Modigraf

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Modigraf 0.2 mg granules for oral suspension 
Modigraf 1 mg granules for oral suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Modigraf 0.2 mg granules for oral suspension 
Each sachet contains 0.2 mg tacrolimus (as monohydrate). 
 

Excipient with known effect:  
Each sachet contains 94.7 mg lactose (as monohydrate). 
Each sachet contains less than 1 mmol sodium (23 mg). 

 
Modigraf 1 mg granules for oral suspension 
Each sachet contains 1 mg tacrolimus (as monohydrate). 
 

Excipient with known effect:  
Each sachet contains 473 mg lactose (as monohydrate). 
Each sachet contains less than 1 mmol sodium (23 mg). 

 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Granules for oral suspension.  
White granules.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.  
 
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal 
products in adult and paediatric patients.  
 
4.2 Posology and method of administration  
 
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. Modigraf is a granular formulation of tacrolimus, for twice-a-day administration. Modigraf 
therapy requires careful monitoring by adequately qualified and equipped personnel. 
 
Posology  
The recommended initial doses presented below are intended to act solely as a guideline. Modigraf 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. 
Modigraf 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.  
 



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Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks 
post-transplant to ensure adequate exposure to the active substance in the immediate post-transplant 
period. As tacrolimus is a substance with low clearance, it may take several days after adjustments to 
the Modigraf dose regimen before steady state is achieved (see below under “Therapeutic drug 
monitoring” and section 5.2).  
 
Modigraf should not be switched with the prolonged-release capsules (Advagraf) as a clinically 
relevant difference in bioavailability between the two formulations cannot be excluded. In general, 
inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations 
of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of undesirable effects, 
including under- or overimmunosuppression, due to clinically relevant differences in systemic 
exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the 
corresponding 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.  
 
Prophylaxis of kidney transplant rejection  
Adults  
Oral Modigraf therapy should commence at 0.20 - 0.30 mg/kg/day administered as 2 divided doses 
(e.g. morning and evening). Administration should commence within 24 hours after the completion of 
surgery.  
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous 
therapy of 0.05 - 0.10 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should 
be initiated as a continuous 24-hour infusion.  
 
Paediatric population  
An initial oral dose of 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and 
evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 
0.075 – 0.100 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be 
administered as a continuous 24-hour infusion.  
 
Dose adjustment during post-transplant period in adults and paediatric patients  
Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to 
withdraw concomitant immunosuppressive therapy, leading to tacrolimus-based dual therapy. 
Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of 
tacrolimus and may necessitate further dose adjustments.  
 
Prophylaxis of liver transplant rejection  
Adults  
Oral Modigraf therapy should commence at 0.10 - 0.20 mg/kg/day administered as 2 divided doses 
(e.g. morning and evening). Administration should commence approximately 12 hours after the 
completion of surgery.  
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous 
therapy of 0.01 - 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should 
be initiated as a continuous 24-hour infusion.  
 
Paediatric population  
An initial oral dose of 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and 
evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 
0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as 
a continuous 24-hour infusion.  
 
Dose adjustment during post-transplant period in adults and paediatric patients  
Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to 
withdraw concomitant immunosuppressive therapy, leading to tacrolimus monotherapy. 



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Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of 
tacrolimus and may necessitate further dose adjustments.  
 
Prophylaxis of heart transplant rejection  
Adults  
Modigraf can be used with antibody induction (allowing for delayed start of tacrolimus therapy) or 
alternatively in clinically stable patients without antibody induction.  
Following antibody induction, oral Modigraf therapy should commence at a dose of 0.075 mg/kg/day 
administered as 2 divided doses (e.g. morning and evening). Administration should commence within 
5 days after the completion of surgery as soon as the patient's clinical condition is stabilised. If the 
dose cannot be administered orally as a result of the clinical condition of the patient, intravenous 
therapy of 0.01 to 0.02 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should 
be initiated as a continuous 24-hour infusion.  
An alternative strategy was published where oral tacrolimus was administered within 12 hours post 
transplantation. This approach was reserved for patients without organ dysfunction (e.g. renal 
dysfunction). In that case, an initial oral tacrolimus dose of 2 to 4 mg per day was used in combination 
with mycophenolate mofetil and corticosteroids or in combination with sirolimus and corticosteroids.  
 
