskeletal and Connective Tissue Disorders
Back pain	12.7%	15.0%	14.2%
Psychiatric Disorders
Insomnia	30.2%	25.7%	21.2%

The following adverse events were also reported in clinical studies of solid organ transplant recipients who were treated with Advagraf at a frequency of ≥3% to <15%.

Cardiac Disorders: tachycardia. Gastrointestinal Disorders: abdominal pain upper, flatulence.

General Disorders and Administration Site Conditions: asthenia, chest pain, edema, pyrexia, pain. Infections and Infestations: cytomegalovirus infection, gastroenteritis, influenza, nasopharyngitis, sinusitis, upper respiratory tract infection. Investigations: hepatic enzyme increased. Metabolism and Nutrition Disorders: dehydration, diabetes mellitus, hypocalcemia, metabolic acidosis. Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramp, pain in extremity. Nervous System Disorders (see Warnings and Precautions): dizziness. Psychiatric Disorders: anxiety, depression. Skin and Subcutaneous Tissue Disorders: acne, pruritus. Renal and Urinary Disorders (See Warnings): hematuria, renal impairment, renal insufficiency. Respiratory, Thoracic and Medistinal Disorders: cough, dyspnea, pharyngolaryngeal pain. Vascular Disorders: hypotension.

Less Common Clinical Trial Adverse Drug Reactions ( ≥1% to <3%)

The following adverse events were reported in clinical trials of solid organ transplant recipients treated with Advagraf at a frequency rate of ≥1% and <3%:

Blood and Lymphatic System Disorders: leukocytosis, neutropenia, polycythemia, thrombocytopenia. Cardiac Disorders: atrial fibrillation. Eye Disorders: vision blurred. Gastrointestinal Disorders: abdominal discomfort, abdominal distension, abdominal pain lower, ascites, gastritis, gastrooesophageal reflux disease, hemorrhoids, loose stools, oesophagitis, post procedural nausea, toothache. General Disorders and Administration Site Conditions: anasarca, rigors. Hepatobiliary Disorders: bile duct stenosis, cholestasis. Infections and Infestations: bronchitis, cellulitis, Escherichia urinary tract infection, fungal infection, herpes simplex, herpes zoster, human polyomavirus infection, oral candidiasis, pharyngitis, pneumonia, pyelonephritis, sepsis, wound infection. Injury, Poisoning and Procedural Complications: complications of transplant surgery, contusion, incisional hernia, necrotic preservation injury of graft, post procedural discharge, therapeutic agent toxicity, wound dehiscence. Investigations: blood glucose increased, blood magnesium decreased, blood phosphorus decreased, blood potassium decreased, cardiac murmur, liver function test abnormal, urine output decreased, weight decreased, weight increased. Metabolism and Nutrition Disorders: Acidosis, anorexia, diabetes mellitus non-insulin-dependant, dyslipidemia, fluid overload, gout, hypercalcemia, hypercholesterolemia, hyperhomocysteinemia, hyperphosphatemia, hyperuricemia, hypoalbuminemia, hypoglycemia, hyponatremia. Musculoskeletal and Connective Tissue Disorders: myalgia, osteopenia, osteoporosis. Nervous System Disorders: hypoesthesia, paraesthesia. Psychiatric Disorders: agitation, confusional state. Renal and Urinary Disorders: dysuria, oliguria, proteinuria, renal failure acute, urethral pain. Reproductive System and Breast Disorders: erectile dysfunction. Respiratory, Thoracic and Medistinal Disorders: dyspnea exertional, epistaxis, nasal congestion, productive cough. Skin and Subcutaneous Tissue Disorders: alopecia, ecchymosis, night sweats, rash, skin lesion. Vascular Disorders: hematoma, hot flush, orthostatic hypotension.

Adverse Events Observed with Prograf but not Advagraf:

The following adverse events were reported in solid organ transplant recipients who were treated with Prograf but have not been reported for Advagraf:

Cardiovascular: atrial flutter, cardiac arrest, cardiac arrhythmia, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation; Gastrointestinal: colitis, enterocolitis, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, fatty liver, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease; Hemic/Lymphatic: coagulation disorder, disseminated intravascular coagulation, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura; Metabolic/Nutritional: alkalosis, glycosuria, increased amylase including pancreatitis; Miscellaneous: feeling hot and cold, feeling jittery, hot flushes, mobility decreased, multi-organ failure, primary graft dysfunction; Nervous System: carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, monoparesis, myoclonus, mutism, psychomotor skills impaired, psychosis, quadriparesis, quadriplegia, speech disorder, syncope, thinking abnormal, writing impaired; Respiratory: acute respiratory distress syndrome, lung infiltration, pneumothorax, respiratory distress, respiratory failure; Skin: hirsutism, Stevens-Johnson syndrome, toxic epidermal necrolysis; Special Senses: amblyopia, blindness, blindness cortical, hearing loss including deafness, photophobia; Urogenital: acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder, urinary frequency.

DRUG INTERACTIONS

Overview

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Advagraf with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B and cisplatin. Initial clinical experience with the co-administration of Prograf and cyclosporine resulted in additive/synergistic nephrotoxicity.

Since tacrolimus is metabolized mainly by the CYP3A (cytochrome P450 IIIA) enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.

