Advagraf

Tacrolimus (as monohydrate).

Each prolonged-release hard capsule contains 0.5 mg or 1 mg or 3 mg tacrolimus (as monohydrate).
Excipients/Inactive Ingredients: Capsule content: Hypromellose, Ethylcellulose, Lactose monohydrate, Magnesium stearate.
Capsule shell: Titanium dioxide (E 171), Yellow iron oxide (E 172), Red iron oxide (E 172), Sodium lauryl sulfate, Gelatin.

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors. ATC code: L04AD02.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the expression of the interleukin-2 receptor.
Results from clinical trials performed with once-daily tacrolimus Advagraf: Liver transplantation: The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared in 471 de novo liver transplant recipients. The event rate of biopsy confirmed acute rejection within the first 24 weeks after transplantation was 32.6% in the Advagraf group (N = 237) and 29.3% in the Prograf group (N = 234). The treatment difference (Advagraf - Prograf) was 3.3% (95% confidence interval [-5.7%, 12.3%]). The 12-month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female, 19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.
Kidney transplantation: The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil (MMF) and corticosteroids, was compared in 667 de novo kidney transplant recipients. The event rate for biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the Advagraf group (N = 331) and 14.9% in the Prograf group (N = 336). The treatment difference (Advagraf-Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were 96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female, 7 male) and in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf and 92.8% for Prograf.
The efficacy and safety of Prograf, ciclosporin and Advagraf, all in combination with basiliximab antibody induction, MMF and corticosteroids, was compared in 638 de novo kidney transplant recipients. The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute rejection, or lost to follow-up) was 14.0% in the Advagraf group (N = 214), 15.1% in the Prograf group (N = 212) and 17.0% in the ciclosporin group (N = 212). The treatment difference was -3.0% (Advagraf-ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Advagraf vs. ciclosporin and -1.9% (Prograf-ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient survival rates were 98.6% for Advagraf, 95.7% for Prograf and 97.6% for ciclosporin; in the Advagraf arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Advagraf, 92.9% for Prograf and 95.7% for ciclosporin.
Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation: In prospective studies oral Prograf was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of oral Prograf in these published studies appeared to be similar to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised as follows.
Lung transplantation: The interim analysis of a recent multicentre study using oral Prograf discussed 110 patients who underwent 1:1 randomisation to either tacrolimus or ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.01 to 0.03 mg/kg/day and oral tacrolimus was administered at a dose of 0.05 to 0.3 mg/kg/day. A lower incidence of acute rejection episodes for tacrolimus- versus ciclosporin-treated patients (11.5% versus 22.6%) and a lower incidence of chronic rejection, the bronchiolitis obliterans syndrome (2.86% versus 8.57%), was reported within the first year after transplantation. The 1-year patient survival rate was 80.8% in the tacrolimus and 83% in the ciclosporin group.
Another randomised study included 66 patients on tacrolimus versus 67 patients on ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 ng/ml. The 1-year patient survival was 83% in the tacrolimus and 71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p = 0.025). Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated patients to ciclosporin (n = 2) (p = 0.02).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).
The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.
Pancreas transplantation: A multicentre study using oral Prograf included 205 patients undergoing simultaneous pancreas-kidney transplantation who were randomised to tacrolimus (n = 103) or to ciclosporin (n = 102). The initial oral per protocol dose of tacrolimus was 0.2 mg/kg/day with subsequent dose adjustments to target trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/mL after Month 6. Pancreas survival at 1 year was significantly superior with tacrolimus: 91.3% versus 74.5% with ciclosporin (p < 0.0005), whereas renal graft survival was similar in both groups. In total 34 patients switched treatment from ciclosporin to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.
Intestinal transplantation: Published clinical experience from a single centre on the use of oral Prograf for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was 0.3 mg/kg/day. Results continuously improved with increasing experience over the course of 11 years. A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15 ng/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.
Pharmacokinetics: Absorption: In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed. Advagraf is a prolonged-release formulation of tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood concentration (C_max) of approximately 2 hours (t_max).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prograf formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral bioavailability of Advagraf was reduced when it was administered after a meal. Both the rate and extent of absorption of Advagraf were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf may commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Advagraf. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
Distribution: In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.
Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on whole blood averaged 47.6 l.
Metabolism: Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4 (CYP3A4) and the cytochrome P450-3A5 (CYP3A5). Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to the pharmacological activity of tacrolimus.
Excretion: Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation.
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.
Following intravenous and oral administration of ¹⁴C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.
Toxicology: Preclinical safety data: The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus. Embryofoetal toxicity was observed in animal studies. Tacrolimus subcutaneously administered to male rats at doses of 2 or 3 mg/kg/day (1.6 to 6.4 times the clinical dose range based on body surface area) resulted in a dose-related decrease in sperm count.
Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction which were indicated by a higher rate of post-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), 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.

Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.

Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoring by adequately qualified and equipped personnel. This 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 immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of adverse reactions, 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 Precautions and Adverse Reactions). 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.
Posology: The recommended initial doses presented as follows are intended to act solely as a guideline. Advagraf is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The dose may vary depending upon the immunosuppressive regimen chosen. Advagraf dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see following text under "Therapeutic drug monitoring"). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.
In de novo kidney and liver transplant patients AUC_0-24 of tacrolimus for Advagraf on Day 1 was 30% and 50% lower respectively, when compared with that for the immediate release capsules (Prograf) at equivalent doses. By Day 4, systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in the first two weeks post-transplant with Advagraf to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Advagraf dose regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.
Prophylaxis of kidney transplant rejection: Advagraf therapy should commence at a dose of 0.20 - 0.30 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Prophylaxis of liver transplant rejection: Advagraf therapy should commence at a dose of 0.10 - 0.20 mg/kg/day administered once daily in the morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Conversion of Prograf-treated patients to Advagraf: Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should be administered in the morning.
In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1 (mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC_0-24) for Advagraf was approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C₂₄) and systemic exposure (AUC_0-24) for Advagraf is similar to that of Prograf. When converting from Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary dose adjustments made to maintain similar systemic exposure. Dose adjustments should be made to ensure that similar systemic exposure is maintained.
Conversion from ciclosporin to tacrolimus: Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see Precautions and Interactions). The combined administration of ciclosporin and tacrolimus is not recommended. Advagraf therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.
Treatment of allograft rejection: Increased doses of tacrolimus, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity such as severe adverse reactions are noted (see Adverse Reactions), the dose of Advagraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation: For conversion from other immunosuppressants to once daily Advagraf, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection.
Treatment of allograft rejection after heart transplantation: In adult patients converted to Advagraf, an initial oral dose of 0.15 mg/kg/day should be administered once daily in the morning.
Treatment of allograft rejection after transplantation of other allografts: Although there is no clinical experience with Advagraf in lung-, pancreas- or intestine-transplanted patients, Prograf has been used in lung-transplanted patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.
Therapeutic drug monitoring: Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship between tacrolimus trough levels (C₂₄) and systemic exposure (AUC_0-24) is similar between the two formulations Advagraf and Prograf.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus blood trough levels should be determined approximately 24 hours post-dosing of Advagraf, just prior to the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored following conversion from Prograf to Advagraf, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see Interactions). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Advagraf dose regimen it may take several days before the targeted steady state is achieved.
Data from clinical studies suggest that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood trough levels have generally been in the range 5 - 20 ng/ml in liver transplant recipients and 10 - 20 ng/ml in kidney and heart transplant patients in the early post-transplant period. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 - 15 ng/ml in liver, kidney and heart transplant recipients.
Special populations: Hepatic impairment: Dose reduction may be necessary in patients with severe liver impairment in order to maintain the tacrolimus blood trough levels within the recommended target range.
Renal impairment: As the pharmacokinetics of tacrolimus are unaffected by renal function (see PHARMACOLOGY: Pharmacokinetics under Actions), no dose adjustment is required. However, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is recommended (including serial serum creatinine concentrations, calculation of creatinine clearance and monitoring of urine output).
Race: In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.
Gender: There is no evidence that male and female patients require different doses to achieve similar trough levels.
Elderly patients: There is no evidence currently available to indicate that dosing should be adjusted in elderly patients.
Paediatric patients: The safety and efficacy of Advagraf in children under 18 years of age have not yet been established. Limited data are available but no recommendation on a posology can be made.
Method of administration: Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be taken immediately following removal from the blister. Patients should be advised not to swallow the desiccant. The capsules should be swallowed whole with fluid (preferably water).
Advagraf should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption (see PHARMACOLOGY: Pharmacokinetics under Actions). A forgotten morning dose should be taken as soon as possible on the same day. A double dose should not be taken on the next morning.
In patients unable to take oral medicinal products during the immediate post-transplant period, tacrolimus therapy can be initiated intravenously (Prograf 5 mg/ml Concentrate for Infusion) at a dose approximately 1/5^th of the recommended oral dose for the corresponding indication.

