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[product monograph template - standard]PRODUCT MONOGRAPH tacrolimus extended release capsules 0.5 mg, 1 mg, 3 mg and 5 mg capsules Astellas Pharma Canada, Inc. Date of Preparation: Date of Revision: Submission Control No: 139725 September 17, 2010 Advagraf® Product Monograph Page 1 of 44 Table of Contents
Advagraf® Product Monograph Page 2 of 44 tacrolimus extended release capsules PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form / Clinically Relevant Nonmedicinal Ingredients
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 (twice daily) to Advagraf (once
daily), in combination with adrenal corticosteroids and MMF, based on equivalent tacrolimus
whole blood trough concentrations. Any changes in immunosuppressive therapy must be
initiated by physicians experienced in immunosuppressive therapy and the management of
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
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.
Advagraf® Product Monograph Page 3 of 44 WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
Increased susceptibility to infection and the possible development of lymphoma may
result from immunosuppression (see Warnings and Precautions – Carcinogenesis
and Mutagenesis, and Immune/Infection).
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.
Medication errors, including inadvertent, unintentional or unsupervised substitution of Prograf
(immediate release) or Advagraf (extended release) tacrolimus formulations, have been
observed. This has led to serious adverse events, including graft rejection, or other side effects
which could be a consequence of either under- or over-exposure to tacrolimus. Patients should be
maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen;
alterations in formulation or regimen should only take place under the close supervision of a
In de novo kidney transplant patients AUC0-24 of tacrolimus for Advagraf (extended release
formulation) on day 1 is significantly lower in comparison with that for Prograf (immediate
release formulation) at equivalent doses. By day 3, tacrolimus exposure as measured by trough
levels is similar for both formulations. All patients in the clinical de novo 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 (immediate release formulation) to
Advagraf (extended release formulation) 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 whole blood trough levels outside the target range.
Tacrolimus whole blood trough levels should be measured and closely monitored prior to and
after conversion. Conversion to Advagraf (extended release formulation) has primarily been
studied from Prograf (immediate release formulation) in combination with adrenal
corticosteroids and MMF based on equivalent tacrolimus whole blood trough concentrations.
Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the
cytochrome P450 system (CYP3A). Tacrolimus does not induce or inhibit CYP3A4 or any other
major CYP isoenzymes.
Since tacrolimus is metabolized mainly by the cytochrome P450 3A 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
Advagraf® Product Monograph Page 4 of 44 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 (see Drug Interactions).
Advagraf contains lactose and is not recommended for patients with rare hereditary disease of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
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
developing lymphomas and other malignancies, particularly of the skin, may be higher in
Advagraf recipients than in the normal, healthy population. This risk appears to be related to the
intensity and duration of immunosuppression rather than to the use of any specific agent.
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
Heart failure, myocardial hypertrophy and arrhythmia have been reported in association with the
administration of Prograf (immediate release formulation).
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 (immediate release formulation), and is generally manifested by echocardiographically
Advagraf® Product Monograph Page 5 of 44 demonstrated concentric increases in left ventricular posterior wall and interventricular septum
thickness. Hypertrophy has been observed in infants, children and adults. This condition
appears reversible in most cases following dose reduction or discontinuance of therapy. In a
group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of
myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to
diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (n=10, age 0.4 to 2
years), 4 to 46 ng/mL in children (n=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (n=3, age
37 to 53 years).
In patients who develop renal failure or clinical manifestations of ventricular dysfunction while
receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial
hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be
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
Immunosuppressed patients are at increased risk for opportunistic infections, including latent
viral infections. These include BK virus associated nephropathy and JC virus associated
progressive multifocal leukoencephalopathy (PML) which have been observed in patients
receiving tacrolimus. These infections are often related to a high immunosuppressive burden and
may lead to serious or fatal conditions that physicians should consider in the differential
diagnosis in immunosuppressed patients with deteriorating renal function or neurological
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 (immediate release formulation). Coma and delirium
also have been associated with high plasma concentrations of tacrolimus received as Prograf
(immediate release formulation).
Patients treated with tacrolimus have been reported to develop posterior reversible
encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental
Advagraf® Product Monograph Page 6 of 44 status, seizures, visual disturbances. Diagnosis should be confirmed by radiological procedure
(e.g., MRI). If PRES is suspected or diagnosed, blood pressure and seizure control and
immediate discontinuation of immunosuppression is advised. Most patients completely recover
after appropriate measures are taken.
Tacrolimus has been associated with hyperglycemia and posttransplant diabetes mellitus. New
onset glucose intolerance, defined as fasting plasma glucose ≥ 7 mmol/L, 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
Fasting Plasma Glucose ≥ 7 mmol/L 56.4% Insulin Use ≥ 30 days Oral Hypoglycemic Use All regimens included corticosteroids. At risk population.
Table 2: New Onset Glucose Intolerance in De Novo Kidney Black Transplant Recipients at 1 Year
Fasting Plasma Glucose ≥ 7 mmol/L 54.3% Insulin Use ≥ 30 days Oral Hypoglycemic Use All regimens included corticosteroids. At risk population.
Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in Prograf-
treated kidney transplant patients in clinical studies. 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 a Prograf study, Black and Hispanic
kidney transplant patients were seen to be at an increased risk of development of PTDM,
regardless of randomized treatment. 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.
Kidney transplant patients on Advagraf treatment may also be expected to be at risk of
developing post-transplant diabetes mellitus (PTDM).
Advagraf® Product Monograph Page 7 of 44 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, when switching
patients from a cyclosporine-based regimen to an Advagraf-based regimen, cyclosporine
should be discontinued at least 24 hours prior to initiating Advagraf. Advagraf dosing may
be further delayed in the presence of elevated cyclosporine levels (see Drug Interactions –
Drug-Drug Interactions - Drug Interactions Potentially Affecting Renal Function). When
switching from tacrolimus to cyclosporine, tacrolimus should be discontinued for at least
24 hours before initiating the other medication.