Drug-Drug Interactions

In a study of 6 normal volunteers, a significant increase in tacrolimus (administered as Prograf) oral bioavailability (14 ± 5% vs 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent clearance of oral tacrolimus (administered as Prograf) 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 (administered as Prograf) 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 4*: 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

lansoprazole

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 (administered as Prograf) 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 (administered as Prograf) and sirolimus (2mg/day or 5mg/day) in stable renal transplant patients, tacrolimus AUC and C_min decreased approximately 30% relative to tacrolimus alone.

Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly.

Table 5*: 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 Advagraf, 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 typhoid².

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

Drug-Food Interactions

Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations.

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 Advagraf could result in reduced tacrolimus levels.

Drug-Laboratory Interactions

Tacrolimus is not known to interfere with laboratory tests.

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

Patients converting from Prograf to Advagraf should be administered a single daily morning dose of Advagraf equivalent to the patients' previous stable total daily dose of Prograf. Subsequent doses of Advagraf should be adjusted in order to maintain trough concentrations similar to those prior to conversion.

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

Advagraf is to be used concomitantly with adrenal corticosteroids and mycophenolate mofetil (MMF) in de novo renal transplant recipients. Antibody induction therapy should be used in kidney transplant recipients.

Patients with Hepatic or Renal Dysfunction

Advagraf has not been studied in patients with hepatic or renal dysfunction, the following are based on experiences obtained from use of Prograf.

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh≥10) may require lower doses of Advagraf. Close monitoring of blood concentrations is warranted. Due to the potential for nephrotoxicity in patients with renal or hepatic impairment, these patients should receive doses at the lowest value of the recommended oral dosing range. Further reductions in dose below these ranges may be required.

Race

The data from Advagraf administration in de novo kidney transplant patients indicate that black patients required a higher dose to attain comparable trough concentrations compared to white patients.

Recommended Dose and Dosage Adjustment

Initial dosage and typical tacrolimus whole blood trough concentrations are shown in the Table 6 below; blood concentration details are described under Warnings and Precautions - Monitoring and Laboratory Tests.

Table 6: Advagraf - Summary of Initial Oral Dosage Recommendations and Typical Whole Blood Trough Concentrations

Patient Population

Recommended Initial Once Daily (am) Oral Dose

Typical Whole Blood Trough Concentrations

Adult Kidney Transplant Patients

0.15-0.2 mg/kg/day

Month 1-3: 7-16 ng/mL

Month 4-12: 5-15 ng/mL

The recommended starting oral dose of Advagraf for kidney transplant patients is 0.15 to 0.2 mg/kg administered once daily in the morning. The initial dose of Advagraf should be administered within 24 hours of transplantation. Dosing should be titrated to maintain the whole blood trough concentration levels noted above; blood concentration details are described under Warnings and Precautions - Monitoring and Laboratory Tests.

Stable kidney transplant recipients can be converted from Prograf bid to once-daily Advagraf dosing on a 1:1 (mg:mg) total daily dose basis to achieve appropriate tacrolimus blood concentrations. The same target trough range and blood concentration monitoring should be used as with Prograf in order to maintain blood trough concentrations of tacrolimus similar to those prior to conversion.

In patients unable to take oral Advagraf capsules, therapy may be initiated with Prograf injection and the patient subsequently converted to oral Advagraf. The recommended starting dose of Prograf injection is 0.03-0.05 mg/kg/day (kidney) as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range.

The data from Advagraf administration in kidney transplant patients indicate that black patients required a higher dose to attain comparable trough concentrations compared to white patients (Table 7).

Table 7: Advagraf trough concentrations in kidney transplant patients
Time After Transplant	White n=160		Black n=41
	Dose (mg/kg)	Mean Trough Concentration (ng/mL)	Dose (mg/kg)	Mean Trough Concentration (ng/mL)
Day 7	0.14	10.79	0.14	7.85
Month 1	0.14	11.11	0.18	10.83
Month 6	0.10	7.96	0.13	8.50
Month 12	0.09	7.54	0.12	7.52

Administration

Advagraf can be administered with or without food; however, doses should be administered in a consistent manner (See Action and Clinical Pharmacology).

OVERDOSAGE

Limited overdosage experience with tacrolimus is available.

An overdosage of 5 times the intended dose has been reported with Advagraf, followed by an adverse event of hypomagnesaemia that was successfully treated with medication.

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

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action / Pharmacodynamics

Tacrolimus, the active ingredient in Advagraf, 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.

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

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

Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters of tacrolimus have been determined following oral administration of Advagraf in healthy volunteers and in kidney transplant recipients (Table 8).

