ADVAGRAF 1mg prolonged release capsules medication leaflet

Advagraf 0.5 mg prolonged-release hard capsules

Advagraf 1 mg prolonged-release hard capsules

Advagraf 3 mg prolonged-release hard capsules

Advagraf 5 mg prolonged-release hard capsules

Advagraf 0.5 mg prolonged-release hard capsules

Each prolonged-release hard capsule contains 0.5 mg tacrolimus (as monohydrate).

Excipients with known effect: Each capsule contains 51.09 mg lactose.

The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% oftotal printing ink composition).

Advagraf 1 mg prolonged-release hard capsules

Each prolonged-release hard capsule contains 1 mg tacrolimus (as monohydrate).

Excipients with known effect: Each capsule contains 102.17 mg lactose.

The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% oftotal printing ink composition).

Advagraf 3 mg prolonged-release hard capsules

Each prolonged-release hard capsule contains 3 mg tacrolimus (as monohydrate).

Excipients with known effect: Each capsule contains 306.52 mg lactose.

The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% oftotal printing ink composition).

Advagraf 5 mg prolonged-release hard capsules

Each prolonged-release hard capsule contains 5 mg tacrolimus (as monohydrate).

Excipients with known effect: Each capsule contains 510.9 mg lactose.

The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% oftotal printing ink composition).

For the full list of excipients, see section 6.1.

Prolonged-release hard capsule.

Advagraf 0.5 mg prolonged-release hard capsules

Gelatin capsules imprinted in red with “0.5 mg” on the light yellow capsule cap and “ 647” on theorange capsule body, containing white powder.

Advagraf 1 mg prolonged-release hard capsules

Gelatin capsules imprinted in red with “1 mg” on the white capsule cap and “ 677” on the orangecapsule body, containing white powder.

Advagraf 3 mg prolonged-release hard capsules

Gelatin capsules imprinted in red with “3 mg” on the orange capsule cap and “ 637” on the orangecapsule body, containing white powder.

Advagraf 5 mg prolonged-release hard capsules

Gelatin capsules imprinted in red with “5 mg” on the greyish red capsule cap and “ 687” on theorange capsule body, containing white powder.

Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinalproducts in adult patients.

Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoringby adequately qualified and equipped personnel. This medicinal product should only be prescribed,and changes in immunosuppressive therapy initiated, by physicians experienced inimmunosuppressive therapy and the management of transplant patients.

Different oral formulations of tacrolimus should not be substituted without clinical supervision.

Inadvertent, unintentional or unsupervised switching between different oral formulations of tacrolimuswith different release characteristics is unsafe. This can lead to graft rejection or increased incidence ofadverse reactions, including under- or over-immunosuppression, due to clinically relevant differencesin systemic exposure to tacrolimus. Patients should be maintained on a single formulation oftacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen shouldonly take place under the close supervision of a transplant specialist (see sections 4.4 and 4.8).

Following conversion to any alternative formulation, therapeutic drug monitoring must be performedand dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

The recommended initial doses presented below are intended to act solely as a guideline. Advagraf isroutinely 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 eachpatient individually aided by blood level monitoring (see below under “Therapeutic drug monitoring”).

If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should beconsidered.

In de novo kidney and liver transplant patients AUC0-24 of tacrolimus for Advagraf on Day 1 was 30%and 50% lower respectively, when compared with that for the immediate release capsules (Prograf) atequivalent doses. By Day 4, systemic exposure as measured by trough levels is similar for both kidneyand liver transplant patients with both formulations. Careful and frequent monitoring of tacrolimustrough levels is recommended in the first two weeks post-transplant with Advagraf to ensure adequatedrug exposure in the immediate post-transplant period. As tacrolimus is a substance with lowclearance, adjustments to the Advagraf dose regimen may take several days before steady state isachieved.

To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to theduration 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 themorning. 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 towithdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplantchanges in the condition of the patient may alter the pharmacokinetics of tacrolimus and maynecessitate 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 themorning. Administration should commence approximately 12-18 hours after the completion ofsurgery.

Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases towithdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplantimprovement in the condition of the patient may alter the pharmacokinetics of tacrolimus and maynecessitate further dose adjustments.

Conversion of Prograf-treated patients to Advagraf

Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion toonce daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should beadministered in the morning.

In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a1:1 (mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC0-24) for Advagraf wasapproximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels(C24) and systemic exposure (AUC0-24) for Advagraf is similar to that of Prograf. When convertingfrom Prograf capsules to Advagraf, trough levels should be measured prior to conversion and withintwo weeks after conversion. Following conversion, tacrolimus trough levels should be monitored andif necessary dose adjustments made to maintain similar systemic exposure. Dose adjustments shouldbe 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 sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is notrecommended. Advagraf therapy should be initiated after considering ciclosporin blood concentrationsand the clinical condition of the patient. Dosing should be delayed in the presence of elevatedciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 - 24 hours afterdiscontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued followingconversion as the clearance of ciclosporin might be affected.

Treatment of allograft rejection

Increased doses of tacrolimus, supplemental corticosteroid therapy, and introduction of short coursesof mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicitysuch as severe adverse reactions are noted (see section 4.8), the dose of Advagraf may need to bereduced.