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
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).
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 - Reproductive and Developmental Toxicity).
Since tacrolimus is excreted in human milk, nursing should be avoided.
Advagraf® Product Monograph Page 8 of 44 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
Forty-three patients ≥ 65 years of age have been treated with Advagraf in phase II and III studies
in solid organs transplantation; there were no patient deaths or graft failures in these patients.
Two of these 43 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 (immediate
release formulation) indicate that trough concentrations of tacrolimus in whole blood, as
Advagraf® Product Monograph Page 9 of 44 measured by IMx®† MEIA (kidney), were most variable during the first week of dosing, and the
relative risk of toxicity is increased with higher whole blood 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 (immediate release formulation) to Advagraf (extended release formulation), the same
type of therapeutic monitoring can be used.
Data from the phase III Advagraf study indicate that trough concentrations of tacrolimus in
whole blood were 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.
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
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 (extended release formulation) plus mycophenolate mofetil (MMF) or Prograf (immediate release formulation) 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. † IMx is a registered trademark of Abbott Laboratories, Inc. Advagraf® Product Monograph Page 10 of 44 Table 3: De Novo Kidney Transplantation: Adverse Events Occurring in 15% of Advagraf (tacrolimus
extended release capsules) + MMF Treated Patients
Neoral + MMF
release) + MMF
release) + MMF
Injury, Poisoning and Procedural Complications
Post procedural pain
Incision site complication Metabolism and Nutritional Disorders
Hypophosphatemia Infections and Infestations
Urinary tract infection General Disorders and Administration Site Conditions
Nervous System Disorder
Blood creatinine increased Blood and Lymphatic System Disorders
Musculoskeletal and Connective Tissue Disorders
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.
Advagraf® Product Monograph Page 11 of 44 General Disorders and Administration Site Conditions: asthenia, chest pain, edema, pyrexia,
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
Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramp, pain in
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 and Precautions): hematuria, renal impairment,
Respiratory, Thoracic and Mediastinal 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,
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.
Advagraf® Product Monograph Page 12 of 44 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-
dependent, dyslipidemia, fluid overload, gout, hypercalcemia, hypercholesterolemia,
hyperhomocysteinemia, hyperphosphatemia, hyperuricemia, hypoalbuminemia, hypoglycemia,
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 Mediastinal Disorders: dyspnea exertional, epistaxis, nasal
congestion, productive cough.
Skin and Subcutaneous Tissue Disorders: alopecia, ecchymosis, night sweats, rash, skin
Vascular Disorders: hematoma, hot flush, orthostatic hypotension.
Post-Market Adverse Drug Reactions
The following adverse events have been reported from worldwide marketing experience with
tacrolimus (Advagraf [extended release formulation] and/or Prograf [immediate release
formulation]). 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 ischemia,
Advagraf® Product Monograph Page 13 of 44 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 hemorrhagic, pancreatitis necrotizing, stomach ulcer,
venoocclusive liver disease;
Hemic/Lymphatic: disseminated intravascular coagulation, neutropenia, pancytopenia,
thrombocytopenic purpura, thrombotic thrombocytopenic purpura;
Infections and Infestations: BK virus associated nephropathy;
Metabolic/Nutritional: glycosuria, increased amylase including pancreatitis, weight decreased;
Miscellaneous: feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary
Nervous System: carpal tunnel syndrome, cerebral infarction, hemiparesis,
leukoencephalopathy, mental disorder, mononeuropathy multiplex, mutism, neuropathy
peripheral, peripheral sensory neuropathy, polyneuropathy, posterior reversible encephalopathy
syndrome (PRES), progressive multifocal leukoencephalopathy (PML) quadriplegia, speech
Respiratory: acute respiratory distress syndrome, interstitial lung disease, lung infiltration,
respiratory distress, respiratory failure;
Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis;
Special Senses: blindness, blindness cortical, hearing loss including deafness, photophobia;
Urogenital: albuminuria, acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome,
There have been rare spontaneous reports of myocardial hypertrophy associated with clinically
manifested ventricular dysfunction in patients receiving Prograf (immediate release formulation)
therapy (see Warnings and Precautions).
There have been reports of pure red cell aplasia in patients receiving tacrolimus.
Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the
cytochrome P450 system (CYP3A). Tacrolimus does not induce or inhibit CYP3A4 or any other
major CYP isoenzymes.
Advagraf® Product Monograph Page 14 of 44 Drug-Drug Interactions
Drug Interactions Potentially Affecting Renal Function
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, ganciclovir, acyclovir and
cisplatin. NSAIDs may interact with Advagraf causing deteriorations in blood pressure (BP)
control and serum creatinine levels. Initial clinical experience with Prograf (immediate release
tacrolimus formulation) and cyclosporine resulted in additive/synergistic nephrotoxicity when
both agents were co-administered. Patients switched from cyclosporine to Advagraf should
receive the first Advagraf dose no sooner than 24 hours after the last cyclosporine dose. Dosing
may be further delayed in the presence of elevated cyclosporine levels.
Drug Interactions Potentially Affecting Tacrolimus Blood Concentrations
Since tacrolimus is metabolized mainly by the CYP3A (cytochrome P450 3A) 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 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
Monitoring of blood concentrations and appropriate dosage adjustments are essential when such
drugs (Table 4) are used concomitantly with tacrolimus.