Table 8: Pharmacokinetic Parameters of Advagraf

Population

Dose

Day§

Pharmacokinetic Parameters

C_max‡

(ng/mL)

T_max†

(hr)

AUC_0-24‡

(nghr/mL)

Healthy Volunteers

4mg

Day 1

Day 10

6.2

11.6

2.0

74.3

155.0

Adult Kidney De Novo

0.19 mg/kg

0.20 mg/kg

Day 1

Day 14

18.2

29.9

3.0

2.0

231.9

363.9

Adult Kidney Conversion

5.8 mg

6.1 mg

Day 1

Day 14

14.8

14.2

2.0

204.6

197.6

Dose is the group mean once daily dose (transplant patients) or the actual administered dose (healthy volunteers). Conversion refers to 1:1 (mg:mg) conversion from Prograf to Advagraf on a total daily dose basis.
† Median values ‡ Arithmetic means § Day of Advagraf treatment

There was a marked reduction of intra-subject variability for exposure (AUC₀₂₄) in black kidney transplant recipients at steady state after converting from Prograf (% coefficient of variation; %CV: 25.4%) to Advagraf (%CV: 12.2%). In white kidney transplant recipients, the intra-subject variability for exposure at steady state was similar after converting from Prograf (%CV: 12.2%) to Advagraf (%CV: 14.1%).

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

Absorption: Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable.

In 20 healthy subjects, oral administration of an aqueous suspension of Advagraf was associated with a 5% higher AUC_0inf and a 30% higher C_max compared with oral administration of intact capsules; administration of the aqueous suspension via nasogastric tube was associated with a 17% lower AUC_0-inf and 28% higher C_max compared with intact capsules.

Stable kidney transplant recipients can be converted from twice-daily Prograf to once-daily Advagraf on a 1:1 (mg:mg) total daily dose basis to achieve appropriate tacrolimus blood concentrations (Table 9).

Table 9: Relative Biopharmaceutics (AUC_0-24) at Steady State in Stable Transplant Recipients Converted from Prograf to Advagraf
	N	Advagraf/ Prograf	90% CI
Adult Kidney Transplant Recipients	66	95.0%	90.7%, 99.4%

CI: confidence interval Least square mean parameters were generated from ANOVA. The ratio of least square mean AUC_0-24 and 90% confidence intervals consist of natural log-transformed values (expressed as a percent) transformed back to linear scale. For all adult studies, data represent a comparison of two steady state profiles for each drug.

There was a strong correlation between trough (C_min) and exposure (AUC_0-24) after Advagraf administration in de novo kidney (r=0.83) transplant recipients as well as postconversion to Advagraf in kidney (r=0.86) transplant recipients.

Food Effects: The presence of food affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 24 healthy volunteers, administration of Advagraf immediately following a high fat meal (150 protein calories, 250 carbohydrate calories and 500 to 600 fat calories) reduced C_max, AUC_0-t,and AUC_0-infby approximately 25%compared with fasting values. Food delayed the median T_max from 2 hours in the fasted state to 4 hours in the fed state; however the terminal half-life remained 36 hours regardless of dosing conditions.

In 24 healthy volunteers, the time of the meal affected tacrolimus bioavailability. When Advagraf was administered immediately after consumption of a high-fat breakfast, tacrolimus AUC_0inf was decreased approximately 25% relative to the fasted state. When Advagraf was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%. Administration of Advagraf 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%.

In 23 healthy volunteers, a diurnal effect on the absorption of tacrolimus was observed. Evening dosing of Advagraf reduced AUC_0inf by 35% relative to morning dosing.

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

Parameter	Volunteers (n=8)	Kidney Transplant Patients (n=26)
Mean IV Dose	0.025 mg/kg/4 hr	0.02 mg/kg/4 hr
V (L/kg)	1.91 ± 0.31	1.41 ± 0.66
Cl (L/hr/kg)	0.040 ± 0.009	0.083 ± 0.050

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 in which tacrolimus was administered as Prograf, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism: Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 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 mean clearance following IV administration of tacrolimus is 0.040 and 0.083 L/hr/kg in healthy volunteers and adult kidney transplant patients respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

Special Populations and Conditions

Pediatrics: Experience with tacrolimus in pediatric kidney transplant patients is limited.

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

Gender: Data from kidney transplant recipients converted from Prograf to Advagraf in a phase II, open-label study showed equivalence in exposure for both male and female patients; the ratio of least square means (Advagraf:Prograf) for AUC₀₂₄ at steady state was 92.0% [90% CI: 86.1%, 98.3%] for females (n=24) and 96.7% [90% CI: 90.9%, 102.9%] for males (n=42).

Race: The data from Advagraf administration in de novo kidney transplant patients indicate that black patients required a higher dose to attain comparable trough concentrations compared to white patients.

Black kidney transplant recipients (n=12) were converted from Prograf to Advagraf on a 1:1 (mg:mg) total daily dose basis. The ratio of least square means (Advagraf:Prograf) for AUC₀₂₄ at steady state was 109.8% [90% CI: 99.0%, 121.7%] for black patients. Intra-subject variability in exposure for black patients was reduced with Advagraf compared with Prograf.

Hepatic Insufficiency: The pharmacokinetics of tacrolimus administered as Prograf were determined in six subjects with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The pharmacokinetic parameters obtained were as follows:

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 also studied in 6 subjects with severe hepatic dysfunction (mean Pugh score > 10) administered Prograf. The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration.

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
PO, n=5†	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: The pharmacokinetics of tacrolimus following a single IV administration of Prograf were determined in 12 subjects (7 not on dialysis and 5 on dialysis). The pharmacokinetic parameters obtained are presented in the table below:

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.

