Advagraf
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

  



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1. NAME OF THE MEDICINAL PRODUCT 
 
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 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
Each capsule contains less than 1 mmol sodium (23 mg). 
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total 
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. 
Each capsule contains less than 1 mmol sodium (23 mg). 
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total 
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. 
Each capsule contains less than 1 mmol sodium (23 mg).  
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total 
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. 
Each capsule contains less than 1 mmol sodium (23 mg). 
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total 
printing ink composition). 

 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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 the 
orange capsule body, containing white powder. 
 



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Advagraf 1 mg prolonged-release hard capsules 
Gelatin capsules imprinted in red with “1 mg” on the white capsule cap and “ 677” on the orange 
capsule 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 orange 
capsule 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 the orange 
capsule body, containing white powder. 
 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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. 
 
Different oral formulations of tacrolimus should not be substituted without clinical supervision. 
Inadvertent, unintentional or unsupervised switching between different oral formulations of tacrolimus 
with different release characteristics 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 sections 4.4 and 4.8). 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 below 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 below 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 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) 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. 
 



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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 (AUC0-24) for Advagraf was 
approximately 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 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 
sections 4.4 and 4.5). 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 section 4.8), 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. 
 



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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 section 4.5). 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 section 5.2), 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. 
 
Older peoples  
There is no evidence currently available to indicate that dosing should be adjusted in older people. 



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Paediatric population 
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 section 5.2). 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 (see Summary of Product Characteristics for Prograf 5 mg/ml 
concentrate for solution for infusion) at a dose approximately 1/5th of the recommended oral dose for the 
corresponding indication. 
 
4.3 Contraindications 
 
Hypersensitivity to tacrolimus, or to any of the excipients listed in section 6.1 
Hypersensitivity to other macrolides 
 
4.4 Special warnings and precautions for use 
 
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 sections 4.2 and 4.8). 
 
Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or 
efficacy. 
 
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 (see section 4.5) - particularly strong inhibitors of 
CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, 
telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, 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. 
 



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Herbal preparations containing St. John’s Wort (Hypericum perforatum) or other herbal preparations 
should be avoided when taking Advagraf due to the risk of interactions that lead to either a decrease in 
blood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in blood 
concentrations of tacrolimus and risk of tacrolimus toxicity (see section 4.5). 
 
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 sections 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 nephrotoxic or neurotoxic effects may 
increase the risk of these effects (see section 4.5). 
 
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. 
 
Gastrointestinal disorders 
Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal 
perforation 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, 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 section 4.5).   
 
Lymphoproliferative disorders and malignancies 
Patients treated with tacrolimus have been reported to develop Epstein-Barr-Virus (EBV)-associated 
lymphoproliferative disorders (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 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 
section 4.8). 
 



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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. 
 

Infections including opportunistic infections  
Patients treated with immunosuppressants, including Advagraf are at increased risk for infections 
including opportunistic infections (bacterial, fungal, viral and protozoal) such as BK virus 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 B and C reactivation and 
de novo infection, as well as hepatitis E, which may become chronic). 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 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 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. 
 
Eye disorders 
Eye disorders, sometimes progressing to loss of vision, have been reported in patients treated with 
tacrolimus. 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 an ophthalmologist as 
appropriate. 
 
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. 
 
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 section 4.2). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 



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It is strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with 
ECG), renal function and other side effects, whenever substances which have the potential to alter 
CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and to 
interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see 
sections 4.2 and 4.4). 
 
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, voriconazole and isavuconazole, the macrolide antibiotic erythromycin, HIV protease 
inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir, and 
the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), or 
the CMV antiviral letermovir, the pharmacokinetic enhancer cobicistat, and the tyrosine kinase inhibitors 
nilotinib and imatinib. 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, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole, nefazodone and 
(Chinese) 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-aluminium-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. 
 
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 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 hormone 
exposure, particular care should be exercised when deciding upon contraceptive measures. 



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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. 
 
Mycophenolic acid. Caution should be exercised when switching combination therapy from ciclosporin, 
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. Drugs which interfere with 
mycophenolic acid's enterohepatic cycle have potential to reduce the plasma level and efficacy of 
mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when 
switching from ciclosporin to tacrolimus or vice versa. 

 
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 section 4.4). 
 
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 section 4.4). 
 
4.6  Fertility, pregnancy and lactation 
 
Pregnancy 
Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients 
show no evidence of an increased risk of adverse reactions on the course and outcome of pregnancy under 
tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of 
spontaneous abortion have been reported. To date, no other relevant epidemiological data are available. 
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 case of in utero exposure, monitoring of 
the newborn for the potential adverse events of tacrolimus is recommended (in particular effects on the 
kidneys). There is a risk for premature delivery (<37 week) (incidence of 66 of 123 births, i.e. 53.7%; 
however, data showed that the majority of the newborns had normal birth weight for their gestational age) 
as well as for hyperkalaemia in the newborn (incidence 8 of 111 neonates, i.e. 7.2 %) which, however 
normalises spontaneously. 
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal 
toxicity (see section 5.3). 
 
Breast-feeding 
Human data demonstrate that tacrolimus is excreted in breast milk. 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 section 5.3). 
 
4.7 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. 



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No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been 
performed. 
 
4.8 Undesirable effects 
 
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 
rare:  thrombotic thrombocytopenic purpura, hypoprothrombinaemia, thrombotic 

microangiopathy 
not known:  pure red cell aplasia, agranulocytosis, haemolytic anaemia 
 
Immune system disorders  
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 
4.4). 
 
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 



12 

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 
 
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, ventricular hypertrophy, palpitations  
rare:   pericardial effusion 
very rare: 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, ileus paralytic, gastrooesophageal reflux disease, 
impaired gastric emptying 

rare:  pancreatic pseudocyst, subileus 
 



13 

Hepatobiliary disorders 
common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice 
rare:  venoocclusive liver disease, hepatitic 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 
uncommon: influenza like illness,  feeling jittery, feeling abnormal, multi-organ failure, chest 

pressure sensation, temperature intolerance 
rare:  fall, ulcer, chest tightness, thirst 
very rare: fat tissue increased 
not known: febrile neutropenia 
 
Investigations 
very common: liver function tests abnormal 
common: blood alkaline phosphatase increased, weight increased 
uncommon: amylase increased, ECG investigations abnormal, heart rate and pulse investigations
  abnormal, weight decreased, blood lactate dehydrogenase increased 
very rare: echocardiogram abnormal, electrocardiogram QT prolonged 
 
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 have been reported (frequency cannot be estimated from available data). 
 