Treatment of allograft rejection after kidney or liver transplantation

For conversion from other immunosuppressants to once daily Advagraf, treatment should begin withthe initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis oftransplant 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 administeredonce 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-transplantedpatients, 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 inintestinal 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 eachindividual patient aided by whole blood tacrolimus trough level monitoring.

As an aid to optimise dosing, several immunoassays are available for determining tacrolimusconcentrations in whole blood. Comparisons of concentrations from the published literature toindividual values in clinical practice should be assessed with care and knowledge of the assay methodsemployed. In current clinical practice, whole blood levels are monitored using immunoassay methods.

The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) is similarbetween 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 posttransplantation is recommended, followed by periodic monitoring during maintenance therapy. Bloodtrough levels of tacrolimus should also be closely monitored following conversion from Prograf to

Advagraf, dose adjustments, changes in the immunosuppressive regimen, or co-administration ofsubstances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency ofblood level monitoring should be based on clinical needs. As tacrolimus is a substance with lowclearance, following adjustments to the Advagraf dose regimen it may take several days before thetargeted steady state is achieved.

Data from clinical studies suggest that the majority of patients can be successfully managed iftacrolimus blood trough levels are maintained below 20 ng/ml. It is necessary to consider the clinicalcondition of the patient when interpreting whole blood levels. In clinical practice, whole blood troughlevels have generally been in the range 5 - 20 ng/ml in liver transplant recipients and 10 - 20 ng/ml inkidney and heart transplant patients in the early post-transplant period. During subsequent maintenancetherapy, blood concentrations have generally been in the range of 5 - 15 ng/ml in liver, kidney andheart transplant recipients.

Dose reduction may be necessary in patients with severe liver impairment in order to maintain thetacrolimus blood trough levels within the recommended target range.

As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), no doseadjustment is required. However, owing to the nephrotoxic potential of tacrolimus careful monitoringof renal function is recommended (including serial serum creatinine concentrations, calculation ofcreatinine clearance and monitoring of urine output).

In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similartrough levels.

There is no evidence that male and female patients require different doses to achieve similar troughlevels.

Older peoples

There is no evidence currently available to indicate that dosing should be adjusted in older people.

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.

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 shouldbe taken immediately following removal from the blister. Patients should be advised not to swallowthe desiccant. The capsules should be swallowed whole with fluid (preferably water). Advagraf shouldgenerally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, toachieve maximal absorption (see section 5.2). A forgotten morning dose should be taken as soon aspossible 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 (see Summary of Product Characteristics for Prograf5 mg/ml concentrate for solution for infusion) at a dose approximately 1/5th of the recommended oraldose for the corresponding indication.

Hypersensitivity to tacrolimus, or to any of the excipients listed in section 6.1.

Hypersensitivity to other macrolides.

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- orprolonged-release tacrolimus formulations, have been observed. This has led to serious adversereactions, including graft rejection, or other adverse reactions which could be a consequence of eitherunder- or over-exposure to tacrolimus. Patients should be maintained on a single formulation oftacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen shouldonly take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8).

Advagraf is not recommended for use in children below 18 years due to limited data on safety and/orefficacy.

For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinalproducts 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 yetavailable for Advagraf.

During the initial post-transplant period, monitoring of the following parameters should be undertakenon 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.

Substances with potential for interaction

Inhibitors or inducers of CYP3A4 should only be co-administered with tacrolimus after consulting atransplant specialist, due to the potential for drug interactions resulting in serious adverse reactionsincluding rejection or toxicity (see section 4.5).

Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which could lead toserious adverse reactions, including nephrotoxicity, neurotoxicity and QT prolongation. It isrecommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat,ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin)with tacrolimus should be avoided. If unavoidable, tacrolimus blood levels should be monitoredfrequently, starting within the first few days of co-administration, under the supervision of a transplantspecialist, to adjust the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure.

Renal function, ECG including the QT interval, and the clinical condition of the patient should also beclosely monitored.

Dose adjustment needs to be based upon the individual situation of each patient. An immediate dosereduction at the time of treatment initiation may be required (see section 4.5).

Similarly, discontinuation of CYP3A4 inhibitors may affect the rate of metabolism of tacrolimus,thereby leading to subtherapeutic blood levels of tacrolimus, and therefore requires close monitoringand supervision of a transplant specialist.

Concomitant use with CYP3A4 inducers may decrease tacrolimus blood levels, potentially increasingthe risk of transplant rejection. It is recommended that concomitant use of strong CYP3A4 inducers(such as rifampicin, phenytoin, carbamazepine) with tacrolimus should be avoided. If unavoidable,tacrolimus blood levels should be monitored frequently, starting within the first few days of co-administration, under the supervision of a transplant specialist, to adjust the tacrolimus dose ifappropriate, in order to maintain similar tacrolimus exposure. Graft function should also be closelymonitored (see section 4.5).

Similarly, discontinuation of CYP3A4 inducers may affect the rate of metabolism of tacrolimus,thereby leading to supratherapeutic blood levels of tacrolimus, and therefore requires close monitoringand supervision of a transplant specialist.