Diabetes: Stable kidney transplant recipients who had diabetes or new onset diabetes after transplant (NODAT) and were converted to Advagraf had ratios of least square means (Advagraf:Prograf) for AUC₀₂₄ of 92.0% [90% CI: 84.8%, 99.7%] in kidney transplant recipients (n=13).

STORAGE AND STABILITY

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

SPECIAL HANDLING INSTRUCTIONS

None required.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Advagraf is available for oral administration as hard gelatin capsules (tacrolimus extended-release capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include ethylcellulose, hydroxypropyl methylcellulose, magnesium stearate and lactose. The ingredients are directly proportional across all capsule strengths. The capsule shells contain gelatin, titanium dioxide and ferric oxide.

Advagraf Capsules (tacrolimus extended release capsules) 0.5 mg

Oblong capsules with a light yellow cap and an orange body. Capsules, supplied in 50-count bottles and 50-count blister packs (10 capsules per card), are imprinted with red " 647" on the capsule body and "0.5 mg" on the capsule cap.

Advagraf Capsules (tacrolimus extended release capsules) 1 mg

Oblong capsules with a white cap and an orange body. Capsules, supplied in 50-count bottles and 50-count blister packs (10 capsules per card), are imprinted with red "677" on the capsule body and "1 mg" on the capsule cap.

Advagraf Capsules (tacrolimus extended release capsules) 5 mg

Oblong capsule with a grayish-red cap and orange body. Capsules, supplied in 30-count bottles and 50-count blister packs (10 capsules per card), are imprinted with red "687" on the capsule body and "5 mg" on the capsule cap.

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

Study demographics and trial design

Table 10: Summary of patient demographics for clinical trials in kidney transplantation

Study #	Trial design	Dosage, route of administration and duration	Number of study subjects	Mean age (Range)	Gender	Race (W/B/A/O)
*KIDNEY - De novo* transplant**
02-0-158	Phase III randomized, open-label, multicentre, comparative	Advagraf:initial dose 0.15mg - 0.20mg/kg/day, orally, QD morning, 1 year.*	214	47.84 ± 12.995 (17 -77)	M=138 F=76	160/41/5/8
		Prograf: initial dose 0.075mg - 0.1mg/kg orally, BID, 1 year.*	212	48.62 ± 12.855 (19 -74)	M=136 F=76	152/51/5/4
		Neoral: initial dose 4 -5mg/kg, orally, BID, 1 year.*	212	47.63 ± 12.953 (17 -77)	M=130 F=82	163/36/8/5
FG-506E-12-01 (Undre, Abs.132)⁴	Phase II, open-label, randomized, multi-center, comparative trial	Advagraf: Initial dose 0.20mg/kg orally, QD morning‡. Study duration 6 weeks.	60	44.0 (19-66)	M=34 F=26	58/0/0/2
FG-506E-12-01 (Undre, Abs.132)⁴		Prograf: Initial dose 0.20mg/kg orally, BID‡. Study duration 6 weeks	59	43.6 (21-65)	M=44 F=15	59/0/0/0
KIDNEY - Transplant Recipients Converted from Prograf to Advagraf
02-0-131	Phase II, open-label, multicenter, safety, PK conversion (1:1) study	Individualized oral dose (tacrolimus through levels 5-20ng/ml). The Prograf BID dose is given for 1 week followed by Advagraf QD dose for 4 weeks.	68	46.7 ± 12.57 (22-71)	M=42 F=26	54/12/1/1
FG-506E-12-02 (Alloway, 2005)¹	Phase II, open-label, multi-centre, single-sequence, four period crossover replicate design, comparative PK study.	Individualized oral dose (tacrolimus through levels 5-15ng/ml). Prograf BID or Advagraf QD for 14 days for each of 4 treatment periods.	69	44.8 (20-65)	M=49 F=20	52/1/8/8

W= White, B= Black, A= Asian, O= other (includes East Indian, Pacific Islander, Native Hawaiian, Filipino, Brazilian Indian) *Target concentration range for tacrolimus (Advagraf and Prograf) was 7-16 ng/mL for days 0-90 and 5 to 15ng/ml thereafter. ‡Target trough concentration 10- 20 ng/mL (day 1 - 14) and 5 - 15 ng/mL (day 15 - week 6).

Study results

Kidney Transplant Recipients

The efficacy and safety of Advagraf + mycophenolate mofetil (MMF) and corticosteroids (S) (n=214) was compared with that of Prograf + MMF + S (n=212) and Neoral®† + MMF + S (n=212) in a phase III, randomized (1:1:1), multi-center, open-label, comparative, non-inferiority study in de novo kidney transplant recipients. Study drugs were administered as initial oral doses as follows: Prograf 0.075-0.10 mg/kg BID, Advagraf 0.150.20 mg/kg QD am; Neoral 4-5 mg/kg BID. MMF was administered according to package insert (CellCept®‡). Dosing of these immunosuppressants was adjusted based on clinical evidence of efficacy, safety and/or whole blood trough concentrations. Patients received two 20 mg IV doses of basiliximab induction therapy. Efficacy failure was a composite endpoint comprising any patient who died, had graft failure (return to dialysis >30 days or retransplant), had a biopsy confirmed acute rejection or was lost to follow-up. Efficacy failure rates at 1 year were similar among treatment groups (Table 11, 12, 13 & 14).