Description of selected adverse reactions 
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 of tacrolimus. 
The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to 
alternative immunosuppression. 

 



14 

Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02 
 
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 



15 

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 below. 
 
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) (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 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 



16 

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. 
 
5.2 Pharmacokinetic properties 
 
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 (Cmax) of approximately 2 hours (tmax). 
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. 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. 



17 

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. 
 
5.3 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. 
When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 
mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved 
with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations 
observed with Advagraf in clinical transplantation. 
Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant 
toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic 
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 was 
observed in rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
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 laurilsulfate 
Gelatin. 
 
Printing ink (Opacode S-1-15083): 
Shellac 
Lecithin (soya) 
Simeticone 
Red iron oxide (E 172) 
Hydroxypropylcellulose. 
 
6.2 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. 
 
6.3 Shelf life 
 
3 years 
 



18 

After opening the aluminium wrapper: 1 year 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium 
wrapper 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 100×1 
prolonged-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 and 100×1 
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 100×1 
prolonged-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 100×1 
prolonged-release hard capsules in unit-dose perforated blisters. 
 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
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 



19 

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 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 April 2007 
Date of latest renewal: 13 April 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  
 
  



20 

 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
  



21 

 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Astellas Ireland Co. Ltd 
Killorglin  
Co. Kerry, V93FC86 
Ireland 

 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  

 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.  
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT  
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the pharmacovigilance activities and interventions detailed in the agreed RMP 
presented in Module 1.8.2 of the Marketing Authorisation  and any subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

- At the request of the European Medicines Agency, 
- Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON Advagraf 0.5 mg prolonged-release hard capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 0.5 mg prolonged-release hard capsules 
Tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 0.5 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and traces of soya lecithin. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Once daily. 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 



25 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/387/001 30 capsules 
EU/1/07/387/002 50 capsules 
EU/1/07/387/009 100 capsules 
EU/1/07/387/014 30×1 capsules 
EU/1/07/387/015 50×1 capsules 
EU/1/07/387/016 100×1 capsules 
 
 
 
13. BATCH NUMBER 
 
Batch: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Advagraf 0.5 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  



26 

SN:  
NN: 
 
 
  



27 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER Advagraf 0.5 mg prolonged-release hard capsules 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 0.5 mg prolonged-release hard capsules 
Tacrolimus 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
 
 

3. EXPIRY DATE 
 
EXP: 
 
 

4. BATCH NUMBER 
 
Batch: 
 
 

5. OTHER 
 
Once daily. 
 
 



28 

MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS 
 
ALUMINIUM WRAPPER Advagraf 0.5 mg prolonged-release hard capsules (30, 50, 100 
Aluminium Wrapper) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Advagraf 0.5 mg prolonged-release hard capsules 
Tacrolimus 
Oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
6. OTHER 
 
Astellas Pharma Europe B.V. 
 
Once daily. 
 
 
  



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON Advagraf 1 mg prolonged-release hard capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 1 mg prolonged-release hard capsules 
Tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 1 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and traces of soya lecithin. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
60 prolonged-release hard capsules 
60×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Once daily. 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP: 



30 

Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/387/003 30 capsules 
EU/1/07/387/004 50 capsules 
EU/1/07/387/005 60 capsules 
EU/1/07/387/006 100 capsules 
EU/1/07/387/017 30×1 capsules 
EU/1/07/387/018 50×1 capsules 
EU/1/07/387/019 60×1 capsules 
EU/1/07/387/020 100×1 capsules 
 
 
13. BATCH NUMBER 
 
Batch: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Advagraf 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



31 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
  



32 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER Advagraf 1 mg prolonged-release hard capsules 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 1 mg prolonged-release hard capsules 
Tacrolimus 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
 
 

3. EXPIRY DATE 
 
EXP: 
 
 

4. BATCH NUMBER 
 
Batch: 
 
 

5. OTHER 
 
Once daily. 
 
 



33 

MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS 
 
ALUMINIUM WRAPPER Advagraf 1 mg prolonged-release hard capsules (30, 50, 60, 100 
Aluminium Wrapper) 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Advagraf 1 mg prolonged-release hard capsules 
Tacrolimus 
Oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
60 prolonged-release hard capsules 
60×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
6. OTHER 
 
Astellas Pharma Europe B.V. 
 
Once daily. 
 
 
 
  



34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON Advagraf 3 mg prolonged-release hard capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 3 mg prolonged-release hard capsules 
Tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 3 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and traces of soya lecithin. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Once daily. 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 



35 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/387/011 30 capsules 
EU/1/07/387/012 50 capsules 
EU/1/07/387/013 100 capsules 
EU/1/07/387/021 30×1 capsules 
EU/1/07/387/022 50×1 capsules 
EU/1/07/387/023 100×1 capsules 
 
 
13. BATCH NUMBER 
 
Batch: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Advagraf 3 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN:  



36 

NN: 
 
  



37 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER Advagraf 3 mg prolonged-release hard capsules 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 3 mg prolonged-release hard capsules 
Tacrolimus 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
 
 

3. EXPIRY DATE 
 
EXP: 
 
 

4. BATCH NUMBER 
 
Batch: 
 

5. OTHER 
 
Once daily. 
 
 



38 

MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS 
 
ALUMINIUM WRAPPER Advagraf 3 mg prolonged-release hard capsules (30, 50, 100 Aluminium 
Wrapper) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Advagraf 3 mg prolonged-release hard capsules 
Tacrolimus 
Oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
6. OTHER 
 
Astellas Pharma Europe B.V. 
 
Once daily. 
 