Experience with overdose is limited. Several cases of accidental overdose have been reported with tacrolimus; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy and increases in blood urea nitrogen, serum creatinine and alanine aminotransferase levels. No specific antidote to tacrolimus therapy is available. If overdose occurs, general supportive measures and symptomatic treatment should be conducted.
Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with very high plasma levels, haemofiltration or -diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.

Hypersensitivity to tacrolimus, or to any of the excipients listed in Description.
Hypersensitivity to other macrolides.

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse reactions, including graft rejection, or other adverse reactions 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 (see Dosage & Administration and Adverse Reactions).
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients clinical data are not yet available for the prolonged-release formulation Advagraf.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for Advagraf.
During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.
When substances with a potential for interaction - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) - are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure. Early and frequent continued monitoring of tacrolimus blood levels within the first few days of coadministration, as well as monitoring for renal function, for QT prolongation with ECG, and for other side effects is strongly recommended when co-administered with CYP3A4 inhibitors (see Interactions).
Herbal preparations containing St. John's wort (Hypericum perforatum) should be avoided when taking Advagraf due to the risk of interactions that lead to a decrease in both blood concentrations and the therapeutic effect of tacrolimus (see Interactions).
Gastrointestinal perforation has been reported in patients treated with tacrolimus, although all cases were considered a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments including surgery should be considered immediately after a suspect symptom occurs.
The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see Dosage & Administration and Interactions).
High potassium intake or potassium-sparing diuretics should be avoided (see Interactions).
Certain combinations of tacrolimus with drugs known to have neurotoxic effects may increase the risk of these effects (see Interactions).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.
Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.
Cardiac disorders: Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed in Prograf treated patients on rare occasions and may also occur with Advagraf. Most cases have been reversible, occurring with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9-12 months). If abnormalities develop, dose reduction of Advagraf, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may cause Torsades de pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see Interactions).
Lymphoproliferative disorders and malignancies: Patients treated with tacrolimus have been reported to develop Epstein-Barr-Virus (EBV)-associated lymphoproliferative disorders (see Adverse Reactions). A combination of immunosuppressives such as antilymphocytic antibodies (e.g. basiliximab, daclizumab) given concomitantly increases the risk of EBV-associated lymphoproliferative disorders. EBV-Viral Capsid Antigen (VCA)-negative patients have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Advagraf. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.
As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see Adverse Reactions).
As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Patients treated with immunosuppressants, including Advagraf are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy (PML), and CMV infection. These infections are often related to a high total 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.
Nephrotoxicity: Tacrolimus can result in both acute and chronic renal function impairment in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubularinterstitial effects. Acute renal impairment can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. Chronic renal impairment is characterized by progressive renal dysfunction, increased blood urea and proteinuria. Patients with impaired renal function should be monitored closely to adjust the dosage of tacrolimus and may need transient reduction or discontinuation. Acute renal impairment without active intervention may progress to chronic renal impairment.
Concurrent use of tacrolimus with other known nephrotoxic drugs could result in potentiation of nephrotoxicity. When concurrent use of tacrolimus with other known nephrotoxic drugs is required, monitor renal function and tacrolimus blood concentrations frequently, and dose adjustments of both tacrolimus and/or concomitant medications should be considered upon initiation, throughout concurrent treatment and at discontinuation of such concomitant drugs.
Posterior reversible encephalopathy syndrome (PRES): Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.
Thrombotic microangiopathy (TMA) (including haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)): Thrombotic microangiopathies may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors, and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may either alone or as a combination effect contribute to the risk of TMA.
Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.
Special populations: There is limited experience in non-Caucasian patients and patients at elevated immunological risk (e.g. retransplantation, evidence of panel reactive antibodies, PRA).
Dose reduction may be necessary in patients with severe liver impairment (see Dosage & Administration).
Excipients: Advagraf capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who are hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the benefit of using Advagraf.
Effects on ability to drive and use machines: Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol.
No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been performed.
Use in Children: Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or efficacy.