Table 11: Efficacy Failure in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
	Advagraf/MMF (n=214)	Prograf/MMF (n=212)	Neoral/MMF (n=212)
Efficacy Failure	14.0%	15.1%	17.0%
Treatment Difference	-3.0%	-1.9%
95.2% CI	-9.9%, 4.0%	-8.9%, 5.2%

CI: confidence interval. Treatment differences are relative to Neoral treatment group (Advagraf minus Neoral; Prograf minus Neoral).

Table 12: Patient and Graft Survival in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
	Advagraf/MMF (n=214)	Prograf/MMF (n=212)	Neoral/MMF (n=212)
Patient Survival	98.6%	95.7%	97.6%
Kaplan-Meier Estimate Difference	1.0%	-1.9%	-
95% CI	-1.6%, 3.6%	-5.3%, 1.5%
Graft Survival	96.7%	92.9%	95.7%
Kaplan-Meier Estimate Difference	1.0%	-2.9%	-
95% CI	-2.7%, 4.6%	-7.3%, 1.6%

CI: confidence interval. Kaplan-Meier estimate differences are relative to Neoral treatment group (Advagraf minus Neoral; Prograf minus Neoral). Data censored at time of last follow-up.

Table 13: Renal Function in De Novo Kidney Transplant Recipients at 6 and 12 Months Posttransplant
	Advagraf/ MMF (n=214)	Prograf/ MMF (n=212)	Neoral/ MMF (n=212)	p-values
	Advagraf/ MMF (n=214)	Prograf/ MMF (n=212)	Neoral/ MMF (n=212)	Advagraf vs. Neoral	Prograf vs. Neoral
Mean Serum Creatinine Levels (mg/dL):
6 Months	1.46±0.55	1.42±0.43	1.51±0.50	0.238	0.015
12 Months	1.39±0.44	1.42±0.56	1.48±0.51	0.047	0.057
Mean Creatinine Clearance Levels (mL/min):
6 Months	56.7± 18.24	56.8± 17.25	53.6± 15.92	0.036	0.015
12 Months	58.7± 18.26	57.7± 18.81	54.6± 17.60	0.008	0.013

Table 14: Additional Efficacy Data in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
	Advagraf/ MMF (n=214)	Prograf/ MMF (n=212)	Neoral/ MMF (n=212)	p-values
	Advagraf/ MMF (n=214)	Prograf/ MMF (n=212)	Neoral/ MMF (n=212)	Advagraf vs. Neoral	Prograf vs. Neoral
Treatment Failure	14.5%	15.6%	28.8%	<0.001	0.001
Cross Over Due to Treatment Failure	4.7%	2.8%	18.4%	<0.001	<0.001
Patient Discontinuations
Adverse Events	8.9%	10.8%	17.5%	0.010	0.069
Non-compliance	0.9%	1.9%	2.4%	0.283	1.000
Rejection	0.5%	0	7.5%	<0.001	<0.001

Treatment failure is defined as discontinuation of randomized study drug for any reason.

Transplant Recipients Converted from Prograf to Advagraf

Data from phase II, randomized, comparative, open-label studies showed that kidney transplant recipients were safely converted from Prograf (BID) to Advagraf (QD) on a 1:1 (mg:mg) total daily dose basis to achieve appropriate tacrolimus whole blood concentrations. The majority of patients in these studies did not require Advagraf dosing adjustments in the early conversion period (Table 15).

Table 15: Patient and Graft Survival in Stable Transplant Recipients 1 or 2 Years After Conversion from Prograf to Advagraf
	Patient Survival	Graft Survival
US Adult Kidney Study (2 Years)	100%	98.5%
EU Adult Kidney Study (1 Year)	97.0%	97.0%

Kaplan-Meier estimates.

There were no graft losses due to rejection in the kidney conversion studies.

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.

Safety pharmacology studies in mice, rats, dogs, cats and rabbits and with various tissues in vitro have been conducted as part of the Prograf (tacrolimus) development program for liver and kidney transplantation.

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.

Tacrolimus as Prograf 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).

To assess the relationship of peak concentration versus area under the curve (AUC) to efficacy, a study was conducted to evaluate the effect of tacrolimus in preventing skin allograft rejection when administered as a bolus (comparable with immediate release) or when continuously infused (sustained-release profile somewhat representative of the extended-release formulation). In this study, ear skin grafts from Fisher rats were transplanted to the thorax of MCH-incompatible recipients (WKAH rats). Tacrolimus (0.01 mg/kg, 0.1 mg/kg, 1.0 mg/kg) or placebo was administered to four groups of male rats (7 or 8/group) by daily bolus intramuscular injections (IM) or continuous intravenous infusion (IV) for 14 days with mini-osmotic pumps starting on the day of graft placement. The median survival times of the allografts were counted in days after transplantation (Table 16).

Table 16: Effect of Tacrolimus (FK506) on Allograft Skin Survival in Rats
	IM Dose		IV Dose
	n	MST (days)	n	MST (days)
Control (placebo)	7	5	7	6
FK506 0.01 mg/kg	7	6	7	7
FK506 0.1 mg/kg	8	10	8	10*
FK506 1.0 mg/kg	8	20**	8	22**

*p<0.05; **p<0.01 versus each control; IM: Intramuscular injection; IV: Intravenous infusion; MST: Median survival time in days after transplantation.