 
  



39 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON Advagraf 5 mg prolonged-release hard capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 5 mg prolonged-release hard capsules 
Tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 5 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and traces of soya lecithin. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Once daily. 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 



40 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/387/007 30 capsules 
EU/1/07/387/008 50 capsules 
EU/1/07/387/010 100 capsules 
EU/1/07/387/024 30×1 capsules 
EU/1/07/387/025 50×1 capsules 
EU/1/07/387/026 100×1 capsules 
 
 
13. BATCH NUMBER 
 
Batch: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Advagraf 5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  



41 

NN:  
 
  



42 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER Advagraf 5 mg prolonged-release hard capsules 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Advagraf 5 mg prolonged-release hard capsules 
Tacrolimus 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
 
 

3. EXPIRY DATE 
 
EXP: 
 
 

4. BATCH NUMBER 
 
Batch: 
 
 

5. OTHER 
 
Once daily. 
 
 



43 

MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS 
 
ALUMINIUM WRAPPER Advagraf 5 mg prolonged-release hard capsules (30, 50, 100 Aluminium 
Wrapper) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Advagraf 5 mg prolonged-release hard capsules 
Tacrolimus 
Oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 prolonged-release hard capsules 
30×1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50×1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100×1 prolonged-release hard capsules 
 
 
6. OTHER 
 
Astellas Pharma Europe B.V. 
 
Once daily. 
 
 
 
  



44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



45 

 Package leaflet: Information for the patient 
 

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 

Tacrolimus 
 

Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs and illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
 
 What is in this leaflet 
1. What Advagraf is and what it is used for 
2.  What you need to know before you take Advagraf 
3. How to take Advagraf 
4. Possible side effects 
5. How to store Advagraf 
6.  Contents of the pack and other information 
 
 
1. What Advagraf is and what it is used for 
Advagraf contains the active substance tacrolimus. It is an immunosuppressant. Following your organ 
transplant (liver, kidney), your body’s immune system will try to reject the new organ. Advagraf is used 
to control your body’s immune response, enabling your body to accept the transplanted organ.  
 
You may also be given Advagraf for an ongoing rejection of your transplanted liver, kidney, heart or 
other organ when any previous treatment you were taking was unable to control this immune response 
after your transplantation. 
 
Advagraf is used in adults. 
 
2. What you need to know before you take Advagraf 
 
Do not take Advagraf 
- if you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Advagraf (see 

section 6). 
- if you are allergic to sirolimus or to any macrolide-antibiotic (e.g. erythromycin, clarithromycin, 

josamycin). 
 
Warnings and precautions 
Prograf and Advagraf both contain the active substance, tacrolimus. However, Advagraf is taken once 
daily, whereas Prograf is taken twice daily. This is because Advagraf capsules allow for a prolonged 
release (more slow release over a longer period) of tacrolimus. Advagraf and Prograf are not 
interchangeable. 
 
Tell your doctor if any of the following apply to you: 
- if you are taking any medicines mentioned below under ‘Other medicines and Advagraf’.  
- if you have or have had liver problems 
- if you have diarrhoea for more than one day 



46 

- if you feel strong abdominal pain accompanied or not with other symptoms, such as chills, fever, 
nausea or vomiting 

- if you have an alteration of the electrical activity of your heart called “QT prolongation”.  
 
Tell your doctor immediately if during treatment you suffer from: 

problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or if 
your field of vision becomes restricted. 
 
Your doctor may need to adjust your dose of Advagraf. 
 
You should keep in regular contact with your doctor. From time to time, your doctor may need to do 
blood, urine, heart, eye tests, to set the right dose of Advagraf.  
 
You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Advagraf. This is 
because immunosuppressants could increase the risk of skin cancer. Wear appropriate protective clothing 
and use a sunscreen with a high sun protection factor.  
 
Children and adolescents 
The use of Advagraf is not recommended in children and adolescents under 18 years. 
 
Other medicines and Advagraf 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription and herbal preparations.  
 
It is not recommended that Advagraf is taken with ciclosporin (another medicine used for the prevention 
of transplant organ rejection). 
 
Advagraf blood levels can be affected by other medicines you take, and blood levels of other medicines 
can be affected by taking Advagraf, which may require interruption, an increase or a decrease in 
Advagraf dose. In particular, you should tell your doctor if you are taking or have recently taken 
medicines like: 
- antifungal medicines and antibiotics, particularly so-called macrolide antibiotics, used to treat 

infections e.g. ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole, and 
isavuconazole, erythromycin, clarithromycin, josamycin, and rifampicin 

- letermovir, used to prevent illness caused by CMV (human cytomegalovirus) 
- HIV protease inhibitors (e.g ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and 

combination tablets, used to treat HIV infection 
- HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination 

ombitasvir/paritaprevir/ritonavir with or without dasabuvir), used to treat hepatitis C infection 
- nilotinib and imatinib (used to treat certain cancers) 
- mycophenolic acid, used to suppress the immune system to prevent transplant rejection 

- medicines for stomach ulcer and acid reflux (e.g. omeprazole, lansoprazole or cimetidine) 
- antiemetics, used to treat nausea and vomiting (e.g. metoclopramide) 
- cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn 
- the contraceptive pill or other hormone treatments with ethinylestradiol, hormone treatments with 

danazol 
- medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem 

and verapamil) 
- anti-arrhythmic drugs (amiodarone) used to control arrhythmia (uneven beating of the heart) 
- medicines known as “statins” used to treat elevated cholesterol and triglycerides 
- phenytoin or phenobarbital, used to treat epilepsy 
- the corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids 

used to treat inflammations or suppress the immune system (e.g. in transplant rejection) 
- nefazodone, used to treat depression 



47 

- Herbal preparations containing St. John’s Wort (Hypericum perforatum) or extracts of Schisandra 
sphenanthera. 

 
Tell your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation and pain), 
amphotericin B (used to treat bacterial infections) or antivirals (used to treat viral infections e.g. 
aciclovir). These may worsen kidney or nervous system problems when taken together with Advagraf. 
 
Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for 
heart failure, hypertension and kidney disease, (e.g. amiloride, triamterene, or spironolactone), non-
steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation and pain, 
anticoagulants (blood thinners), or oral medicines for diabetes, while you take Advagraf. 
 