Table 4 – Established or Potential Drug-Drug Interactions
Concomitant Drug Class:
tacrolimus In a single-dose crossover study in healthy volunteers, co- administration of tacrolimus (administered as Prograf [immediate release formulation]) and magnesium-aluminium-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone. Azole antifungals: tacrolimus In a study of 6 normal volunteers, a significant increase in tacrolimus (administered as Prograf [immediate release formulation]) oral bioavailability (14 ± 5% vs 30 ± 8%) was observed with concomitant administration of ketoconazole (200 mg), a strong CYP3A4 and P-glycoprotein inhibitor. 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. †When co-administered with ketoconazole, a dose adjustment of tacrolimus is required in most patients. Advagraf® Product Monograph Page 15 of 44 Table 4 – Established or Potential Drug-Drug Interactions
Concomitant Drug Class:
Azole antifungals, cont'd: tacrolimus The concomitant use of Advagraf with azole antifungals that are strong or moderate CYP3A4 and P-glycoprotein inhibitors (e.g. itraconazole, fluconazole, voriconazole) might lead to an increased Advagraf concentration. ‡When co-administered with fluconazole, itraconazole and voriconazole, a dose adjustment of tacrolimus is required in most patients. Calcium channel blockers: tacrolimus Co-administration of substrates and/or inhibitors of CYP3A4 and P-glycoprotein with Advagraf might increase blood concentrations of tacrolimus. nifedipine verapamil GI Prokinetic Agents: tacrolimus Co-administration of Advagraf with substrates of CYP3A4 might increase blood concentrations of tacrolimus. Macrolide antibiotics: tacrolimus Co-administration of Advagraf with substrates and/or erythromycin‡‡ inhibitors of CYP3A4 and P-glycoprotein might increase blood concentrations of tacrolimus. ‡‡When co-administered with erythromycin, a dose adjustment of tacrolimus is required in most patients. Proton pump inhibitor: tacrolimus Lansoprazole and omeprazole (CYP2C19 and CYP3A4 substrate, inhibitor) may potentially inhibit CYP3A4- mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. tacrolimus Co-administration of Advagraf with substrates and/or inhibitors of CYP3A4 and P-glycoprotein might increase blood concentrations of tacrolimus. chloramphenicol cyclosporine danazol ethinyl estradiol methylprednisolone nefazodone Advagraf® Product Monograph Page 16 of 44 Table 4 – Established or Potential Drug-Drug Interactions
Concomitant Drug Class:
Protease inhibitors tacrolimus Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are metabolized by CYP3A4 (e.g., nelfinavir, ritonavir, saquinavir) are administered concomitantly with tacrolimus. Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus (administered as Prograf [immediate release formulation]) with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are essential when nelfinavir is used concomitantly. Anticonvulsants: tacrolimus Co-administration of Advagraf with inducers of CYP3A4 and P-glycoprotein might decrease blood concentrations of ††When co-administered with phenytoin, a dose adjustment of tacrolimus is required in most patients. Anti-Infectives: tacrolimus In a study of 6 normal volunteers, a significant decrease in tacrolimus (administered as Prograf [immediate release formulation]) oral bioavailability (14 ± 6% vs 7 ± 3%) was observed with concomitant administration of rifampicin (600 mg), a strong CYP3A4 and P-glycoprotein inducer. 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 rifampicin 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 Cmax, Tmax and AUC0-t. **When co-administered with rifampicin, a dose adjustment of tacrolimus is required in most patients. Anti-infectives, cont'd: tacrolimus Co-administration of Advagraf with inducers of CYP3A4 and P-glycoprotein might decrease blood concentrations of Calcineurin inhibitor: tacrolimus Following 14 days co-administration of tacrolimus (administered as Prograf [immediate release formulation]) and sirolimus (2 mg/day or 5 mg/day; a substrate for both CYP3A4 and P-glycoprotein) in stable renal transplant patients, tacrolimus AUC and Cmin decreased approximately 30% relative to tacrolimus alone. Mean tacrolimus AUC0-12 and Cmin following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and efficacy of the use of tacrolimus with sirolimus has not been established. Advagraf® Product Monograph Page 17 of 44 Table 4 – Established or Potential Drug-Drug Interactions
Concomitant Drug Class:
Herbal preparation: tacrolimus 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. *No longer marketed in Canada CT=Clinical Trial T=Theoretical
Advagraf and Vaccinations
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
Lack of Drug Interaction With Advagraf
At a given mycophenolate mofetil (MMF) dose, mycophenolic acid (MPA) exposure is higher
with tacrolimus (administered as Prograf [immediate release formulation]) co-administration
than with cyclosporine co-administration due to the inhibitory action of cyclosporine on biliary
excretion of MPA-glucuronide by MRP-2 and the resulting reduction in enterohepatic
recirculation of MPA. As a result, exposure to MPA when mycophenolate mofetil is given in
combination with cyclosporine is approximately 30-40% lower than that observed when given
alone or with tacrolimus. No effect on enterohepatic MPA-glucuronide recirculation is exerted
by tacrolimus; thus, clinicians should be aware that there is a potential for increased MPA
exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving
MMF or mycophenolate sodium (MPS). Conversely, there is a potential for decreased MPA
exposure after crossover from tacrolimus to cyclosporine in patients concomitantly receiving
MMF or MPS.
Grapefruit juice affects P450 3A-mediated metabolism and should be avoided.
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.
Interactions with laboratory tests have not been established.
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.
Advagraf® Product Monograph Page 18 of 44 DOSAGE AND ADMINISTRATION
Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful
monitoring by adequately qualified and equipped personnel. The medicinal product should only
be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in
immunosuppressive therapy and the management of transplant patients.