At each dose tested, there were no significant differences in median skin allograft survival times between rats administered tacrolimus by intramuscular bolus injections and those receiving continuous intravenous infusion, supporting the concept that total exposure (i.e., AUC) is the critical component for the efficacy of an extended-release formulation.

Human Studies

The pharmacokinetic profile of tacrolimus as Prograf after intravenous or oral administration is well defined³. Tacrolimus as Prograf requires twice-a-day dosing. Tacrolimus extended-release formulation (Advagraf) was developed as a once-a-day morning dosing formulation. Evidence to date with tacrolimus as Prograf indicates that the total exposure over a dosing interval as measured by AUC or trough whole blood concentration is most important for determining the risk of acute rejection after organ transplantation.

In contrast, tacrolimus whole blood peak concentrations (C_max) following administration as Prograf do not appear to be predictive of either the risk of biopsy-confirmed acute rejection or the likelihood of an adverse event. No statistically significant relationship between tacrolimus whole blood C_max and adverse events or biopsy-confirmed acute rejection was found using a Cox regression analysis (with time to the first event as the dependent variable and maximum value of the peak concentration as a covariate) of data from 181 kidney transplant recipients who received Prograf. However, while not predictive of any individual adverse event, a higher C_max could potentially increase the overall safety risk.

Therefore, the target biopharmaceutic goals for the development of a once-a-day formulation of tacrolimus were to achieve AUC relative to Prograf within equivalence criteria and an equal or reduced C_max as compared with that of Prograf. In addition, clinical development of a once-a-day formulation required a good correlation of trough concentration to AUC (similar to that obtained for Prograf) and the same trough target range as Prograf, using the same therapeutic monitoring system.

The pharmacokinetic parameters of the tacrolimus extended-release formulation (Advagraf) has been studied in patients (see Table 8). Results indicate that the same therapeutic monitoring as used with Prograf can be used with tacrolimus extended-release formulation. In addition, the same trough target range as used with Prografcan be used with tacrolimus extended-release formulation. In conversion patients, tacrolimus exposure (AUC_0-24) at steady state is equivalent between Prograf and extended-release formulation supporting continued prophylaxis of organ rejection (Table 17). Data from studies of transplant recipients indicate that once-daily administration of tacrolimus extended-release formulation results in consistently lower C_max values than twice-daily administration of Prograf. In addition, pharmacokinetic profiles for tacrolimus extended-release formulation did not indicate signs of dose dumping (i.e., complete dose is more rapidly released from the dosage form) during any treatment.

Table 17: Relative Biopharmaceutics (AUC_0-24) at Steady State

Study Population

Advagraf/Prograf

(Ratio of Least Square Means)

90% CI

Adult Kidney

95.0%

90.7%, 99.4%

Patient Base: stable transplant recipients converted from Prograf to tacrolimus extended-release formulation (Advagraf). The least square mean parameters were generated from ANOVA. Ratio of parameter means and 90% confidence intervals consist of natural log-transformed parameters (expressed as a percent) transformed back to linear scale. For all adult studies, data represent a comparison of two steady state profiles for each drug. CI: confidence interval

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. Advagraf 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.

TOXICOLOGY

The tacrolimus toxicology profile is well defined and was established as part of the development program for Prograf. No additional toxicology studies were performed as part of the development for the tacrolimus extended-release formulation (Advagraf). Toxicology data sumarized from the Prograf Product Monogragh is presented below in tables 18-20.

Acute Toxicology

Table 18: 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	Hyper-reactivity, 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

Repeat Dose Toxicity

Table 19: Overview of Repeated Dose Toxicity Studies of Tacrolimus
Species	Strain	No. / Group	Route	Dose (mg/kg/day)	Duration (Weeks)	NOAEL (mg/kg/day)
Rat	Crl:CD(SD)BR	20/sex	Gavage	0, 0.15, 0.5, 1.5	52	0.15
	Crl:CD(SD)BR	12/sex	Gavage	0, 0.32, 1, 3.2	13	1
	Jcl:SD †	12/sex	Gavage	0, 0.32, 1, 3.2	4	0.32
	Crl:SC(SD)BR	12/sex	IV	0, 0.032, 0.1, 0.32, 1	4	0.032
Baboon	Papio spp.	4/sex	Gavage	0, 1, 3.2, 10	52	1
		3/sex	Gavage	0, 18, 36	13	-
		3/sex	Gavage	0, 1, 3, 6, 9	13	1
		3/sex	IV	0, 0.5, 1, 2	4	-

NOAEL (no observable adverse effect level (no observable toxic effect) † Immature rats

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.

Genotoxicity

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.

Carcinogenicity

Dietary carcinogenicity studies were carried out in rats (104-week) and mice (80-week). In the rat studies, no increased incidence of tumors was observed compared to concurrent controls and all tumor incidence was within the range found in historical control groups. Similarly in the mouse study, there were no tumors reported in the treated groups that showed a higher incidence or a dose response as compared with controls.