Paediatric population  
Tacrolimus has been used with or without antibody induction in paediatric heart transplantation.  
In patients without antibody induction, if tacrolimus therapy is initiated intravenously, the 
recommended starting dose is 0.03 - 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution 
for infusion) as a continuous 24-hour infusion targeted to achieve tacrolimus whole blood 
concentrations of 15 - 25 nanogram/ml. Patients should be converted to oral therapy as soon as 
clinically practicable. The first dose of oral therapy should be 0.30 mg/kg/day starting 8 to 12 hours 
after discontinuing intravenous therapy.  
Following antibody induction, if Modigraf therapy is initiated orally, the recommended starting dose is 
0.10 - 0.30 mg/kg/day administered as 2 divided doses (e.g. morning and evening).  
 
Dose adjustment during post-transplant period in adults and paediatric patients  
Tacrolimus doses are usually reduced in the post-transplant period. Post-transplant improvement in the 
condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose 
adjustments.  
 
Conversion between Modigraf and Prograf tacrolimus formulations  
In healthy subjects the systemic exposure to tacrolimus (AUC) for Modigraf was approximately 18% 
higher than that for Prograf capsules when administered as single doses. There are no safety data 
available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in 
critically ill patients.  
 
Stable allograft recipients maintained on Modigraf granules, requiring conversion to Prograf capsules, 
should be converted on a 1:1 mg:mg total daily dose basis. If equal doses are not possible, the total 
daily dose of Prograf should be rounded-up to the nearest amount possible, with the higher dose given 
in the morning and the lower dose in the evening.  
 
Similarly, for conversion of patients from Prograf capsules to Modigraf granules, the total daily 
Modigraf dose should preferably be equal to the total daily Prograf dose. If conversion on the basis of 
equal quantities is not possible, the total daily dose of Modigraf should be rounded down to the nearest 
total daily dose possible with sachets 0.2 mg and 1 mg.  
The total daily dose of Modigraf granules should be administered in 2 equal doses. If equal doses are 
not possible, then the higher dose should be administered in the morning and the lower dose in the 
evening. Modigraf sachets must not be used partially.  
 
Example: Total daily dose Prograf capsules given as 1 mg in the morning and 0.5 mg in the evening. 
Then give a total daily dose of Modigraf 1.4 mg divided as 0.8 mg in the morning and 0.6 mg in the 
evening.  
 



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Tacrolimus trough levels should be measured prior to conversion and within 1 week after conversion. 
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. Tacrolimus 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 tacrolimus doses, 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 Modigraf may need to be reduced. 
 
Treatment of allograft rejection after kidney or liver transplantation – adults and paediatric patients 
For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with 
the initial oral dose recommended for primary immunosuppression.  
 
Treatment of allograft rejection after heart transplantation therapy – adults and paediatric patients 
In adult patients converted to Modigraf, an initial oral dose of 0.15 mg/kg/day should be administered 
in 2 divided doses (e.g. morning and evening).  
In paediatric patients converted to tacrolimus, an initial oral dose of 0.20 - 0.30 mg/kg/day should be 
administered in 2 divided doses (e.g. morning and evening).  
 
Treatment of allograft rejection after transplantation of other allografts  
The dose recommendations for lung, pancreas and intestinal transplantation are based on limited 
prospective clinical trial data with the Prograf formulation. 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 (C12) and systemic exposure (AUC0-12) is similar 
between the 2 formulations Modigraf granules and Prograf capsules.  
 
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. 
Tacrolimus blood trough levels should be determined approximately 12 hours post-dosing of Modigraf 
granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post 
transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood 
trough levels should be monitored at least twice weekly during the early post-transplant period and 
then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be closely 
monitored when clinical signs of toxicity or acute rejection are observed, following conversion 
between Modigraf granules to Prograf capsules, 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, it may take several days after adjustments to the 
Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).  
 



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Data from clinical studies suggests that the majority of patients can be successfully managed if 
tacrolimus blood trough levels are maintained below 20 nanogram/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 nanogram/ml in liver transplant recipients and 
10 - 20 nanogram/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 nanogram/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 
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.  
 
Elderly patients  
There is no evidence currently available to indicate that dosing should be adjusted in older people. 
  
Paediatric population  
In general, paediatric patients require doses 1½ - 2 times higher than the adult doses to achieve similar 
blood levels.  
 
Method of administration  
Tacrolimus therapy is generally initiated by the oral route. If necessary, tacrolimus dosing may 
commence by administering Modigraf granules suspended in water, via nasogastric tubing.  
 
It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. 
morning and evening).  
 
Modigraf granules 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).  
 
The required dose is calculated from the weight of the patient, using the minimum number of sachets 
possible. 2 ml of water (at room temperature) should be used per 1 mg tacrolimus to produce a 
suspension (up to a maximum of 50 ml, depending on body weight) in a cup. Materials containing 
polyvinyl chloride (PVC) should not be used (see section 6.2). Granules are added to the water and 
stirred. It is not advised to use any liquids or utensils to empty the sachets. The suspension can be 
drawn up via a syringe or swallowed directly by the patient. Thereafter the cup is rinsed once with the 
same quantity of water and the rinsings consumed by the patient. The suspension should be 
administered immediately after preparation.  
 