Pregnancy: Human data show that tacrolimus crosses the placenta and infants exposed to tacrolimus in utero may be at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress.
The use of tacrolimus during pregnancy has been associated with preterm delivery, neonatal hyperkalemia and renal dysfunction.
Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly.
Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure.
Females and males of reproductive potential should consider the use of appropriate contraception prior to starting treatment with tacrolimus.
Tacrolimus treatment can be considered in pregnant women, when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
Breast-feeding: Human data demonstrate that tacrolimus is excreted in breast milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Advagraf.
Fertility: A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.
The most commonly reported adverse reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.
The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations: As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.
Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Advagraf.
Neoplasms benign, malignant and unspecified: Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.
Blood and lymphatic system disorders: Common: anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis.
Uncommon: coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses abnormal, thrombotic microangiopathy.
Rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia.
Not known: pure red cell aplasia, agranulocytosis, haemolytic anaemia, febrile neutropenia.
Immune system disorders: Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Precautions).
Endocrine disorders: Rare: hirsutism.
Metabolism and nutrition disorders: Very common: diabetes mellitus, hyperglycaemic conditions, hyperkalaemia.
Common: metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, hypophosphataemia.
Uncommon: dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia.
Psychiatric disorders: Very common: insomnia.
Common: confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare.
Uncommon: psychotic disorder.
Nervous system disorders: Very common: headache, tremor.
Common: nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired.
Uncommon: encephalopathy, central nervous system haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia.
Rare: hypertonia.
Very rare: myasthenia.
Not known: posterior reversible encephalopathy syndrome.
Eye disorders: Common: eye disorders, vision blurred, photophobia.
Uncommon: cataract.
Rare: blindness.
Not known: optic neuropathy.
Ear and labyrinth disorders: Common: tinnitus.
Uncommon: hypoacusis.
Rare: deafness neurosensory.
Very rare: hearing impaired.
Cardiac disorders: Common: ischaemic coronary artery disorders, tachycardia.
Uncommon: heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy, palpitations, heart rate and pulse investigations abnormal.
Rare: pericardial effusion.
Very rare: echocardiogram abnormal, electrocardiogram QT prolonged, Torsades de pointes.
Vascular disorders: Very common: hypertension.
Common: thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders.
Uncommon: venous thrombosis deep limb, shock, infarction.
Respiratory, thoracic and mediastinal disorders: Common: parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations.
Uncommon: respiratory failures, respiratory tract disorders, asthma.
Rare: acute respiratory distress syndrome.
Gastrointestinal disorders: Very common: diarrhoea, nausea.
Common: gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal pains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages, gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools.
Uncommon: acute and chronic pancreatitis, amylase increased, ileus paralytic, gastrooesophageal reflux disease, impaired gastric emptying.
Rare: pancreatic pseudocyst, subileus.
Hepatobiliary disorders: Very common: liver function tests abnormal.
Common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice.
Rare: venoocclusive liver disease, hepatic artery thrombosis.
Very rare: hepatic failure.
Skin and subcutaneous tissue disorders: Common: rash, pruritus, alopecias, acne, sweating increased.
Uncommon: dermatitis, photosensitivity.
Rare: toxic epidermal necrolysis (Lyell's syndrome).
Very rare: Stevens-Johnson syndrome.
Musculoskeletal and connective tissue disorders: Common: arthralgia, back pain, muscle spasms, pain in extremity*.
Uncommon: joint disorders.
Rare: mobility decreased.
Renal and urinary disorders: Very common: renal impairment.
Common: renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms.
Uncommon: haemolytic uraemic syndrome, anuria.
Very rare: nephropathy, cystitis haemorrhagic.
Reproductive system and breast disorders: Uncommon: dysmenorrhoea and uterine bleeding.
General disorders and administration site conditions: Common: febrile disorders, pain and discomfort, asthenic conditions, oedema, body temperature perception disturbed, blood alkaline phosphatase increased, weight increased.
Uncommon: weight decreased, influenza like illness, blood lactate dehydrogenase increased, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance.
Rare: fall, ulcer, chest tightness, thirst.
Very rare: fat tissue increased.
Injury, poisoning and procedural complications: Common: primary graft dysfunction.
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection has been reported (frequency cannot be estimated from available data).
*In isolated cases, pain in extremity has been reported as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS), which typically presents bilaterally and symmetrical, severe, ascending pain in the lower extremities.