If you need to have any vaccinations, please tell your doctor before. 
 
Advagraf with food and drink 
Avoid grapefruit (also as juice) while on treatment with Advagraf, since it can affect its levels in the blood. 
 
Pregnancy and breast-feeding 
If you are, think you might be or are planning to become pregnant, ask your doctor for advice before 
using Advagraf. 
Advagraf passes into breast milk. Therefore, you should not breast-feed whilst using Advagraf. 
 
Driving and using machines 
Do not drive or use any tools or machines if you feel dizzy or sleepy, or have problems seeing clearly 
after taking Advagraf. These effects are more frequent if you also drink alcohol. 
 
Advagraf contains lactose, sodium and lecithin (soya) 
Advagraf contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance 
to some sugars, contact your doctor before taking this medicine. 
This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-
free’. 
The printing ink used on Advagraf capsules contains soya lecithin. If you are allergic to peanut or soya, 
talk to your doctor to determine whether you should use this medicine. 
 
 
3. How to take Advagraf 
 
Always take Advagraf exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. This medicine should only be prescribed to you by a doctor with 
experience in the treatment of transplant patients. 
 
Make sure that you receive the same tacrolimus medicine every time you collect your prescription, unless 
your transplant specialist has agreed to change to a different tacrolimus medicine. This medicine should 
be taken once a day. If the appearance of this medicine is not the same as usual, or if dosage instructions 
have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right 
medicine. 
 
The starting dose to prevent the rejection of your transplanted organ will be determined by your doctor 
calculated according to your body weight. Initial daily doses just after transplantation will generally be in 
the range of 

0.10 – 0.30 mg per kg body weight per day 
 

depending on the transplanted organ. When treating rejection, these same doses may be used. 
 



48 

Your dose depends on your general condition and on which other immunosuppressive medication you are 
taking.  
 
Following the initiation of your treatment with Advagraf, frequent blood tests will be taken by your 
doctor to define the correct dose. Afterwards regular blood tests by your doctor will be required to define 
the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your Advagraf 
dose once your condition has stabilised. Your doctor will tell you exactly how many capsules to take. 
 
You will need to take Advagraf every day as long as you need immunosuppression to prevent rejection of 
your transplanted organ. You should keep in regular contact with your doctor. 
 
Advagraf is taken orally once daily in the morning. Take Advagraf on an empty stomach or 2 to 3 hours 
after a meal. Wait at least 1 hour until the next meal. Take the capsules immediately following removal 
from the blister. The capsules should be swallowed whole with a glass of water. Do not swallow the 
desiccant contained in the foil wrapper. 
 
If you take more Advagraf than you should 
If you have accidentally taken too much Advagraf, contact your doctor or nearest hospital emergency 
department immediately.  
 
If you forget to take Advagraf 
If you have forgotten to take your Advagraf capsules in the morning, take them as soon as possible on the 
same day. Do not take a double dose the next morning. 
 
If you stop taking Advagraf 
Stopping your treatment with Advagraf may increase the risk of rejection of your transplanted organ. Do 
not stop your treatment unless your doctor tells you to do so. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Advagraf can cause side effects, although not everybody gets them. 
 
Advagraf reduces your body’s defence mechanism (immune system), which will not be as good at 
fighting infections. Therefore, you may be more prone to infections while you are taking Advagraf. 
 
Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant tumours 
have been reported following Advagraf treatment. 
 
Cases of pure red cell aplasia (a very severe reduction in red blood cell counts), agranulocytosis (a 
severely lowered number of white blood cells), haemolytic anaemia (decreased number of red blood cells 
due to abnormal breakdown) and febrile neutropenia (a decrease in the type of white blood cells which 
fight infection, accompanied by fever) have been reported. It is not known exactly how often these side 
effects occur. 
 
Very common side effects (may affect more than 1 in 10 people): 
- Increased blood sugar, diabetes mellitus, increased potassium in the blood 
- Difficulty in sleeping 
- Trembling, headache 
- Increased blood pressure 
- Liver function tests abnormal 
- Diarrhoea, nausea 
- Kidney problems 



49 

 
Common side effects (may affect up to 1 in 10 people): 
- Reduction in blood cell counts (platelets, red or white blood cells), increase in white blood cell 

counts, changes in red blood cell counts (seen in blood tests) 
- Reduced magnesium, phosphate, potassium, calcium or sodium in the blood, fluid overload, 

increased uric acid or lipids in the blood, decreased appetite, increased acidity of the blood, other 
changes in the blood salts (seen in blood tests) 

- Anxiety symptoms, confusion and disorientation, depression, mood changes, nightmare, 
hallucination, mental disorders 

- Fits, disturbances in consciousness, tingling and numbness (sometimes painful) in the hands and 
feet, dizziness, impaired writing ability, nervous system disorders 

- Blurred vision, increased sensitivity to light, eye disorders 
- Ringing sound in your ears 
- Reduced blood flow in the heart vessels, faster heartbeat 
- Bleeding, partial or complete blocking of blood vessels, reduced blood pressure 
- Shortness in breath, disorders of the respiratory tissues in the lung, collection of liquid around the 

lung, inflammation of the pharynx, cough, flu-like symptoms 
- Stomach problems such as inflammation or ulcer causing abdominal pain or diarrhoea, bleeding in 

the stomach, inflammation or ulcer in the mouth, collection of fluid in the belly, vomiting, 
abdominal pain, indigestion, constipation, passing wind, bloating, loose stools 

- Bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage and 
inflammation of the liver 

- Itching, rash, hair loss, acne, increased sweating 
- Pain in joints, limbs, back and feet, muscle spasms 
- Insufficient function of the kidneys, reduced production of urine, impaired or painful urination 
- General weakness, fever, collection of fluid in your body, pain and discomfort, increase of the 

enzyme alkaline phosphatase in your blood, weight gain, feeling of temperature disturbed 
- Insufficient function of your transplanted organ 
 