Reproductive and Developmental Toxicity

The reproductive toxicity of tacrolimus was evaluated in Segment 1 (rats), Segment 2 (rats and rabbits) and Segment 3 (rats) studies. The results of these studies are summarized below in table 20.

Table 20: Reproductive and Developmental Toxicity Studies of Orally Administered Tacrolimus
Study	Oral Dose (mg/kg/day)	Major Findings
Study	Oral Dose (mg/kg/day)	Parental	F₁ Offspring
Segment 1, Rat	0.32	No observable effect	No observable effect
	1	Incomplete delivery	No observable effect
	3.2	Body weight with food consumption Male copulatory index Copulatory interval Incomplete delivery Female diestrus period	Some lethality; Implantation Post-implantation loss Embryo/offspring viability
Segment 2, Rat	0.32	No observable effect	No observable effect
	1	No observable effect	Fetal body weight
	3.2	Some lethality; Body weight with food consumption	Fetal body weight Post-implantation loss Offspring viability Skeletal variations
Segment 2, Rabbit	0.1	Body weight	No observable effect
	0.32	Body weight Abortions	Developmental variations
	1	Body weight Abortions	Developmental variations Post-implantation loss Viable fetuses Morphological variations
Segment 3, Rat	0.32, 1	No observable effect	No observable effect
Segment 3, Rat	3.2	Body weight	Body weight

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).

Special Studies

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

Alloway R, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf based regimen to a once daily modified release tacrolimus based regimen. Transplant Proc. 2005 Mar 37(2):867-70.
CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 2002;51(RR-2):22-23.
Prograf® tacrolimus capsules, tacrolimus injection (for intravenous infusion only), Product Monograph, Markham, ON. Astellas Pharma Canada, Inc. January 09, 2006.
Undre A, et al. Use of once a daily modified release tacrolimus regimen in de novo kidney transplant recipients presented in the ATC 2005 Meeting [Abstract 132, pg.190].
Jusko WJ, Thomson AW, Fung J, McMaster P, Wong SH, Zylber-Katz E et al. Consensus document: Therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit 1995 Dec; 17(6):606-14.
McMaster P, Mirza DF, Ismail T, Vennarecci G, Patapis P, Mayer AD. Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit 1995 Dec;17(6):602-5.
Jusko WJ. Analysis of tacrolimus (FK 506) in relation to therapeutic drug monitoring. Ther Drug Monit 1995 Dec;17(6):595-601.

PART III: CONSUMER INFORMATION

^Pr Advagraf ^TM

(tacrolimus extended release capsules)

Read this important information before you start using Advagraf and each time you refill your prescription.

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

ABOUT THIS MEDICATION

What the medication is used for:

Advagraf is the brand name for tacrolimus extended release capsules. Advagraf helps to prevent your body from rejecting a kidney transplant.

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. Advagraf is an anti-rejection drug that helps your body accept your transplanted organ.

When it should not be used:

Do not take Advagraf if you are allergic to any of the ingredients in Advagraf.

What the medicinal ingredient is:

tacrolimus

What the important nonmedicinal ingredients are:

ethylcellulose, hydroxypropyl methylcellulose, magnesium stearate and lactose.

What dosage forms it comes in:

Advagraf is available in an extended release capsule. Each capsule contains 0.5 mg, 1 mg or 5 mg of tacrolimus.

The 0.5 mg capsule has a light yellow cap and an orange body. The capsule is imprinted in red with "647" on the capsule body and "0.5 mg" on capsule cap.

The 1 mg capsule has a white cap and an orange body. The capsule is imprinted in red with "677" on the capsule body and "1 mg" on capsule cap.

The 5 mg capsule has a greyish red cap and an orange body. The capsule is imprinted in red with "687" on the capsule body and "5 mg" on capsule cap.

WARNINGS AND PRECAUTIONS

Advagraf should be prescribed by doctors experienced in the use of immunosuppressive drugs and management of organ transplants. Advagraf suppresses your body's immune system. As a result, it may increase your chances of getting infections and some kinds of cancer, including skin and lymph gland cancer (lymphoma). Wear protective clothing and use a sunscreen with a high sun protection factor (SPF ≥30) to limit exposure to sunlight and UV light. However, getting cancer from taking an anti-rejection medicine is not common.

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

If you have taken Prograf, Advagraf or tacrolimus before and had a bad, unusual or allergic reaction;
About all other health conditions, including kidney and/or liver problems, 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 Advagraf because its effect on pregnancy or on an unborn baby is not known. It is important to notify your doctor right away if you become pregnant or father a child while taking Advagraf. Do not nurse a baby while taking Advagraf since the medicine will be in the breast milk.

INTERACTIONS WITH THIS MEDICATION

Some medicines and even some foods can affect how well Advagraf works. After you start taking Advagraf:

Be sure to tell your transplant team, family doctor, dentist, pharmacist and any other health care professional treating you the names of all the medicines you are taking. This includes Advagraf as well as all other prescription and non-prescription medicines. This is the only way that your health care team can help prevent drug interactions that could be serious. Make sure you know if you are to stop, or continue, other drugs you had been taking.
Always check with your transplant team before you start taking any new medicine, or any products you buy off the shelf such as over-the-counter drugs, herbal or nutritional supplements (especially St. John's Wort), vitamins or home remedies
While you are taking Advagraf, do not get any vaccinations without your transplant team's approval. The vaccination may not work as well as it should or may result in serious side effects.
Do not eat or drink any product that contains grapefruit or grapefruit juice in combination with your medicine unless your transplant team approves.