P-glycoprotein

Caution should be observed when co-administering tacrolimus with drugs that inhibit P-glycoprotein,as an increase in tacrolimus levels may occur. Tacrolimus whole blood levels and the clinicalcondition of the patient should be monitored closely. An adjustment of the tacrolimus dose may berequired (see section 4.5).

Herbal preparations

Herbal preparations containing St. John’s wort (Hypericum perforatum) or other herbal preparationsshould be avoided when taking Advagraf due to the risk of interactions that lead to either a decrease inblood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in bloodconcentrations of tacrolimus and risk of tacrolimus toxicity (see section 4.5).

The combined administration of ciclosporin and tacrolimus should be avoided and care should betaken when administering tacrolimus to patients who have previously received ciclosporin (seesections 4.2 and 4.5).

High potassium intake or potassium-sparing diuretics should be avoided (see section 4.5).

Certain combinations of tacrolimus with drugs known to have neurotoxic effects may increase the riskof these effects (see section 4.5).

Immunosuppressants may affect the response to vaccination and vaccination during treatment withtacrolimus may be less effective. The use of live attenuated vaccines should be avoided.

Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairmentwithout active intervention may progress to chronic renal impairment. Patients with impaired renalfunction should be monitored closely as the dosage of tacrolimus may need to be reduced. The risk fornephrotoxicity may increase when tacrolimus is concomitantly administered with drugs associatedwith nephrotoxicity (see section 4.5). Concurrent use of tacrolimus with drugs known to havenephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus troughblood level and renal function should be monitored closely and dosage reduction should be consideredif nephrotoxicity occurs.

Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinalperforation is a medically important event that may lead to a life-threatening or serious condition,adequate treatments should be considered immediately after suspected symptoms or signs occur.

Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extramonitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have beenobserved in Prograf treated patients on rare occasions and may also occur with Advagraf. Most caseshave been reversible, occurring with tacrolimus blood trough concentrations much higher than therecommended maximum levels. Other factors observed to increase the risk of these clinical conditionsincluded pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction,infections, fluid overload, and oedema. Accordingly, high-risk patients receiving substantialimmunosuppression 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, dosereduction of Advagraf, or change of treatment to another immunosuppressive agent should beconsidered. Tacrolimus may prolong the QT interval and may cause Torsades de pointes. Cautionshould be exercised in patients with risk factors for QT prolongation, including patients with apersonal or family history of QT prolongation, congestive heart failure, bradyarrhythmias andelectrolyte 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 medicationsknown to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimusexposure (see section 4.5).

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been reported to develop Epstein-Barr-Virus (EBV)-associatedlymphoproliferative disorders and other malignancies, including skin cancers and Kaposi's sarcoma(see section 4.8).

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 ofdeveloping lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology shouldbe 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 oflymphoproliferative disease or lymphoma.

Kaposi’s sarcoma, including cases with aggressive forms of disease and fatal outcomes, has beenreported in patients receiving tacrolimus. In some cases, regression of Kaposi’s sarcoma has beenobserved after reducing the intensity of immunosuppression.

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 asunscreen with a high protection factor.

As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown.

Infections including opportunistic infections

Patients treated with immunosuppressants, including Advagraf are at increased risk for infectionsincluding opportunistic infections (bacterial, fungal, viral and protozoal) such as CMV infection, BKvirus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy(PML). Patients are also at an increased risk of infections with viral hepatitis (for example, hepatitis Band C reactivation and de novo infection, as well as hepatitis E, which may become chronic). Theseinfections are often related to a high total immunosuppressive burden and may lead to serious or fatalconditions including graft rejection that physicians should consider in the differential diagnosis inimmunosuppressed patients with deteriorating hepatic or renal function or neurological symptoms.

Prevention and management should be in accordance with appropriate clinical guidance.

Posterior reversible encephalopathy syndrome (PRES)

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathysyndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such asheadache, 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 andimmediate discontinuation of systemic tacrolimus is advised. Most patients completely recover afterappropriate measures are taken.

Eye disorders, sometimes progressing to loss of vision, have been reported in patients treated withtacrolimus. Some cases have reported resolution on switching to alternative immunosuppression.

Patients should be advised to report changes in visual acuity, changes in colour vision, blurred vision,or visual field defect, and in such cases, prompt evaluation is recommended with referral to anophthalmologist as appropriate.

Thrombotic microangiopathy (TMA) (including haemolytic uraemic syndrome (HUS) and thromboticthrombocytopenic purpura (TTP))

The diagnosis of TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolyticuraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, should be consideredin patients presenting with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurologicalmanifestation, renal impairment, and fever. If TMA is diagnosed, prompt treatment is required, anddiscontinuation of tacrolimus should be considered at the discretion of the treating physician.

The concomitant administration of tacrolimus with a mammalian target of rapamycin (mTOR)inhibitor (e.g., sirolimus, everolimus) may increase the risk of thrombotic microangiopathy (includinghaemolytic uraemic syndrome and thrombotic thrombocytopenic purpura).

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. Allpatients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease orconcomitant medications associated with PRCA.

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 section 4.2).

As Advagraf capsules contain lactose, patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who arehypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed againstthe benefit of using Advagraf. This medicine contains less than 1 mmol sodium (23 mg) per capsule,that is to say essentially ‘sodium-free’.