Uncommon side effects (may affect up to 1 in 100 people): 
- Changes in blood clotting, reduction in the number of all types of blood cells (seen in blood tests) 
- Dehydration, inability to urinate 
- Abnormal blood test results: reduced protein or sugar, increased phosphate, increase of the 

enzyme lactate dehydrogenase  
- Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language abnormalities, 

memory problems 
- Clouding of the eye lens, impaired hearing 
- Irregular heartbeat, stop of heartbeat, reduced performance of your heart, disorder of the heart 

muscle, enlargement of the heart muscle, stronger heartbeat, abnormal ECG, heart rate and pulse 
abnormal 

- Blood clot in a vein of a limb, shock 
- Difficulties in breathing, respiratory tract disorders, asthma 
- Obstruction of the gut, increased blood level of the enzyme amylase, reflux of stomach content in 

your throat, delayed emptying of the stomach 
- Inflammation of the skin, burning sensation in the sunlight 
- Joint disorders 
- Painful menstruation and abnormal menstrual bleeding 
- Multiple organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on 

your chest, jittery or abnormal feeling, weight loss 
 
Rare side effects (may affect up to 1 in 1,000 people): 
- Small bleedings in your skin due to blood clots 
- Increased muscle stiffness 
- Blindness, deafness 
- Collection of fluid around the heart 
- Acute breathlessness 



50 

- Cyst formation in your pancreas 
- Problems with blood flow in the liver 
- Serious illness with blistering of skin, mouth, eyes and genitals; increased hairiness 
- Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer 
 
Very rare side effects (may affect up to 1 in 10,000 people): 
- Muscular weakness 
- Abnormal heart scan 
- Liver failure 
- Painful urination with blood in the urine 
- Increase of fat tissue 
 
Not known (frequency cannot be estimated from the available data): 
-    Abnormality of the optic nerve (optic neuropathy) 

 
Reporting of side effects  
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
5. How to store Advagraf 
 
Keep out of the sight and reach of children. 
 
Do not use Advagraf after the expiry date which is stated on the carton after “Exp”. The expiry date refers 
to the last day of that month. Use all the prolonged-release hard capsules within 1 year of opening the 
aluminium wrapping. 
 
Store in the original package in order to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
6. Contents of the pack and other information 
 
What Advagraf contains 
- The active substance is tacrolimus. 

Each capsule of Advagraf 0.5 mg contains 0.5 mg of tacrolimus (as monohydrate). 
Each capsule of Advagraf 1 mg contains 1 mg of tacrolimus (as monohydrate). 
Each capsule of Advagraf 3 mg contains 3 mg of tacrolimus (as monohydrate). 
Each capsule of Advagraf 5 mg contains 5 mg of tacrolimus (as monohydrate). 
 

- The other ingredients are: 
Capsule content: Hypromellose, ethylcellulose, lactose, magnesium stearate. 
Capsule shell: Titanium dioxide (E171), yellow iron oxide (E 172), red iron oxide (E 172), sodium 
laurilsulfate, gelatin. 
Printing ink: Shellac, lecithin (soya), simeticone, red iron oxide (E 172), hydroxypropylcellulose. 

 
What Advagraf looks like and contents of the pack 
Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with 
“0.5 mg” on the light yellow capsule cap and “ 647” on the orange capsule body, containing white 
powder. 
Advagraf 0.5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a 
protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are 



51 

available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in 
perforated unit-dose blisters. 
 
Advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “1 mg” on 
the white capsule cap and “ 677” on the orange capsule body, containing white powder. 
Advagraf 1 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a 
protective foil wrapper, including a desiccant. Packs of 30, 50, 60 and 100 prolonged-release capsules are 
available in blisters and packs of 30×1, 50×1, 60×1 and 100×1 prolonged-release capsules are available in 
perforated unit-dose blisters. 
 
Advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “3 mg” on 
the orange capsule cap and “ 637” on the orange capsule body, containing white powder. 
Advagraf 3 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a 
protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are 
available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in 
perforated unit-dose blisters. 
 
Advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “5 mg” on 
the greyish red capsule cap and “ 687” on the orange capsule body, containing white powder. 
Advagraf 5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a 
protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules 
are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in 
perforated unit-dose blisters.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
Marketing Authorisation Holder: 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
Netherlands 
 
Manufacturer: 
Astellas Ireland Co., Ltd. 
Killorglin, County Kerry, V93FC86 
 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Astellas Pharma B.V. Branch 
Tél/Tel: + 32 (0)2 5580710 
 

Lietuva 
 Biocodex UABTel.: +370 37 408 681 
Faks.: +370 37 408 682 
 

България 
Астелас Фарма ЕООД  
Teл.: + 359 2 862 53 72 
 

Luxembourg/Luxemburg 
Astellas Pharma B.V. Branch 
Belgique/Belgien 
Tél/Tel: + 32 (0)2 5580710 
 