PROPER USE OF THIS MEDICATION

Advagraf can protect your new kidney only if you take the medicine correctly.

Your new organ needs around-the-clock protection so your body does not reject it. The success of your transplant depends a great deal upon how well you help Advagraf do its job. Here is what you need to do.

Take Advagraf exactly as prescribed

Your transplant team will tell you what dose to take and how to take it. It is important to take Advagraf capsules exactly as told by your transplant team. Your transplant team may adjust your dose until they find what works best for you. Never change your dose on your own. Never stop taking Advagraf even if you are feeling well. However, if you feel poorly on Advagraf, discuss this with your transplant team.

Take Advagraf once-a-day, in the morning

Try to pick a time that will be easy for you. Do not vary the time. You must take Advagraf at the same time every day. If you decide to take Advagraf at 7:00 a.m., take it at this same time every day. This will make sure you always have enough medicine in your body to give your new organ the around-the-clock protection it needs.

Take Advagraf the same way each day

Most people are directed to take Advagraf on an empty stomach, 2 hours before or after a meal. However, some people prefer to take Advagraf with food to help reduce possible stomach upset. Whether you take Advagraf with or without food, it is important to take Advagraf the same way every day. For example, if you take Advagraf with food, you should always take it with food. Do not change the way you take this medicine without telling your transplant team, since this could change the amount of protection you get from Advagraf.

Take your full dose of medication, every day

It is important to take your dose exactly as prescribed by your doctor. If you miss even one dose, your new kidney could lose the protection it needs against rejection by your body.

If you travel and change time zones, be sure to ask your transplant team how to adjust your dosage schedule so your new organ does not lose its protection.

Plan ahead so that you do not run out of Advagraf

Make sure you have your prescription for Advagraf refilled and at home before you need it. Circle the date on a calendar when you need to order your refill. Allow extra time if you receive your medicines through the mail.

When having a blood test to measure Advagraf

On the days you are going to have a blood test to measure the amount of Advagraf in your body, your transplant team will ask you not to take your dose until after the blood sample is taken.

Missed dose

If you have forgotten to take your Advagraf capsules in the morning, take them as soon as possible on the same day. Do not take a double dose the next morning.

Overdose

For management of a suspected drug overdose, please contact your doctor or your regional Poison Control Center.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Tell your transplant team right away if you think you might be having a side effect. Your transplant team will decide if it is a medicine side effect or a sign that has nothing to do with the medicine but needs to be treated. Infection or reduced urination can be signs of serious problems that you should discuss with your transplant team.

Your transplant team will also follow your progress and watch for the early signs of any side effects. This is why you will have blood tests done often during the first few months after your transplant.

The most common drug-related side effects are headache, tremors (shaking of the hands), digestive tract disturbances (upset stomach, nausea, vomiting, diarrhea, or constipation/reduced bowel movements), abdominal or back pain, fatigue, reduced kidney function, increased blood pressure, swelling of the legs, feet and/or hands, difficulty sleeping, collection of fluid in chest or abdominal cavity and abnormal laboratory results.

Other less common side effects include gastrointestinal disorders (upper abdominal pain or gas), dehydration, low blood pressure, dizziness, weakness, fever, pain (chest pain, muscle cramp, sore throat, pain in joints or hands and feet), cough, trouble breathing, nervousness, depression, acne, itching and increased heartbeat.

Immunosuppressive drugs including Advagraf 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 Advagraf.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect	Talk with your doctor or pharmacist		Stop taking drug and call your doctor or pharmacist
Symptom / effect	Only if severe	In all cases	Stop taking drug and call your doctor or pharmacist
Common
Infection (urinary tract, sinusitis, gastroenteritis, influenza, upper respiratory tract)
Early signs of high blood sugar or diabetes: more thirsty than usual, have to urinate more often, have blurred vision or seem to get confused.
Decreased or increased urine volumes, dark coloured urine which may be a sign of kidney problems

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

HOW TO STORE IT

Keep Advagraf out of the reach and away from children. A child who accidentally takes Advagraf 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 Advagraf, contact your physician immediately.

Store Advagraf in a dry area at room temperature (25ºC) in the container or package that was dispensed by your pharmacist. Do not let the medicine get colder than -15ºC or hotter than 30ºC. For instance, do not leave Advagraf in the glove compartment of your car in the summer or winter. Do not keep Advagraf capsules in a hot or moist place such as the medicine cabinet in the bathroom or near the stove or sink in the kitchen.

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

or Astellas Pharma Canada, Inc. by:

Toll-free telephone: 1-888-338-1824
Toll-free fax: 1-866-493-3419
By regular mail:
Astellas Pharma Canada, Inc.
675 Cochrane Drive, Suite 500
Markham, Ontario L3R 0B8

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: 1-888-338-1824

This leaflet was prepared by Astellas Pharma Canada, Inc.

Last revised: October 9, 2007

Immunology Pr Advagraf TM

Immunology ^PrAdvagraf ^TM