Inadvertent, unintentional or unsupervised switching of Prograf (immediate release) or Advagraf
(extended release) is unsafe (see Warnings and Precautions – General). This can lead to graft
rejection or increased incidence of side effects, including under- or overimmunosuppression, due
to clinically relevant differences in systemic exposure to tacrolimus. Patients should be
maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen;
alterations in formulation or regimen should only take place under the close supervision of a
transplant specialist (see Dosage and Administration – Recommended Dose and Dosage
Adjustment). Following conversion to any alternative formulation, therapeutic drug monitoring
must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is
Patients converting from Prograf (immediate release formulation) to Advagraf (extended release
formulation) should be administered a single daily morning dose of Advagraf equivalent to the
patient's previous stable total daily dose of Prograf (immediate release formulation). 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.
Recommended Dose and Dosage Adjustment
Initial dosage and typical tacrolimus whole blood trough concentrations are shown in Table 5
below; blood concentration details are described under Warnings and Precautions –
Monitoring and Laboratory Tests.
Table 5: Advagraf (tacrolimus extended release capsules) – Summary of Initial Oral Dosage
Recommendations and Typical Whole Blood Trough Concentrations
Recommended Initial Once Daily
Typical Whole Blood Trough
(AM) Oral Dose
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 Advagraf® Product Monograph Page 19 of 44 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.
Conversion from Prograf (immediate release formulation) to Advagraf (extended release
Stable kidney transplant recipients can be converted from Prograf (immediate release
formulation) twice daily to once-daily Advagraf (extended release formulations). Patients
converting from Prograf (immediate release formulation) to Advagraf (extended release
formulation) should be administered a single daily morning dose of Advagraf (extended release
formulation) equivalent to the patient's previous stable total daily dose of Prograf (immediate
release formulation). The same target trough range and whole blood trough concentration
monitoring should be used as with Prograf (immediate release formulation) in order to maintain
whole blood trough concentrations of tacrolimus similar to those prior to conversion.
In patients unable to take oral Advagraf (extended release) 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.
Patients with Hepatic or Renal Dysfunction
Advagraf (extended release formulation) has not been studied in patients with hepatic or renal
dysfunction; the following are based on experiences obtained from use of Prograf (immediate
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.
Conversion from Cyclosporine to Advagraf
Patients converted from cyclosporine to Advagraf should receive the first Advagraf dose no
sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the
presence of elevated cyclosporine levels.
Conversion from Advagraf to Cyclosporine
Patients converted from Advagraf to cyclosporine should receive the first cyclosporine dose no
sooner than 24 hours after the last Advagraf dose. Dosing may be further delayed in the presence
of elevated tacrolimus levels.
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 (Table 6).
Advagraf® Product Monograph Page 20 of 44 Table 6: Advagraf (tacrolimus extended release capsules) trough concentrations in kidney transplant patients
If a dose of Advagraf is missed, the dose may be taken up to 14 hours after the scheduled time
without risk of overexposure (i.e., for a missed 8:00 am dose, take by 10:00 pm). Beyond the
14-hour time frame, the patient should wait until the usual scheduled time the following morning
to take the next regular daily dose.
Advagraf can be administered with or without food; however, doses should be administered in a
consistent manner (see Action and Clinical Pharmacology).
For management of a suspected drug overdose, please contact your regional Poison Control
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
(immediate release formulation). 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.
Advagraf® Product Monograph Page 21 of 44 ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action / Pharmacodynamics
Tacrolimus, the active ingredient in Advagraf, is a macrolide immunosuppressant produced by
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,
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
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 7).
Table 7: Pharmacokinetic Parameters of Advagraf (tacrolimus extended release capsules)
Healthy Volunteers Adult Kidney De Novo Adult Kidney Conversion 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 (immediate release formulation) to Advagraf (extended
release formulation) 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 (AUC0-24) in black kidney
transplant recipients at steady state after converting from Prograf (immediate release
Advagraf® Product Monograph Page 22 of 44 formulation) (% coefficient of variation; %CV: 25.4%) to Advagraf (extended release
formulation) (%CV: 12.2%). In white kidney transplant recipients, the intra-subject variability
for exposure at steady state was similar after converting from Prograf (immediate release
formulation) (% CV: 12.2%) to Advagraf (extended release formulation) (% 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 AUC0-inf and a 30% higher Cmax compared with oral administration of intact
capsules; administration of the aqueous suspension via nasogastric tube was associated with a
17% lower AUC0-inf and 28% higher Cmax compared with intact capsules.
Stable kidney transplant recipients can be converted from twice-daily Prograf (immediate release
formulation) to once-daily Advagraf (extended release formulation) on a 1:1 (mg:mg) total daily
dose basis to achieve appropriate tacrolimus blood concentrations (Table 8).
Table 8: Relative Biopharmaceutics (AUC0-24) at Steady State in Stable Transplant Recipients Converted
from Prograf (immediate release formulation) to Advagraf (extended release formulation)
Adult Kidney Transplant Recipients CI: confidence interval Least square mean parameters were generated from ANOVA. The ratio of least square mean AUC0-24 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 (Cmin) and exposure (AUC0-24) 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 Cmax, AUC0-t, and AUC0-inf by approximately 25% compared with fasting values. Food delayed the median Tmax 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 AUC0-inf 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 Advagraf® Product Monograph Page 23 of 44 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 AUC0-inf 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 (Table 9).
Table 9: Distribution in healthy volunteers and kidney transplant patients
Kidney Transplant Patients
0.025 mg/kg/4 hr
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 (immediate
release formulation), 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
Advagraf® Product Monograph Page 24 of 44
Gender: Data from kidney transplant recipients converted from Prograf (immediate release
formulation) to Advagraf (extended release formulation) 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 AUC0-24 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
Black kidney transplant recipients (n=12) were converted from Prograf (immediate release
formulation) to Advagraf (extended release formulation) on a 1:1 (mg:mg) total daily dose basis.