Metabolic interactions

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence ofgastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal productsor herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus andthereby increase or decrease tacrolimus blood levels. Similarly, discontinuation of such products orherbal remedies may affect the rate of metabolism of tacrolimus and thereby the blood levels oftacrolimus.

Pharmacokinetics studies have indicated that the increase in tacrolimus blood levels when co-administered with inhibitors of CYP3A4 is mainly a result of increase in oral bioavailability oftacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is lesspronounced.

It is recommended strongly to closely monitor tacrolimus blood levels under supervision of atransplant specialist, as well as, monitor for graft function, QT prolongation (with ECG), renalfunction and other side effects including neurotoxicity, whenever substances which have the potentialto alter CYP3A4 metabolism are used concomitantly, and to adjust or interrupt the tacrolimus dose ifappropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4). Similarly,patients should be closely monitored when using tacrolimus concomitantly with multiple substancesthat affect CYP3A4 as the effects on tacrolimus exposure may be enhanced or counteracted.

Medicinal products which have effects on tacrolimus are listed in the table below. The examples ofdrug-drug interactions are not intended to be inclusive or comprehensive and therefore the label ofeach drug that is co-administered with tacrolimus should be consulted for information related to theroute of metabolism, interaction pathways, potential risks, and specific actions to be taken with regardsto co-administration.

Medicinal products which have effects on tacrolimus

Drug/Substance Class or Drug interaction effect Recommendations concerning

Name co-administration

Grapefruit or grapefruit juice May increase tacrolimus whole Avoid grapefruit or grapefruitblood trough concentrations and juice.

increase the risk of serious adversereactions (e.g., neurotoxicity, QTprolongation) [see section 4.4].

Ciclosporin May increase tacrolimus whole The simultaneous use ofblood trough concentrations. In ciclosporin and tacrolimusaddition, synergistic/additive should be avoided [seenephrotoxic effects can occur. section 4.4].

Products known to have May enhance nephrotoxic or Concurrent use of tacrolimusnephrotoxic or neurotoxic neurotoxic effects of tacrolimus. with drugs known to haveeffects: nephrotoxic effects should beaminoglycosides, gyrase avoided. When co-inhibitors, vancomycin, administration cannot besulfamethoxazole + avoided, monitor renaltrimethoprim, NSAIDs, function and other side effectsganciclovir, acyclovir, and adjust tacrolimus dose ifamphotericin B, ibuprofen, needed.

cidofovir, foscarnet

Drug/Substance Class or Drug interaction effect Recommendations concerning

Name co-administration

Strong CYP3A4 inhibitors: May increase tacrolimus whole It is recommended thatantifungal agents (e.g., blood trough concentrations and concomitant use should beketoconazole, itraconazole, increase the risk of serious adverse avoided. If co-administrationposaconazole, voriconazole), reactions (e.g., nephrotoxicity, of a strong CYP3A4 inhibitorthe macrolide antibiotics neurotoxicity, QT prolongation) is unavoidable, consider(e.g., telithromycin, which requires close monitoring omitting the dose of tacrolimustroleandomycin, [see section 4.4]. the day the strong CYP3A4clarithromycin, josamycin), Rapid and sharp increases in inhibitor is initiated. Reinitiate

HIV protease inhibitors tacrolimus levels may occur, as tacrolimus the next day at a(e.g., ritonavir, nelfinavir, early as within 1-3 days after co- reduced dose based onsaquinavir), HCV protease administration, despite immediate tacrolimus bloodinhibitors (e.g., telaprevir, reduction of tacrolimus dose. concentrations. Changes inboceprevir, and the Overall tacrolimus exposure may both tacrolimus dose and/orcombination of ombitasvir increase > 5 fold. When ritonavir dosing frequency should beand paritaprevir with combinations are co-administered, individualized and adjusted asritonavir, when used with tacrolimus exposure may increase needed based on tacrolimusand without dasabuvir), > 50 fold. Nearly all patients may trough concentrations, whichnefazodone, the require a reduction in tacrolimus should be assessed at initiation,pharmacokinetic enhancer dose and temporary interruption of monitored frequentlycobicistat, and the kinase tacrolimus may also be necessary. throughout (starting within theinhibitors idelalisib, The effect on tacrolimus blood first few days) and re-ceritinib. concentrations may remain for evaluated on and after

Strong interactions have also several days after co-administration completion of the CYP3A4been observed with the is completed. inhibitor. Upon completion,macrolide antibiotic appropriate dose and dosingerythromycin frequency of tacrolimus shouldbe guided by tacrolimus bloodconcentrations. Monitor renalfunction, ECG for QTprolongation, and other sideeffects closely.

