[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 ContentsAdvagraf® Product Monograph Page 2 of 44 tacrolimus extended release capsules PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form / Clinically Relevant Nonmedicinal Ingredients
Strength
For a complete listing see Dosage Forms, Composition and Packaging section.
INDICATIONS AND CLINICAL USE
De novo
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.
Conversion
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
transplant patients.
Pediatrics (< 18 years of age): Experience with Advagraf in pediatric kidney transplant
patients is limited.
Geriatrics ( 65 years of age): Experience with Advagraf in patients older than 65 years of age
is limited.
CONTRAINDICATIONS
Advagraf (tacrolimus extended release capsules) is contraindicated in patients with
hypersensitivity to tacrolimus or to any ingredient in the formulation or component of the
capsules. For a complete listing, see the Dosage Forms, Composition and Packaging section of
the product monograph.
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.
General
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
transplant specialist.
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
surface area.
Cardiovascular
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
considered.
Immune/Infection
A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been
reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in
young children who are at risk for primary EBV infection while immunosuppressed or who are
switched to Advagraf following long-term immunosuppression therapy. Because of the danger
of oversuppression of the immune system which can increase susceptibility to infection,
combination immunosuppressant therapy other than corticosteroids and MMF is not
recommended.
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
symptoms.
Neurologic
Tacrolimus can cause neurotoxicity, particularly when used in high doses.
Nervous system disorders, including tremor, headache, and other changes in motor function,
mental status, and sensory function were reported in 63.1% of de novo kidney transplant
recipients. Tremor occurred in 35.0% of Advagraf-treated kidney transplant patients compared
to 19.8% of Neoral-treated kidney transplant patients. The incidence of other neurological
events in kidney transplant patients was similar in the two treatment groups (see Adverse
Reactions). Tremor and headache have been associated with high whole blood concentrations of
tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric
patients receiving tacrolimus as Prograf (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.
Pancreatic
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
Neoral/MMF
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
Posttransplant
Neoral/MMF
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
Laboratory Tests).
Sexual Function/Reproduction
No impairment of fertility was demonstrated in studies of male and female rats. In reproduction
studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that
were toxic to dams. However, in female rats dosed during organogenesis, embryo toxicity
(expressed as reduced pup weights) was seen at a dose which was one-third of the maternally
toxic dose. At this same dose, when administered prior to mating and during gestation,
tacrolimus was associated with adverse effects on female reproductive parameters and
embryolethality. This dose was equivalent to 0.5X the clinical dose. (See Warnings and
Precautions - Special Populations).
Special Populations
Pregnant Women
There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred
across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal
hyperkalemia and renal dysfunction. Advagraf should be used during pregnancy only if the
potential benefit to the mother justifies potential risk to the fetus (Please see Detailed
Pharmacology - Human studies and Toxicology - Reproductive and Developmental Toxicity).
Nursing Women
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
geriatric population.
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.
ADVERSE REACTIONS
Overview
The most common adverse reactions reported were infection, tremor, hypertension, decreased
renal function, constipation, diarrhea, headache, abdominal pain and insomnia. Many of these
adverse reactions were mild and responded to a reduction in dosage. Insulin-dependent post-
transplant diabetes mellitus (PTDM) was related to increased whole blood trough concentrations
of tacrolimus and higher doses of corticosteroids. The median time to onset of PTDM was 68
days.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. In a large (n=668), phase III, randomized, comparative trial, de novo kidney transplant recipients received either Advagraf (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
Prograf (immediate
Advagraf (extended
Neoral + MMF
release) + MMF
release) + MMF
Gastrointestinal Disorders
Diarrhea
Injury, Poisoning and Procedural Complications
Post procedural pain
Incision site complication Metabolism and Nutritional Disorders
Hypomagnesemia
Hypophosphatemia Infections and Infestations
Urinary tract infection General Disorders and Administration Site Conditions
Edema peripheral
Nervous System Disorder
Tremor
Blood creatinine increased Blood and Lymphatic System Disorders
Anemia
Vascular Disorders
Musculoskeletal and Connective Tissue Disorders
Psychiatric 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,
pain.
Infections and Infestations: cytomegalovirus infection, gastroenteritis, influenza,
nasopharyngitis, sinusitis, upper respiratory tract infection.
Investigations: hepatic enzyme increased.
Metabolism and Nutrition Disorders: dehydration, diabetes mellitus, hypocalcemia, metabolic
acidosis.
Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramp, pain in
extremity.
Nervous System Disorders (see Warnings and Precautions): dizziness.
Psychiatric Disorders: anxiety, depression.
Skin and Subcutaneous Tissue Disorders: acne, pruritus.
Renal and Urinary Disorders (see Warnings and Precautions): hematuria, renal impairment,
renal insufficiency.
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,
thrombocytopenia.
Cardiac Disorders: atrial fibrillation.
Eye Disorders: vision blurred.
Gastrointestinal Disorders: abdominal discomfort, abdominal distension, abdominal pain
lower, ascites, gastritis, gastrooesophageal reflux disease, hemorrhoids, loose stools,
oesophagitis, post procedural nausea, toothache.
General Disorders and Administration Site Conditions: anasarca, rigors.
Hepatobiliary Disorders: bile duct stenosis, cholestasis.
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,
hyponatremia.
Musculoskeletal and Connective Tissue Disorders: myalgia, osteopenia, osteoporosis.
Nervous System Disorders: hypoesthesia, paraesthesia.
Psychiatric Disorders: agitation, confusional state.
Renal and Urinary Disorders: dysuria, oliguria, proteinuria, renal failure acute, urethral pain.
Reproductive System and Breast Disorders: erectile dysfunction.
Respiratory, Thoracic and Mediastinal Disorders: dyspnea exertional, epistaxis, nasal
congestion, productive cough.
Skin and Subcutaneous Tissue Disorders: alopecia, ecchymosis, night sweats, rash, skin
lesion.
Vascular Disorders: hematoma, hot flush, orthostatic hypotension.
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
graft dysfunction;
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
disorder, syncope;
Respiratory: acute respiratory distress syndrome, interstitial lung disease, lung infiltration,
respiratory distress, respiratory failure;
Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis;
Special Senses: blindness, blindness cortical, hearing loss including deafness, photophobia;
Urogenital: albuminuria, acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome,
micturition disorder.
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.
DRUG INTERACTIONS
Overview
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
concentrations.
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:
Reference
Effect on
Drug Name
of tacrolimus
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:
Reference
Effect on
Drug Name
of tacrolimus
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:
Reference
Effect on
Drug Name
of tacrolimus
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:
Reference
Effect on
Drug Name
of tacrolimus
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
21a typhoid3.
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.
Drug-Food Interactions
Grapefruit juice affects P450 3A-mediated metabolism and should be avoided.
Drug-Herb Interactions
St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus
is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients
receiving Advagraf could result in reduced tacrolimus levels.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions
As with other immunosuppressive agents, owing to the potential risk of malignant skin changes,
exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing
and using sunscreen with a high protection factor.
Advagraf® Product Monograph Page 18 of 44 DOSAGE AND ADMINISTRATION
Dosing Considerations
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
maintained.
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
Patient Population
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
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