Česká republika 
Astellas Pharma s.r.o. 
Tel: +420 221 401 500 
 

Magyarország 
Astellas Pharma Kft. 
Tel.: +36 1 577 8200 
 



52 

Danmark 
Astellas Pharma a/s 
Tlf: + 45 43 430355 
 

Malta 
Astellas Pharmaceuticals AEBE 
Τηλ: +30 210 8189900 
 

Deutschland 
Astellas Pharma GmbH 
Tel: + 49 (0)89 454401 
 

Nederland 
Astellas Pharma B.V. 
Tel: + 31 (0)71 5455745 
 

Eesti 
Biocodex OÜTel.: +372 6 056 014 
Fax: +372 6 056 011 
 

Norge 
Astellas Pharma  
Tlf: + 47 66 76 46 00 
 

Ελλάδα 
Astellas Pharmaceuticals AEBE 
Τηλ: +30 210 8189900 
 

Österreich 
Astellas Pharma Ges.m.b.H. 
Tel: + 43 (0)1 8772668 
 

España 
Astellas Pharma S.A. 
Tel: + 34 91 4952700 
 

Polska 
Astellas Pharma Sp.z.o.o. 
Tel.: + 48 225451 111 
 

France 
Astellas Pharma S.A.S. 
Tél: + 33 (0)1 55917500 
 

Portugal 
Astellas Farma, Lda. 
Tel: + 351 21 4401320 
 

Hrvatska 
Astellas d.o.o. 
Tel: + 385 1 670 01 02 
 

România 
S.C.Astellas Pharma SRL  
Tel: +40 (0)21 361 04 95/96/92 
 

Ireland 
Astellas Pharma Co. Ltd. 
Tel: + 353 (0)1 4671555 
 

Slovenija 
Astellas Pharma d.o.o. 
Tel: +386 (0) 14011 400 
 

Ísland 
Vistor hf 
Sími: + 354 535 7000  
 

Slovenská republika 
Astellas Pharma s.r.o.  
Tel: +421 2 4444 2157 
 

Italia 
Astellas Pharma S.p.A. 
Tel: + 39 (0)2 921381 
 
Κύπρος 
Astellas Pharmaceuticals AEBE 
Ελλάδα 
Τηλ: +30 210 8189900 

Suomi/Finland 
Astellas Pharma  
Puh/Tel: + 358 9 85606000 
 
Sverige 
Astellas Pharma AB 
Tel: + 46 (0)40-650 15 00 
 

  
Latvija 
Biocodex SIA                                                                                                                       
Tel: + 371 67 619365                                            

United Kingdom 
Astellas Pharma Ltd. 
Tel: + 44 (0) 203 379 8700 
 

 
 