Moderate or weak CYP3A4 May increase tacrolimus whole Monitor tacrolimus wholeinhibitors: blood trough concentrations and blood trough concentrationsantifungal agents (e.g., increase the risk of serious adverse frequently, starting within thefluconazole, isavuconazole, reactions (e.g., neurotoxicity, QT first few days of co-clotrimazole, miconazole), prolongation) [see section 4.4]. A administration. Reducethe macrolide antibiotics rapid increase in tacrolimus level tacrolimus dose if needed [see(e.g., azithromycin), calcium may occur. section 4.2]. Monitor renalchannel blockers (e.g., function, ECG for QTnifedipine, nicardipine, prolongation, and other sidediltiazem, verapamil), effects closely.

amiodarone, danazol,ethinylestradiol,lansoprazole, omeprazole,the HCV antiviralselbasvir/grazoprevir andglecaprevir/pibrentasvir, the

CMV antiviral letermovir,and the tyrosine kinaseinhibitors nilotinib,crizotinib and imatinib and(Chinese) herbal remediescontaining extracts of

Schisandra sphenanthera

Drug/Substance Class or Drug interaction effect Recommendations concerning

Name co-administration

In vitro the following May increase tacrolimus whole Monitor tacrolimus wholesubstances have been shown blood trough concentrations and blood trough concentrationsto be potential inhibitors of increase the risk of serious adverse and reduce tacrolimus dose iftacrolimus metabolism: reactions (e.g., neurotoxicity, QT needed [see section 4.2].

bromocriptine, cortisone, prolongation) [see section 4.4]. Monitor renal function, ECGdapsone, ergotamine, for QT prolongation, and othergestodene, lidocaine, side effects closely.

mephenytoin, midazolam,nilvadipine, norethisterone,quinidine, tamoxifen

Strong CYP3A4 inducers: May decrease tacrolimus whole It is recommended thatrifampicin, phenytoin, blood trough concentrations and concomitant use should becarbamazepine, apalutamide, increase the risk of rejection [see avoided. If unavoidable,enzalutamide, mitotane, or section 4.4]. patients may require an

St. John’s wort (Hypericum Maximal effect on tacrolimus blood increase in tacrolimus dose.

perforatum) concentrations may be achieved 1-2 Changes in tacrolimus doseweeks after co-administration. The should be individualized andeffect may remain 1-2 weeks after adjusted as needed based oncompletion of the treatment. tacrolimus troughconcentrations, which shouldbe assessed at initiation,monitored frequentlythroughout (starting within thefirst few days) and re-evaluated on and aftercompletion of the CYP3A4inducer. After use of the

CYP3A4 inducer has ended,tacrolimus dose may need tobe adjusted gradually. Monitorgraft function closely.

Moderate CYP3A4 inducers: May decrease tacrolimus whole Monitor tacrolimus wholemetamizole, phenobarbital, blood trough concentrations and blood trough concentrationsisoniazid, rifabutin, increase the risk of rejection [see and increase tacrolimus dose ifefavirenz, etravirine, section 4.4]. needed [see section 4.2].

nevirapine; weak CYP3A4 Monitor graft function closely.

inducers: flucloxacillin

Caspofungin May decrease tacrolimus whole Monitor tacrolimus wholeblood trough concentrations and blood trough concentrationsincrease the risk of rejection. and increase tacrolimus dose if

Mechanism of interaction has not needed [see section 4.2].

been confirmed. Monitor graft function closely.

Cannabidiol (P-gp inhibitor) There have been reports of Tacrolimus and cannabidiolincreased tacrolimus blood levels should be co-administered withduring concomitant use of caution, closely monitoring fortacrolimus with cannabidiol. This side effects. Monitormay be due to inhibition of tacrolimus whole blood troughintestinal P-glycoprotein, leading to concentrations and adjust theincreased bioavailability of tacrolimus dose if needed [seetacrolimus. sections 4.2 and 4.4].

Drug/Substance Class or Drug interaction effect Recommendations concerning

Name co-administration

Products known to have high Tacrolimus is extensively bound to Monitor tacrolimus wholeaffinity for plasma proteins, plasma proteins. Possible blood trough concentrationse.g.: NSAIDs, oral interactions with other active and adjust tacrolimus dose ifanticoagulants, oral substances known to have high needed [see section 4.2].

antidiabetics affinity for plasma proteins shouldbe considered.

Prokinetic agents: May increase tacrolimus whole Monitor tacrolimus wholemetoclopramide, cimetidine blood trough concentrations and blood trough concentrationsand magnesium-aluminium- increase the risk of serious adverse and reduce tacrolimus dose ifhydroxide reactions (e.g., neurotoxicity, QT needed [see section 4.2].

prolongation). Monitor closely for renalfunction, for QT prolongationwith ECG, and for other sideeffects.

Maintenance doses of May decrease tacrolimus whole Monitor tacrolimus wholecorticosteroids blood trough concentrations and blood trough concentrationsincrease the risk of rejection [see and increase tacrolimus dose ifsection 4.4]. needed [see section 4.2].

Monitor graft function closely.

High dose prednisolone or May have impact on tacrolimus Monitor tacrolimus wholemethylprednisolone blood levels (increase or decrease) blood trough concentrationswhen administered for the treatment and adjust tacrolimus dose ifof acute rejection. needed.

Direct-acting antiviral May have impact on the Monitor tacrolimus whole(DAA) therapy pharmacokinetics of tacrolimus by blood trough concentrationschanges in liver function during and adjust tacrolimus dose if

DAA therapy, related to clearance needed to ensure continuedof hepatitis virus. A decrease in efficacy and safety.

tacrolimus blood levels may occur.

However, the CYP3A4 inhibitingpotential of some DAAs maycounteract that effect or lead toincreased tacrolimus blood levels.