The ratio of least square means (Advagraf:Prograf) for AUC0-24 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 (immediate
release formulation) 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:
Table 10: Tacrolimus (Immediate Release Formulation) Pharmacokinetics in Patients with Mild Hepatic
Dose and Route
Absolute Bioavailability (%) *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. Advagraf® Product Monograph Page 25 of 44 Tacrolimus pharmacokinetics were also studied in 6 subjects with severe hepatic dysfunction (mean Pugh score > 10) administered Prograf (immediate release formulation). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration. Table 11: Tacrolimus (Immediate Release Formulation) Pharmacokinetics in Patients with Severe Hepatic
AUC ng•hr/mL (0-t)
289±117 (t=144 hr) 533 ± 156 (t=144 hr) † 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:
Table 12: Tacrolimus Pharmacokinetics in Patients with Renal Insufficiency
Serum Creatinine (mg/dL) 3.9 ± 1.6 (not on dialysis) 12.0 ± 2.4 (on dialysis) AUC 0-60 (ng•hr/mL) AUC 0-inf (ng•hr/mL) 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. Advagraf® Product Monograph Page 26 of 44
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 AUC0-24 of 92.0% [90% CI: 84.8%, 99.7%] in kidney transplant
STORAGE AND STABILITY
Store and dispense at controlled room temperature, 15 oC - 30 oC.
SPECIAL HANDLING INSTRUCTIONS
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, 3 mg or 5 mg of anhydrous
tacrolimus. Inactive ingredients include ethylcellulose, hypromellose, magnesium stearate and
lactose. The ingredients are directly proportional across all capsule strengths. The capsule shells
contain gelatin, titanium dioxide, sodium lauryl sulfate 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
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 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) 3 mg
Oblong capsules with an orange cap and an orange body. Capsules supplied in 50-count blister
packs (10 capsules per card) are imprinted with red " 637" on the capsule body and "3 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 50-count blister
packs (10 capsules per card), are imprinted with red " 687" on the capsule body and "5 mg" on the capsule cap. Advagraf® Product Monograph Page 27 of 44 PART II: SCIENTIFIC INFORMATION
Proper name: tacrolimus Molecular formula and molecular mass: C 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) Advagraf® Product Monograph Page 28 of 44 CLINICAL TRIALS
Study demographics and trial design
Table 13: Summary of patient demographics for clinical trials in kidney transplantation
Dosage, route of
KIDNEY – De novo transplant
Advagraf (extended release): initial dose 0.20mg/kg/day, orally, once daily morning, 1 year.* Prograf (immediate release): initial dose 0.075mg - 0.1mg/kg orally, twice daily, 1 year.* Neoral: initial dose 4 -5mg/kg, orally, twice daily, 1 year.* Advagraf (extended release): Initial dose 0.20mg/kg orally, once daily morning‡. comparative trial Study duration 6 weeks. Prograf (immediate release): Initial dose 0.20mg/kg orally, twice daily‡. Study duration 6 weeks KIDNEY – Transplant Recipients Converted from Prograf (immediate release formulation) to Advagraf
(extended release formulation)
Individualized oral dose (tacrolimus conversion (1:1) Prograf (immediate release) twice daily dose is given for 1 week followed by Advagraf (extended release) once daily dose for 4 weeks. Advagraf® Product Monograph Page 29 of 44 Trial design
Dosage, route of
Individualized oral dose (tacrolimus (Alloway, sequence, four 5-15ng/ml). Prograf period crossover (immediate release) replicate design, Advagraf (extended release) once daily for 14 days for each of 4 treatment periods. W= White, B= Black, A= Asian, O= other (includes East Indian, Pacific Islander, Native Hawaiian, Filipino,
Brazilian Indian) *Target concentration range for tacrolimus (Advagraf [extended release formulation] and Prograf
[immediate release formulation]) 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).
Kidney Transplant Recipients
The efficacy and safety of Advagraf (extended release formulation) + mycophenolate mofetil
(MMF) and corticosteroids (S) (n=214) was compared with that of Prograf (immediate release
formulation) + 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 (immediate
release formulation) 0.075-0.10 mg/kg twice daily, Advagraf (extended release formulation)
0.15-0.20 mg/kg once daily AM; Neoral 4-5 mg/kg twice daily. 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 14, 15, 16 and 17).
Table 14: Efficacy Failure in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
Efficacy Failure Treatment Difference CI: confidence interval. Treatment differences are relative to Neoral treatment group (Advagraf minus Neoral; Prograf minus Neoral). † Neoral is a registered trademark of Novartis Pharmaceuticals Corporation. ‡ CellCept is a registered trademark of Roche Pharmaceuticals Advagraf® Product Monograph Page 30 of 44 Table 15: Patient and Graft Survival in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
Patient Survival Kaplan-Meier Estimate Difference Kaplan-Meier Estimate Difference 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 16: Renal Function in De Novo Kidney Transplant Recipients at 6 and 12 Months Posttransplant
release) vs. Neoral
Mean Serum Creatinine Levels (mg/dL): Mean Creatinine Clearance Levels (mL/min): Advagraf® Product Monograph Page 31 of 44 Table 17: Additional Efficacy Data in De Novo Kidney Transplant Recipients at 1 Year Posttransplant
Treatment Failure Cross Over Due to Treatment Failure Patient Discontinuations 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 (twice daily) to Advagraf (once daily) 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 (extended release formulation)
dosing adjustments in the early conversion period (Table 18).
Table 18: Patient and Graft Survival in Stable Transplant Recipients 1 or 2 Years After
Conversion from Prograf (Immediate Release Formulation) to Advagraf (Extended Release
US Adult Kidney Study (2 Years) EU Adult Kidney Study (1 Year) Kaplan-Meier estimates.