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
Significant tacrolimus dose reductions and prolongation of dosing interval may be required in order to maintain similar tacrolimus exposure when co-administered with strong CYP3A4 inhibitors, particularly telaprevir. Rapid increase in tacrolimus level may occur when co-administered with CYP3A4 inhibitors. Cases have been reported in which a sharp rise in tacrolimus levels occurred very rapidly, as early as within 1-3 days after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite immediate reduction of tacrolimus dose. Therefore early, within the first few days of co-administration, and frequent continued monitoring of tacrolimus blood levels, as well as monitoring for renal function, for QT prolongation with ECG, and for other side effects is strongly recommended (see Dosage & Administration and Precautions).
CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels: Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (for example but not limited to ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (for example but not limited to telaprevir, boceprevir), or letermovir. Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients. Pharmacokinetics studies have indicated that the increase in blood levels is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, amiodarone, verapamil, danazol, ethinylestradiol, omeprazole, nefazodone and herbal remedies containing extracts of Schisandra sphenanthera.
In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin.
Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.
Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.
Other interactions potentially leading to increased tacrolimus blood levels: Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics).
Other potential interactions that may increase systemic exposure of tacrolimus include prokinetic agents (such as metoclopramide and cisapride), cimetidine and magnesium-aluminum-hydroxide.
CYP3A4 inducers potentially leading to decreased tacrolimus blood levels: Clinically the following substances have been shown to decrease tacrolimus blood levels: Strong interactions have been observed with rifampicin, phenytoin, St. John's wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels.
High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels.
Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.
Caspofungin has been shown to decrease the blood levels of tacrolimus; the mechanism of interaction is not confirmed.
Effect of tacrolimus on the metabolism of other medicinal products: Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see Dosage & Administration and Precautions).
Tacrolimus has been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.
Limited knowledge of interactions between tacrolimus and statins is available. Clinical data suggest that the pharmacokinetics of statins are largely unaltered by the co-administration of tacrolimus.
Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and antipyrine.
Combination therapy with mycophenolic acid (MPA) products: Caution should be exercised when switching combination therapy from ciclosporin to tacrolimus and vice versa. Exposure to MPA is higher with tacrolimus co-administration than with ciclosporin coadministration because ciclosporin interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Therapeutic drug monitoring of MPA is recommended.
Other interactions leading to clinically detrimental effects: Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase these effects (e.g., aminoglycosides, gyrase inhibitors, vancomycin, cotrimoxazole, NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene, or spironolactone) should be avoided (see Precautions).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see Precautions).
Impact of direct-acting antiviral (DAA) therapy: The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy and safety.

Incompatibilities: Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used to prepare a suspension of Advagraf capsule contents must not contain PVC.
Special precautions for use and handling: Based on immunosuppressive effects of tacrolimus, inhalation or direct contact with skin or mucous membranes of powder contained in tacrolimus products should be avoided during preparation. If such contact occurs, wash the skin and eyes.

Store below 30°C.
Store in the original package and in a dry place in order to protect from moisture.
Shelf-life: 3 years.
After opening the aluminium wrapper: 1 year.

Immunosuppressants

L04AD02 - tacrolimus ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.

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