Concomitant administration of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor(e.g., sirolimus, everolimus) may increase the risk of thrombotic microangiopathy (includinghaemolytic uraemic syndrome and thrombotic thrombocytopenic purpura) (see section 4.4).

As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existinghyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene, orspironolactone) should be avoided (see section 4.4). Care should be taken when tacrolimus is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole(trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic likeamiloride. Close monitoring of serum potassium is recommended.

Effect of tacrolimus on the metabolism of other medicinal products

Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal productsknown 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 ofciclosporin and tacrolimus is not recommended and care should be taken when administeringtacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.4).

Tacrolimus has been shown to increase the blood level of phenytoin.

As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormoneexposure, particular care should be exercised when deciding upon contraceptive measures.

Limited knowledge of interactions between tacrolimus and statins is available. Clinical data suggestthat 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.

Mycophenolic acid. Caution should be exercised when switching combination therapy fromciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus,which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Drugswhich interfere with mycophenolic acid's enterohepatic cycle have potential to reduce the plasma leveland efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may beappropriate when switching from ciclosporin to tacrolimus or vice versa.

Immunosuppressants may affect the response to vaccination and vaccination during treatment withtacrolimus may be less effective. The use of live attenuated vaccines should be avoided (seesection 4.4).

Data from women show that tacrolimus crosses the placenta. There is a risk for hyperkalaemia in thenewborn (e.g. incidence in neonates of 7.2%, i.e., 8 of 111) which tends to normalise spontaneously.

Tacrolimus treatment can be considered in pregnant women, when there is no safer alternative andwhen the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure,monitoring of the newborn for the potential adverse events of tacrolimus is recommended (inparticular effects on the kidneys).

Results from a non-interventional post-authorisation safety study [EUPAS37025]

A post-authorisation safety study analysed 2,905 pregnancies from the Transplant Pregnancy Registry

International (TPRI), assessing outcomes in women treated with tacrolimus (383 reportedprospectively, including 247 kidney and 136 liver transplant patients), and those on otherimmunosuppressants. Based on limited data (289 prospectively-reported pregnancies with 1st trimestertacrolimus exposure), study results did not indicate an increased risk of major malformations. A higherprevalence of spontaneous abortion was observed among women treated with tacrolimus comparedwith alternative immunosuppressants. Among kidney transplant patients there was also a higherprevalence of pre-eclampsia in women treated with tacrolimus. However, overall, there wereinsufficient evidence to conclude on the risk of these outcomes. Among kidney and liver transplantpatients exposed to tacrolimus, 45% - 55% of their live births were premature, with 75% - 85% havinga normal birth weight for gestational age. Similar results were observed for other immunosuppressants,although conclusions were hindered by limited evidence.

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternaltoxicity (see section 5.3).

Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on thenewborn cannot be excluded, women should not breast-feed whilst receiving Advagraf.

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility wasobserved in rats (see section 5.3).

Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimusis administered in association with alcohol.

No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have beenperformed.

The adverse reaction profile associated with immunosuppressive agents is often difficult to establishowing 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, renalimpairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertensionand 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), notknown (cannot be estimated from the available data). Within each frequency grouping, undesirableeffects are presented in order of decreasing seriousness.

As is well known for other potent immunosuppressive agents, patients receiving tacrolimus arefrequently 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 CMV infection, BK virus associated nephropathy, as well as cases of JC virus associatedprogressive multifocal leukoencephalopathy (PML), have been reported in patients treated withimmunosuppressants, including Advagraf.

Patients receiving immunosuppressive therapy are at increased risk of developing malignancies.

Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders, skinmalignancies and Kaposi’s sarcoma have been reported in association with tacrolimus treatment.

Blood and lymphatic system disorderscommon: anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal,leukocytosisuncommon: coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses,abnormal, thrombotic microangiopathyrare: thrombotic thrombocytopenic purpura, hypoprothrombinaemianot known: pure red cell aplasia, agranulocytosis, haemolytic anaemia, febrile neutropenia

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (seesection 4.4).

Endocrine disordersrare: hirsutism

Metabolism and nutrition disordersvery common: diabetes mellitus, hyperglycaemic conditions, hyperkalaemiacommon: metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload,hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, appetitedecreased, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia,hypophosphataemiauncommon: dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia

Psychiatric disordersvery common: insomniacommon: confusion and disorientation, depression, anxiety symptoms, hallucination, mentaldisorders, depressed mood, mood disorders and disturbances, nightmareuncommon: psychotic disorder

Nervous system disordersvery common: headache, tremorcommon: nervous system disorders, seizures, disturbances in consciousness, peripheralneuropathies, dizziness, paraesthesias and dysaesthesias, writing impaireduncommon: encephalopathy, central nervous system haemorrhages and cerebrovascularaccidents, coma, speech and language abnormalities, paralysis and paresis, amnesiarare: hypertoniavery rare: myasthenianot known: posterior reversible encephalopathy syndrome (PRES)

Eye disorderscommon: eye disorders, vision blurred, photophobiauncommon: cataractrare: blindnessnot known: optic neuropathy

Ear and labyrinth disorderscommon: tinnitusuncommon: hypoacusisrare: deafness neurosensoryvery rare: hearing impaired