There were no graft losses due to rejection in the kidney conversion 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
Advagraf® Product Monograph Page 32 of 44 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) immediate release capsules 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 (immediate release formulation) 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). Advagraf® Product Monograph Page 33 of 44 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 19). Table 19: Effect of Tacrolimus (FK506) on Allograft Skin Survival in Rats
FK506 0.01 mg/kg
FK506 0.1 mg/kg
FK506 1.0 mg/kg
*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 a extended release formulation.
The pharmacokinetic profile of tacrolimus as Prograf (immediate release formulation) after
intravenous or oral administration is well defined3. Tacrolimus as Prograf (immediate release
formulation) 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 (immediate release formulation) 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 (Cmax) following administration as
Prograf (immediate release formulation) 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 Cmax 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 (immediate release formulation).
However, while not predictive of any individual adverse event, a higher Cmax could potentially
increase the overall safety risk.
Advagraf® Product Monograph Page 34 of 44 Therefore, the target biopharmaceutic goals for the development of a once-a-day formulation of tacrolimus were to achieve AUC relative to Prograf (immediate release formulation) within equivalence criteria and an equal or reduced Cmax as compared with that of Prograf (immediate release formulation). 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 [immediate release formulation]) and the same trough target range as Prograf (immediate release formulation), using the same therapeutic monitoring system. The pharmacokinetic parameters of the tacrolimus extended release formulation (Advagraf) has been studied in patients (see Table 7). Results indicate that the same therapeutic monitoring as used with Prograf (immediate release formulation) can be used with tacrolimus extended release formulation. In addition, the same trough target range as used with Prograf (immediate release formulation) can be used with tacrolimus extended release formulation. In conversion patients, tacrolimus exposure (AUC0-24) at steady state is equivalent between Prograf (immediate release formulation) and extended release formulation supporting continued prophylaxis of organ rejection (Table 20). Data from studies of transplant recipients indicate that once-daily administration of tacrolimus extended release formulation results in consistently lower Cmax values than twice-daily administration of Prograf (immediate release formulation). 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 20: Relative Biopharmaceutics (AUC0-24) at Steady State
Advagraf (extended release) /
Prograf (immediate release)
(Ratio of Least Square Means)
Patient Base: stable transplant recipients converted from Prograf (immediate release formulation) 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 Advagraf® Product Monograph Page 35 of 44 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.
The tacrolimus toxicology profile is well defined and was established as part of the development
program for Prograf (immediate release formulation). 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 21-23.
Table 21: Acute Toxicology Studies of Tacrolimus in Rats and Baboon
Overt Signs of Toxicology
Tremor, ptosis, salivation, hyperreactivity, decreased spontaneous motility Rat, Sprague-Dawley Bloody urine, prone position, ptosis, hyper-reactivity, salivation, decreased motility Rat, Sprague-Dawley Hyperreactivity, salivation, decreased motility Huddled posture, emesis Debility and exhaustion: 1 of 2 *Not determined Advagraf® Product Monograph Page 36 of 44 Repeat Dose Toxicity
Table 22: Overview of Repeated Dose Toxicity Studies of Tacrolimus
No. / Group
0, 0.15, 0.5, 1.5 0, 0.032, 0.1, 0.32, 1 Papio spp. 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.
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.
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
Advagraf® Product Monograph Page 37 of 44 Table 23: Reproductive and Developmental Toxicity Studies of Orally Administered Tacrolimus
No observable effect No observable effect Incomplete delivery No observable effect Body weight with food consumption Male copulatory index Copulatory interval Post-implantation loss Incomplete delivery Embryo/offspring viability Female diestrus period No observable effect No observable effect No observable effect Fetal body weight Fetal body weight Post-implantation loss Body weight with food Offspring viability Skeletal variations Segment 2, Rabbit No observable effect Developmental variations Developmental variations Post-implantation loss Viable fetuses Morphological variations No observable effect No observable effect 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 Advagraf® Product Monograph Page 38 of 44 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
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
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
Advagraf® Product Monograph Page 39 of 44 REFERENCES
1. 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. 2. Alloway R, Steinberg S, Khalil K, et al. Two years postconversion from a Prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation 2007;83:1648-51. 3. 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. 4. 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. 5. Jusko WJ. Analysis of tacrolimus (FK 506) in relation to therapeutic drug monitoring. Ther Drug Monit 1995 Dec;17(6):595-601. 6. 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. 7. Prograf® tacrolimus immediate release capsules, tacrolimus injection (for intravenous infusion only), Product Monograph, Markham, ON. Astellas Pharma Canada, Inc, August 27, 2009. 8. Silva HT, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007;7:595-608. 9. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant receipients. Clin Pharmacokinet 2007; 46(1):13-58. Advagraf® Product Monograph Page 40 of 44 IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
The 3 mg capsule has an orange cap and an orange body. The capsule is imprinted in red with " 637" on the capsule body Advagraf®
and "3 mg" on capsule cap. tacrolimus extended release capsules
The 5 mg capsule has a greyish red cap and an orange body. The Read this important information before you start using
Advagraf and each time you refill your prescription.
capsule is imprinted in red with " 687" on the capsule body and "5 mg" on capsule cap. This leaflet is part III of a three-part "Product Monograph"
published when Advagraf was approved for sale in Canada
WARNINGS AND PRECAUTIONS
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
Advagraf should be prescribed by doctors experienced in the
questions about the drug.