This leaflet was last revised in  
 



53 

Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/.  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
{'Title': '1. what advagraf is and what it is used for', 'Section_Content': "advagraf contains the active substance tacrolimus. it is an immunosuppressant. following your organ transplant (liver, kidney), your body's immune system will try to reject the new organ. advagraf is used to control your body's immune response, enabling your body to accept the transplanted organ. you may also be given advagraf for an ongoing rejection of your transplanted liver, kidney, heart or other organ when any previous treatment you were taking was unable to control this immune response after your transplantation. advagraf is used in adults.", 'Entity_Recognition': [{'Text': 'advagraf', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'advagraf', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 8}, {'Text': 'the active substance tacrolimus', 'Type': 'TREATMENT', 'BeginOffset': 18, 'EndOffset': 49}, {'Text': 'an immunosuppressant', 'Type': 'TREATMENT', 'BeginOffset': 57, 'EndOffset': 77}, {'Text': 'your organ transplant', 'Type': 'TREATMENT', 'BeginOffset': 89, 'EndOffset': 110}, {'Id': 0, 'BeginOffset': 112, 'EndOffset': 117, 'Score': 0.7666672468185425, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 1, 'BeginOffset': 119, 'EndOffset': 125, 'Score': 0.919157087802887, 'Text': 'kidney', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': "your body's immune system", 'Type': 'TREATMENT', 'BeginOffset': 128, 'EndOffset': 153}, {'Text': 'advagraf', 'Type': 'TREATMENT', 'BeginOffset': 188, 'EndOffset': 196}, {'Id': 11, 'BeginOffset': 278, 'EndOffset': 290, 'Score': 0.3767845332622528, 'Text': 'transplanted', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 320, 'EndOffset': 328, 'Score': 0.84352707862854, 'Text': 'advagraf', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'an ongoing rejection of your transplanted liver, kidney, heart or other organ', 'Type': 'PROBLEM', 'BeginOffset': 333, 'EndOffset': 410}, {'Text': 'any previous treatment', 'Type': 'TREATMENT', 'BeginOffset': 416, 'EndOffset': 438}, {'Text': 'your transplantation', 'Type': 'TREATMENT', 'BeginOffset': 504, 'EndOffset': 524}, {'Id': 7, 'BeginOffset': 526, 'EndOffset': 534, 'Score': 0.414588063955307, 'Text': 'advagraf', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}]}
{'Title': '2. what you need to know before you take advagraf', 'Section_Content': 'do not take advagraf - if you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of advagraf (see section 6). - if you are allergic to sirolimus or to any macrolide-antibiotic (e.g. erythromycin, clarithromycin, josamycin). warnings and precautions prograf and advagraf both contain the active substance, tacrolimus. however, advagraf is taken once daily, whereas prograf is taken twice daily. this is because advagraf capsules allow for a prolonged release (more slow release over a longer period) of tacrolimus. advagraf and prograf are not interchangeable. tell your doctor if any of the following apply to you: - if you are taking any medicines mentioned below under \'other medicines and advagraf\'. - if you have or have had liver problems - if you have diarrhoea for more than one day 46 - if you feel strong abdominal pain accompanied or not with other symptoms, such as chills, fever, nausea or vomiting - if you have an alteration of the electrical activity of your heart called "qt prolongation". tell your doctor immediately if during treatment you suffer from: problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or if your field of vision becomes restricted. your doctor may need to adjust your dose of advagraf. you should keep in regular contact with your doctor. from time to time, your doctor may need to do blood, urine, heart, eye tests, to set the right dose of advagraf. you should limit your exposure to the sun and uv (ultraviolet) light whilst taking advagraf. this is because immunosuppressants could increase the risk of skin cancer. wear appropriate protective clothing and use a sunscreen with a high sun protection factor. children and adolescents the use of advagraf is not recommended in children and adolescents under 18 years. other medicines and advagraf please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription and herbal preparations. it is not recommended that advagraf is taken with ciclosporin (another medicine used for the prevention of transplant organ rejection). advagraf blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking advagraf, which may require interruption, an increase or a decrease in advagraf dose. in particular, you should tell your doctor if you are taking or have recently taken medicines like: - antifungal medicines and antibiotics, particularly so-called macrolide antibiotics, used to treat infections e.g. ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole, and isavuconazole, erythromycin, clarithromycin, josamycin, and rifampicin - letermovir, used to prevent illness caused by cmv (human cytomegalovirus) - hiv protease inhibitors (e.g ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and combination tablets, used to treat hiv infection - hcv protease inhibitors (e.g. telaprevir, boceprevir, and the combination ombitasvir/paritaprevir/ritonavir with or without dasabuvir), used to treat hepatitis c infection - nilotinib and imatinib (used to treat certain cancers) - mycophenolic acid, used to suppress the immune system to prevent transplant rejection - medicines for stomach ulcer and acid reflux (e.g. omeprazole, lansoprazole or cimetidine) - antiemetics, used to treat nausea and vomiting (e.g. metoclopramide) - cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn - the contraceptive pill or other hormone treatments with ethinylestradiol, hormone treatments with danazol - medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem and verapamil) - anti-arrhythmic drugs (amiodarone) used to control arrhythmia (uneven beating of the heart) - medicines known as "statins" used to treat elevated cholesterol and triglycerides - phenytoin or phenobarbital, used to treat epilepsy - the corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids used to treat inflammations or suppress the immune system (e.g. in transplant rejection) - nefazodone, used to treat depression 47 - herbal preparations containing st. john\'s wort (hypericum perforatum) or extracts of schisandra sphenanthera. tell your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation and pain), amphotericin b (used to treat bacterial infections) or antivirals (used to treat viral infections e.g. aciclovir). these may worsen kidney or nervous system problems when taken together with advagraf. your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, hypertension and kidney disease, (e.g. amiloride, triamterene, or spironolactone), non- steroidal anti-inflammatory drugs (nsaids, e.g. ibuprofen) used for fever, inflammation and pain, anticoagulants (blood thinners), or oral medicines for diabetes, while you take advagraf. if you need to have any vaccinations, please tell your doctor before. advagraf with food and drink avoid grapefruit (also as juice) while on treatment with advagraf, since it can affect its levels in the blood. pregnancy and breast-feeding if you are, think you might be or are planning to become pregnant, ask your doctor for advice before using advagraf. advagraf passes into breast milk. therefore, you should not breast-feed whilst using advagraf. driving and using machines do not drive or use any tools or machines if you feel dizzy or sleepy, or have problems seeing clearly after taking advagraf. these effects are more frequent if you also drink alcohol. advagraf contains lactose, sodium and lecithin (soya) advagraf contains lactose (milk sugar). if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. this medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially \'sodium- free\'. the printing ink used on advagraf capsules contains soya lecithin. if you are allergic to peanut or soya, talk to your doctor to determine whether you should use this medicine.', 'Entity_Recognition': [{'Text': 'advagraf', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 5, 'BeginOffset': 12, 'EndOffset': 20, 'Score': 0.9243769645690918, 'Text': 'advagraf', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.9074466824531555}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 32, 'BeginOffset': 44, 'EndOffset': 58, 'Score': 0.7001740336418152, 'Text': 'hypersensitive', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 63, 'EndOffset': 73, 'Score': 0.9483619928359985, 'Text': 'tacrolimus', 'Category': 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'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9264983534812927, 'RelationshipScore': 0.9991596937179565, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 999, 'EndOffset': 1004, 'Text': 'heart', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 1, 'BeginOffset': 999, 'EndOffset': 1004, 'Score': 0.9264983534812927, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'qt prolongation"', 'Type': 'PROBLEM', 'BeginOffset': 1013, 'EndOffset': 1029}, {'Text': 'your vision', 'Type': 'PROBLEM', 'BeginOffset': 1111, 'EndOffset': 1122}, {'Id': 42, 'BeginOffset': 1131, 'EndOffset': 1145, 'Score': 0.9666538834571838, 'Text': 'blurred vision', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9666118025779724}]}, {'Id': 43, 'BeginOffset': 1147, 'EndOffset': 1171, 'Score': 0.980720579624176, 'Text': 'changes in colour vision', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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{'Title': '3. how to take advagraf', 'Section_Content': 'always take advagraf exactly as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. this medicine should only be prescribed to you by a doctor with experience in the treatment of transplant patients. make sure that you receive the same tacrolimus medicine every time you collect your prescription, unless your transplant specialist has agreed to change to a different tacrolimus medicine. this medicine should be taken once a day. if the appearance of this medicine is not the same as usual, or if dosage instructions have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine. the starting dose to prevent the rejection of your transplanted organ will be determined by your doctor calculated according to your body weight. initial daily doses just after transplantation