Cardiac disorderscommon: ischaemic coronary artery disorders, tachycardiauncommon: heart failures, ventricular arrhythmias and cardiac arrest, supraventriculararrhythmias, cardiomyopathies, ventricular hypertrophy, palpitationsrare: pericardial effusionvery rare: Torsades de pointes

Vascular disordersvery common: hypertensioncommon: thromboembolic and ischaemic events, vascular hypotensive disorders,haemorrhage, peripheral vascular disordersuncommon: venous thrombosis deep limb, shock, infarction

Respiratory, thoracic and mediastinal disorderscommon: parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasalcongestion and inflammationsuncommon: respiratory failures, respiratory tract disorders, asthmarare: acute respiratory distress syndrome

Gastrointestinal disordersvery common: diarrhoea, nauseacommon: gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominalpains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages,gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration,constipation, dyspeptic signs and symptoms, flatulence, bloating and distension,loose stoolsuncommon: acute and chronic pancreatitis, ileus paralytic, gastrooesophageal reflux disease,impaired gastric emptyingrare: pancreatic pseudocyst, subileus

Hepatobiliary disorderscommon: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundicerare: venoocclusive liver disease, hepatic artery thrombosisvery rare: hepatic failure

Skin and subcutaneous tissue disorderscommon: rash, pruritus, alopecias, acne, sweating increaseduncommon: dermatitis, photosensitivityrare: toxic epidermal necrolysis (Lyell’s syndrome)very rare: Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorderscommon: arthralgia, back pain, muscle spasms, pain in extremityuncommon: joint disordersrare: mobility decreased

Renal and urinary disordersvery common: renal impairmentcommon: renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinaryabnormalities, oliguria, bladder and urethral symptomsuncommon: haemolytic uraemic syndrome, anuriavery rare: nephropathy, cystitis haemorrhagic

Reproductive system and breast disordersuncommon: dysmenorrhoea and uterine bleeding

General disorders and administration site conditionscommon: febrile disorders, pain and discomfort, asthenic conditions, oedema, bodytemperature perception disturbeduncommon: influenza like illness, feeling jittery, feeling abnormal, multi-organ failure, chestpressure sensation, temperature intolerancerare: fall, ulcer, chest tightness, thirstvery rare: fat tissue increased

Investigationsvery common: liver function tests abnormalcommon: blood alkaline phosphatase increased, weight increaseduncommon: amylase increased, ECG investigations abnormal, heart rate and pulseinvestigations abnormal, weight decreased, blood lactate dehydrogenase increasedvery rare: echocardiogram abnormal, electrocardiogram QT prolonged

Injury, poisoning and procedural complicationscommon: primary graft dysfunction

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- orprolonged-release tacrolimus formulations, have been observed. A number of associated cases oftransplant rejection have been reported (frequency cannot be estimated from available data).

Pain in extremity has been described in a number of published case reports as part of Calcineurin-

Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical,severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels oftacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessaryto switch to alternative immunosuppression.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience with overdose is limited. Several cases of accidental overdose have been reported withtacrolimus; 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 supportivemeasures and symptomatic treatment should be conducted.

Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasmaprotein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with veryhigh plasma levels, haemofiltration or -diafiltration have been effective in reducing toxicconcentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such asactivated charcoal) may be helpful, if used shortly after intake.

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02

At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolicprotein (FKBP12) which is responsible for the intracellular accumulation of the compound. The

FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leadingto a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventingtranscription of a discrete set of cytokine genes.

Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro andin vivo experiments.

In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsiblefor graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cellproliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) andthe 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, wascompared in 471 de novo liver transplant recipients. The event rate of biopsy confirmed acute rejectionwithin 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 Advagrafand 90.8% for Prograf; in the Advagraf arm 25 patients died (14 female, 11 male) and in the Prografarm 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 ratefor 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 survivalrates 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 basiliximabantibody induction, MMF and corticosteroids, was compared in 638 de novo kidney transplantrecipients. 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% inthe Prograf group (N = 212) and 17.0% in the ciclosporin group (N = 212). The treatment differencewas -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%, pct. 5.2%]) for Prograf vs.

ciclosporin. The 12-month patient survival rates were 98.6% for Advagraf, 95.7% for Prograf and97.6% for ciclosporin; in the Advagraf arm 3 patients died (all male), in the Prograf arm 10 patientsdied (3 female, 7 male) and in the ciclosporin arm 6 patients died (3 female, 3 male). 12-month graftsurvival 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 approximately175 patients following lung, 475 patients following pancreas and 630 patients following intestinaltransplantation. Overall, the safety profile of oral Prograf in these published studies appeared to besimilar 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 aresummarised below.