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
ABOUT THIS MEDICATION
infections and some kinds of cancer, including skin and lymph
gland cancer (lymphoma). Wear protective clothing and use a
What the medication is used for:
Advagraf is the brand name for tacrolimus extended release
sunscreen with a high sun protection factor (SPF 30) to limit
exposure to sunlight and UV light. However, getting cancer
capsules. Advagraf helps to prevent your body from rejecting a kidney transplant. Advagraf is used concomitantly with adrenal from taking an anti-rejection medicine is not common.
corticosteroids and mycophenolate mofetil. BEFORE you use Advagraf, be sure that you are taking the
What it does:
correct dose and correct formulation of tacrolimus (Advagraf, Your body's immune system is your defence system. Immunity tacrolimus extended release capsules) and you have told your is the way your body protects itself from infections and other doctor the following: foreign material. When you receive a transplant, your immune If you have taken Prograf, Advagraf or tacrolimus before system recognizes the transplanted organ as foreign and will try and had a bad, unusual or allergic reaction to reject it. Advagraf is an anti-rejection drug that helps your About all other medicines or treatments you use, body accept your transplanted organ. including any products you buy off the shelf such as over-the-counter drugs and herbal or home remedies When it should not be used:
About all other health conditions, including kidney Do not take Advagraf if you are allergic to any of the and/or liver problems, you have now, or have had in the ingredients in Advagraf (see "What the nonmedicinal ingredients are"). If you are pregnant, plan to become pregnant, or are breastfeeding a baby. Advagraf may cause fetal What the medicinal ingredient is:
abnormalities and malformations. Pregnancy should be
avoided while taking Advagraf because its effect on
pregnancy or on an unborn baby is not known. You What the nonmedicinal ingredients are:
must use as reliable method of birth control before, Ethylcellulose, hypromellose, magnesium stearate, lactose, during your treatment and for 6 weeks after stopping sodium lauryl sulfate, gelatin, titanium dioxide and ferric oxide. your treatment with Advagraf. Advagraf has been found in human breastmilk. Breast-feeding is not recommended What dosage forms it comes in:
while taking Advagraf. It is important to notify your Advagraf is available in an extended release capsule, once a doctor right away if you become pregnant or father a day. Each capsule contains 0.5 mg, 1 mg, 3 mg or 5 mg of child while taking Advagraf. It is recommended that you do not take Advagraf if you are, or become, pregnant. However, never stop taking Advagraf without first The 0.5 mg capsule has a light yellow cap and an orange body. consulting your doctor If you have a rare hereditary disease of galactose The capsule is imprinted in red with " 647" on the capsule intolerance, the Lapp lactase deficiency or glucose- mg" on capsule cap. galactose malabsorption, as this product contains lactose. 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. Advagraf® Product Monograph Page 41 of 44 IMPORTANT: PLEASE READ
INTERACTIONS WITH THIS MEDICATION
PROPER USE OF THIS MEDICATION
Some medicines and even some foods can affect how well Advagraf can protect your new kidney only if you take the Advagraf works. After you start taking Advagraf: medicine correctly. Be sure to tell your transplant team, family doctor, Your new organ needs around-the-clock protection so your body dentist, pharmacist and any other health care does not reject it. The success of your transplant depends a great professional treating you the names of all the
deal upon how well you help Advagraf do its job. Here is what medicines you are taking. This is the only way that your health care team can help prevent drug interactions that could be serious. Make sure you know 1. Take Advagraf exactly as prescribed
if you are to stop, or continue, other drugs you had 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 Always check with your transplant team before you by your transplant team. Your transplant team may adjust your start taking any new medicine, or any products you buy dose until they find what works best for you. Never change your off the shelf such as over-the-counter drugs, herbal or dose on your own. Never stop taking Advagraf even if you are nutritional supplements (especially St. John's Wort), feeling well. However, if you feel poorly on Advagraf, discuss vitamins or home remedies this with your transplant team. While you are taking Advagraf, do not get any
vaccinations without your transplant team's
2. Take Advagraf once-a-day, in the morning
approval. The vaccination may not work as well as it
Try to pick a time that will be easy for you. Do not vary the time. should or may result in serious side effects 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 Do not eat or drink any product that contains grapefruit every day. This will make sure you always have enough or grapefruit juice in combination with your medicine medicine in your body to give your new organ the around-the- unless your transplant team approves clock protection it needs. Advagraf blood levels can be affected by other medicines you 3. Take Advagraf the same way each day
take, and blood levels of other medicines can be affected by Most people are directed to take Advagraf on an empty stomach, taking Advagraf, which may require an increase or decrease in 2 hours before or after a meal. However, some people prefer to the Advagraf dose. In particular, you should tell you doctor if take Advagraf with food to help reduce possible stomach upset. you have recently taken medicines such as: Whether you take Advagraf with or without food, it is important to take Advagraf the same way every day. For example, if you Antacids: magnesium aluminum hydrochloride take Advagraf with food, you should always take it with food. Do Antifungals: clotrimazole, fluconazole, ketoconazole, not change the way you take this medicine without telling your itraconazole, voriconazole transplant team, since this could change the amount of protection Calcium channel blockers: diltiazem nicardipine, you get from Advagraf. nifedipine, verapamil Gastrointestinal prokinetic agents: cisapride*, 4. Take your full dose of medication, every day
It is important to take your dose exactly as prescribed by your Macrolide antibiotics: erythromycin, clarithromycin, doctor. If you miss even one dose, your new kidney could lose the protection it needs against rejection by your body. Proton pump inhibitor: lansoprazole, omeprazole Other drugs: bromocriptine, cimetidine, If you travel and change time zones, be sure to ask your transplant chloramphenicol, cyclosporine, danazol, ethinyl team how to adjust your dosage schedule so your new organ does estradiol, methylprednisolone, nefazodone not lose its protection. Protease inhibitors: nelfinavir, ritonavir, saquinavir Anticonvulsants: carbamazepine, phenobarbital, 5. Take the same tacrolimus medicine every time