will generally be in the range of 0.10 0.30 mg per kg body weight per day depending on the transplanted organ. when treating rejection, these same doses may be used. your dose depends on your general condition and on which other immunosuppressive medication you are taking. following the initiation of your treatment with advagraf, frequent blood tests will be taken by your doctor to define the correct dose. afterwards regular blood tests by your doctor will be required to define the correct dose and to adjust the dose from time to time. your doctor will usually reduce your advagraf dose once your condition has stabilised. your doctor will tell you exactly how many capsules to take. you will need to take advagraf every day as long as you need immunosuppression to prevent rejection of your transplanted organ. you should keep in regular contact with your doctor. advagraf is taken orally once daily in the morning. take advagraf on an empty stomach or 2 to 3 hours after a meal. wait at least 1 hour until the next meal. take the capsules immediately following removal from the blister. the capsules should be swallowed whole with a glass of water. do not swallow the desiccant contained in the foil wrapper. if you take more advagraf than you should if you have accidentally taken too much advagraf, contact your doctor or nearest hospital emergency department immediately. if you forget to take advagraf if you have forgotten to take your advagraf capsules in the morning, take them as soon as possible on the same day. do not take a double dose the next morning. if you stop taking advagraf stopping your treatment with advagraf may increase the risk of rejection of your transplanted organ. do not stop your treatment unless your doctor tells you to do so. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'advagraf', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 127, 'EndOffset': 140}, {'Text': 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, advagraf can cause side effects, although not everybody gets them. advagraf reduces your body's defence mechanism (immune system), which will not be as good at fighting infections. therefore, you may be more prone to infections while you are taking advagraf. severe effects may occur, including allergic and anaphylactic reactions. benign and malignant tumours have been reported following advagraf treatment. cases of pure red cell aplasia (a very severe reduction in red blood cell counts), agranulocytosis (a severely lowered number of white blood cells), haemolytic anaemia (decreased number of red blood cells due to abnormal breakdown) and febrile neutropenia (a decrease in the type of white blood cells which fight infection, accompanied by fever) have been reported. it is not known exactly how often these side effects occur. very common side effects (may affect more than 1 in 10 people): - increased blood sugar, diabetes mellitus, increased potassium in the blood - difficulty in sleeping - trembling, headache - increased blood pressure - liver function tests abnormal - diarrhoea, nausea - kidney problems 49 common side effects (may affect up to 1 in 10 people): - reduction in blood cell counts (platelets, red or white blood cells), increase in white blood cell counts, changes in red blood cell counts (seen in blood tests) - reduced magnesium, phosphate, potassium, calcium or sodium in the blood, fluid overload, increased uric acid or lipids in the blood, decreased appetite, increased acidity of the blood, other changes in the blood salts (seen in blood tests) - anxiety symptoms, confusion and disorientation, depression, mood changes, nightmare, hallucination, mental disorders - fits, disturbances in consciousness, tingling and numbness (sometimes painful) in the hands and feet, dizziness, impaired writing ability, nervous system disorders - blurred vision, increased sensitivity to light, eye disorders - ringing sound in your ears - reduced blood flow in the heart vessels, faster heartbeat - bleeding, partial or complete blocking of blood vessels, reduced blood pressure - shortness in breath, disorders of the respiratory tissues in the lung, collection of liquid around the lung, inflammation of the pharynx, cough, flu-like symptoms - stomach problems such as inflammation or ulcer causing abdominal pain or diarrhoea, bleeding in the stomach, inflammation or ulcer in the mouth, collection of fluid in the belly, vomiting, abdominal pain, indigestion, constipation, passing wind, bloating, loose stools - bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage and inflammation of the liver - itching, rash, hair loss, acne, increased sweating - pain in joints, limbs, back and feet, muscle spasms - insufficient function of the kidneys, reduced production of urine, impaired or painful urination - general weakness, fever, collection of fluid in your body, pain and discomfort, increase of the enzyme alkaline phosphatase in your blood, weight gain, feeling of temperature disturbed - insufficient function of your transplanted organ uncommon side effects (may affect up to 1 in 100 people): - changes in blood clotting, reduction in the number of all types of blood cells (seen in blood tests) - dehydration, inability to urinate - abnormal blood test results: reduced protein or sugar, increased phosphate, increase of the enzyme lactate dehydrogenase - coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language abnormalities, memory problems - clouding of the eye lens, impaired hearing - irregular heartbeat, stop of heartbeat, reduced performance of your heart, disorder of the heart muscle, enlargement of the heart muscle, stronger heartbeat, abnormal ecg, heart rate and pulse abnormal - blood clot in a vein of a limb, shock - difficulties in breathing, respiratory tract disorders, asthma - obstruction of the gut, increased blood level of the enzyme amylase, reflux of stomach content in your throat, delayed emptying of the stomach - inflammation of the skin, burning sensation in the sunlight - joint disorders - painful menstruation and abnormal menstrual bleeding - multiple organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on your chest, jittery or abnormal feeling, weight loss rare side effects (may affect up to 1 in 1,000 people): - small bleedings in your skin due to blood clots - increased muscle stiffness - blindness, deafness - collection of fluid around the heart - acute breathlessness 50 - cyst formation in your pancreas - problems with blood flow in the liver - serious illness with blistering of skin, mouth, eyes and genitals; increased hairiness - thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer very rare side effects (may affect up to 1 in 10,000 people): - muscular weakness - abnormal heart scan - liver failure - painful urination with blood in the urine - increase of fat tissue not known (frequency cannot be estimated from the available data): - abnormality of the optic nerve (optic neuropathy) reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'advagraf', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Id': 7, 'BeginOffset': 20, 'EndOffset': 28, 'Score': 0.7763838768005371, 'Text': 'advagraf', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 39, 'EndOffset': 51, 'Score': 0.9580377340316772, 'Text': 'side effects', 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{'Title': '5. how to store advagraf', 'Section_Content': 'keep out of the sight and reach of children. do not use advagraf after the expiry date which is stated on the carton after "exp". the expiry date refers to the last day of that month. use all the prolonged-release hard capsules within 1 year of opening the aluminium wrapping. store in the original package in order to protect from moisture. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'advagraf', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 56, 'EndOffset': 64, 'Score': 0.525202751159668, 'Text': 'advagraf', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'all the prolonged-release hard capsules', 'Type': 'TREATMENT', 'BeginOffset': 188, 'EndOffset': 227}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 235, 'EndOffset': 236}, {'Text': 'opening the aluminium wrapping', 'Type': 'TREATMENT', 'BeginOffset': 245, 'EndOffset': 275}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what advagraf contains - the active substance is tacrolimus. each capsule of advagraf 0.5 mg contains 0.5 mg of tacrolimus (as monohydrate). each capsule of advagraf 1 mg contains 1 mg of tacrolimus (as monohydrate). each capsule of advagraf 3 mg contains 3 mg of tacrolimus (as monohydrate). each capsule of advagraf 5 mg contains 5 mg of tacrolimus (as monohydrate). - the other ingredients are: capsule content: hypromellose, ethylcellulose, lactose, magnesium stearate. capsule shell: titanium dioxide (e171), yellow iron oxide (e 172), red iron oxide (e 172), sodium laurilsulfate, gelatin. printing ink: shellac, lecithin (soya), simeticone, red iron oxide (e 172), hydroxypropylcellulose. what advagraf looks like and contents of the pack advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with "0.5 mg" on the light yellow capsule cap and " 647" on the orange capsule body, containing white powder. advagraf 0.5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. packs of 30, 50 and 100 prolonged-release capsules are 51 available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters. advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with "1 mg" on the white capsule cap and " 677" on the orange capsule body, containing white powder. advagraf 1 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. packs of 30, 50, 60 and 100 prolonged-release capsules are available in blisters and packs of 30×1, 50×1, 60×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters. advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with "3 mg" on the orange capsule cap and " 637" on the orange capsule body, containing white powder. advagraf 3 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. packs of 30, 50 and 100 prolonged-release capsules are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters. advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with "5 mg" on the greyish red capsule cap and " 687" on the orange capsule body, containing white powder. advagraf 5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. packs of 30, 50 and 100 prolonged-release hard capsules are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters. not all pack sizes may be 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