Lung transplantation

The interim analysis of a recent multicentre study using oral Prograf discussed 110 patients whounderwent 1:1 randomisation to either tacrolimus or ciclosporin. Tacrolimus was started as continuousintravenous infusion at a dose of 0.01 to 0.03 mg/kg/day and oral tacrolimus was administered at adose of 0.05 to 0.3 mg/kg/day. A lower incidence of acute rejection episodes for tacrolimus- versusciclosporin-treated patients (11.5% versus 22.6%) and a lower incidence of chronic rejection, thebronchiolitis obliterans syndrome (2.86% versus 8.57%), was reported within the first year aftertransplantation. The 1-year patient survival rate was 80.8% in the tacrolimus and 83% in theciclosporin 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 oraltacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to targettrough levels of 10 to 20 ng/ml. The 1-year patient survival was 83% in the tacrolimus and 71% in theciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodesper 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporingroup (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimusgroup compared with 38.0% of patients in the ciclosporin group (p = 0.025). Significantly moreciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated patients tociclosporin (n = 2) (p = 0.02) (Keenan et al., Ann Thoracic Surg 1995;60:580).

In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients tothe ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day withsubsequent dose adjustments to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection washigher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lungtransplantation (50% versus 33.3%).

The three studies demonstrated similar survival rates. The incidences of acute rejection werenumerically lower with tacrolimus in all three studies and one of the studies reported a significantlylower 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). Theinitial oral per protocol dose of tacrolimus was 0.2 mg/kg/day with subsequent dose adjustments totarget trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/ml after Month 6. Pancreas survival at1 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 fromciclosporin 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 treatmentfollowing intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestinealone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was0.3 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 CMVinfections, 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 allograftirradiation were considered to have contributed to improved results in this indication over time.

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 oftacrolimus resulting in an extended oral absorption profile with an average time to maximum bloodconcentration (Cmax) of approximately 2 hours (tmax).

Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prografformulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oralbioavailability of Advagraf was reduced when it was administered after a meal. Both the rate andextent of absorption of Advagraf were reduced when administered with food.

Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf maycommence 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.

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 20:1distribution 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 onplasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on wholeblood averaged 47.6 l.

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4 (CYP3A4) andthe cytochrome P450-3A5 (CYP3A5). Tacrolimus is also considerably metabolised in the intestinalwall. There are several metabolites identified. Only one of these has been shown in vitro to haveimmunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or noimmunosuppressive activity. In systemic circulation only one of the inactive metabolites is present atlow concentrations. Therefore, metabolites do not contribute to the pharmacological activity oftacrolimus.

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearanceestimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplantpatients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as lowhaematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, orcorticosteroid-induced increased metabolism, are considered to be responsible for the higher clearancerates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole bloodis approximately 43 hours.

Following intravenous and oral administration of 14C-labelled tacrolimus, most of the radioactivity waseliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almostcompletely metabolised prior to elimination: bile being the principal route of elimination.

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in ratsand baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversiblecardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.

When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrationsachieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peakconcentrations observed with Advagraf in clinical transplantation.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significanttoxicity in maternal animals. In rats, female reproductive function including birth was impaired attoxic doses and the offspring showed reduced birth weights, viability and growth.

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility wasobserved in rats.

Hypromellose

Ethylcellulose

Lactose monohydrate

Magnesium stearate.

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Sodium laurilsulfate

Gelatin.

Printing ink (Opacode S-1-15083):

Shellac

Lecithin (soya)

Simeticone

Red iron oxide (E 172)

Hydroxypropylcellulose.

Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipmentused to prepare a suspension of Advagraf capsule contents must not contain PVC.

3 years.

After opening the aluminium wrapper: 1 year

Store in the original package in order to protect from moisture.

Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminiumwrapper with a desiccant containing 10 capsules per blister.

Advagraf 0.5 mg prolonged-release hard capsules

Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1 and 100×1prolonged-release hard capsule in unit-dose perforated blisters.

Advagraf 1 mg prolonged-release hard capsules

Pack sizes: 30, 50, 60 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1, 60×1 and100×1 prolonged-release hard capsule in unit-dose perforated blisters.

Advagraf 3 mg prolonged-release hard capsules

Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1 and 100×1prolonged-release hard capsules in unit-dose perforated blisters.

Advagraf 5 mg prolonged-release hard capsules

Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1 and 100×1prolonged-release hard capsules in unit-dose perforated blisters.

Not all pack sizes may be marketed.

Based on immunosuppressive effects of tacrolimus, inhalation or direct contact with skin or mucousmembranes by the formulations for injection, powder or granule contained in tacrolimus productsshould be avoided during preparation. If such contact occurs, wash the skin and flush the affected eyeor eyes.

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

Netherlands

Advagraf 0.5 mg prolonged-release hard capsules

EU/1/07/387/001

EU/1/07/387/002

EU/1/07/387/009

EU/1/07/387/014

EU/1/07/387/015

EU/1/07/387/016

Advagraf 1 mg prolonged-release hard capsules

EU/1/07/387/003

EU/1/07/387/004

EU/1/07/387/005

EU/1/07/387/006

EU/1/07/387/017

EU/1/07/387/018

EU/1/07/387/019

EU/1/07/387/020

Advagraf 3 mg prolonged-release hard capsules

EU/1/07/387/011

EU/1/07/387/012

EU/1/07/387/013

EU/1/07/387/021

EU/1/07/387/022

EU/1/07/387/023

Advagraf 5 mg prolonged-release hard capsules

EU/1/07/387/007

EU/1/07/387/008

EU/1/07/387/010

EU/1/07/387/024

EU/1/07/387/025

EU/1/07/387/026

Date of first authorisation: 23 April 2007

Date of latest renewal: 13 April 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.