Make sure that you receive the same tacrolimus medicine (the Anti-infectives: rifampin, rifabutin, capsofungin brand name of the medicine should always be the same) every Calcineurin inhibitor: sirolimus time you collect your prescription, unless your transplant Herbal preparations: St. John's Wort specialist has agreed to change to a different tacrolimus medicine. This medicine should be taken once a day. If the appearance of *drugs no longer marketed in Canada this medicine is not the same as usual, or if dosage instructions have changed, or if the brand name is different, speak to your Advagraf® Product Monograph Page 42 of 44 IMPORTANT: PLEASE READ
doctor or pharmacist as soon as possible to make sure that you diabetes/increased blood sugar, swelling or tingling have the right medicine. in your hands and feet palpitations, abnormal heart rhythms, chest pain, 6. Plan ahead so that you do not run out of Advagraf
high blood pressure Make sure you have your prescription for Advagraf refilled and fever, back pain, changes in mood or emotions, at home before you need it. Circle the date on a calendar when difficulty in breathing you need to order your refill. Allow extra time if you receive headache, seizures, visual disturbances or altered your medicines through the mail. mental state, which could be symptoms of posterior encephalopathy syndrome (PRES) 7. When having a blood test to measure Advagraf
progressive weakness on one side of the body, On the days you are going to have a blood test to measure the clumsiness of limbs, disturbance of vision, changes amount of Advagraf in your body, your transplant team will ask in thinking, memory and orientation, confusion, you not to take your dose until after the blood sample is taken. personality changes, which could be symptoms of a rare brain infection called progressive multifocal 8. Missed dose
leukoencephalopathy (PML) If a dose of Advagraf is missed, the dose may be taken up to 14 hours after the scheduled time without risk of overexposure Immunosuppressive drugs including Advagraf may also (i.e., for a missed 8:00 am dose, take by 10:00 pm). Beyond the increase your chances of developing certain types of 14-hour time frame, you should wait until the usual scheduled cancer. The following are possible warning signs of time the following morning to take the next regular daily dose. cancer and should be reported to your doctor as soon as Do not double dose. any sore that does not heal unusual bleeding or discharge 9. Overdose
the appearance of a lump or thickened areas in your breast or anywhere else on your body In case of drug overdose, contact a healthcare practitioner
unexplained stomach upset or any trouble with (e.g. doctor), hospital emergency department or regional
poison control centre, even if there are no symptoms.
any noticeable change in a wart or a mole If you take too much Advagraf please contact your doctor, a nagging cough or hoarseness hospital emergency department or regional poison control night sweats centre immediately. persistent and severe headaches swollen lymph nodes a change in your bowel or bladder habits SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Medication errors, including inadvertent, unintentional or Like other medicines, Advagraf may cause side effects in some unsupervised substitution of immediate or extended release people. If you think that you are having side effects, talk to tacrolimus oral formulations, have been observed. This has led to your doctor right away. DO NOT stop taking Advagraf on
serious adverse events, including graft rejection, or other side your own.
effects which could be a consequence of either under- or over- exposure to tacrolimus. You should be maintained on a single Because Advagraf decreases the function of your formulation of tacrolimus with the corresponding daily dosing immune system you may be more likely to get an regimen; alterations in formulation or regimen should only take infection. Tell your doctor right away about any cold place under the close supervision of a transplant specialist. or flu-like symptoms (such as fever or sore throat), any mouth sores or burning discomfort with urination. It is important to regularly tell your doctor how you are
feeling and if you have developed any new symptoms while
Be sure to tell your doctor right away if you notice any taking Advagraf.
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 Advagraf® Product Monograph Page 43 of 44 IMPORTANT: PLEASE READ
REPORTING SUSPECTED SIDE EFFECTS
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
You can report any suspected adverse reactions associated
with the use of health products to the Canada Vigilance
Symptom / effect
Talk with your
Program by one of the following 3 ways:
Report online at
Call toll-free at 1-866-234-2345
Complete a Canada Vigilance Reporting Form and:
Fax toll-free to 1-866-678-6789, or
Mail to: Canada Vigilance Program
Infection (urinary tract, sinusitis, Health Canada
gastroenteritis, influenza, upper Postal Locator 0701C
respiratory tract) Ottawa, ON K1A 0K9
Early signs of high blood sugar or diabetes: more thirsty than Postage paid labels, the Canada Vigilance Reporting Form
usual, have to urinate more and the adverse reaction reporting guidelines are available
often, have blurred vision or on the MedEffect™ Canada web site at
seem to get confused. Decreased or increased urine volumes, dark coloured urine NOTE: Should you require information related to the
which may be a sign of kidney problems management of side effects, contact your health
professional. The Canada Vigilance Program does not
provide medical advice.
Posterior Encephalopathy Syndrome (PRES) with MORE INFORMATION
symptoms such as headache, seizures, visual disturbances or altered mental state If you have additional questions or would like to talk with *Unable to determine frequency since this is a post-marketing event someone to explain something you are worried about, ask your doctor, nurse or pharmacist. They are your best resource for This is not a complete list of side effects. For any unexpected
guidance and information. effects while taking Advagraf, contact your doctor or
This document plus the full product monograph, prepared for health professionals can be found at: HOW TO STORE IT
or by contacting the sponsor, Astellas Pharma Canada, Inc., at: Keep Advagraf out of the reach and away from children. A child who accidentally takes Advagraf may be seriously This leaflet was prepared by Astellas Pharma Canada, Inc. harmed. All drugs should be kept in a locked drawer or cupboard if there are children who may accidentally take your Last revised: September 17, 2010 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. Advagraf® Product Monograph Page 44 of 44
Limitations of New LORNA WEIR The term "new social movements" (NSMs) entered the lexicon of social theory during the 1980s. At the most obvious level, "new social movements" de- signates the broad range of contemporary social movements,including environmental, peace, feminist, ethnic, anti-racistand national minority organizing. These movements arethought to be defined by an orientation to identity and cul-tural politics rather than to state and class politics. NSMs