4.3 Contraindications 
 
Hypersensitivity to tacrolimus or to any of the excipients listed in section 6.1. 
Hypersensitivity to other macrolides.  



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4.4 Special warnings and precautions for use 
 
There are no safety data available on the use of Modigraf granules following a temporary switch from 
Prograf or Advagraf in critically ill patients.  
 
Modigraf should not be switched with Advagraf as a clinically relevant difference in bioavailability 
between the two formulations cannot be excluded. 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 formulations or regimen should only take place 
under the close supervision of a transplant specialist (see sections 4.2 and 4.8).  
 
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.  
 
Herbal preparations containing St. John’s Wort (Hypericum perforatum) or other herbal preparations 
should be avoided when taking Modigraf 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 risks 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 on rare occasions. 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, 



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hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, 
high-risk patients, particularly young children and those 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 Modigraf, 
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 
Modigraf. 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).  
 
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 Modigraf, 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 



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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 
Modigraf granules contain lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.  
 
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.  
 
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, norethisterone, quinidine, tamoxifen, troleandomycin.  
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 medicinal 
products 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.  
 



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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 or 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.  
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 phenazone.  
 
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 which have led 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, 
sulfamethoxazole+trimethoprim, 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 



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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). Tacrolimus affected fertility in male rats (see section 5.3).  
 
Breast-feeding 
Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the 
newborn cannot be excluded, women should not breast-feed whilst receiving tacrolimus.  
 
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.  
 
No studies on the effects of tacrolimus (Modigraf) on the ability to drive and use machines have been 
performed.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
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.  
 
List of adverse reactions 
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 groupingadverse 
reactions 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 Modigraf.  
 
Neoplasms benign, malignant and unspecified (inl. cysts and polyps)  
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  



 12 

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  
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  



 13 

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  
 
Hepatobiliary disorders  
  
common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and 

jaundice  
rare: venoocclusive liver disease, hepatic artery thrombosis  
very rare: hepatic failure  

 
Skin and subcutaneous tissue disorders  
common: rash, pruritus, alopecias, acne, sweating increased  
uncommon: dermatitis, photosensitivity  
rare: toxic epidermal necrolysis (Lyell’s syndrome)  
very rare: Stevens Johnson syndrome  

 
Musculoskeletal and connective tissue disorders  
common: arthralgia, back pain, muscle spasms, pain in extremity 
uncommon: joint disorders  
rare: mobility decreased 

 
Renal and urinary disorders  
very common:  renal impairment 
common:  renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, 

urinary abnormalities, oliguria, bladder and urethral symptoms  
uncommon: haemolytic uraemic syndrome, anuria 
very rare: nephropathy, cystitis haemorrhagic  

 
Reproductive system and breast disorders  
uncommon: dysmenorrhoea and uterine bleeding  

 
General disorders and administration site conditions  
common: febrile disorders, pain and discomfort, asthenic conditions, oedema, body 

temperature perception disturbed  
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  



 14 

 
 
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  

 
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. 

 
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 
 
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 concentrations 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 and pharmacodynamic effects  
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 lymphokine genes. 
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and 
in vivo experiments.  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 15 

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.  
 
Clinical efficacy and safety of tacrolimus administered twice daily in other primary organ 
transplantation  
In prospective published studies oral tacrolimus (given as Prograf capsules) 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 
tacrolimus in these published studies appeared to be similar to what was reported in the large studies, 
where tacrolimus 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 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 nanogram/ml. The 1-year patient survival was 83% in the tacrolimus and 
71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute 
rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than 
in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in 
the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p = 0.025). 
Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than 
tacrolimus-treated patients to ciclosporin (n = 2) (p = 0.02).  
 
In an additional 2-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 nanogram/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 3 studies demonstrated similar survival rates. The incidences of acute rejection were numerically 
lower with tacrolimus in all 3 studies and one of the studies reported a significantly lower incidence of 
bronchiolitis obliterans syndrome with tacrolimus.  
 
Pancreas transplantation  
A multicentre study 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 nanogram/ml by Day 5 and 5 to 10 nanogram/ml after Month 6. Pancreas survival at 1 year was 
significantly superior with tacrolimus: 91.3% versus 74.5% with ciclosporin (p < 0.0005), whereas 
renal graft survival was similar in both groups. In total 34 patients switched treatment from ciclosporin 
to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.  
 
Intestinal transplantation  



 16 

Published clinical experience from a single centre on the use of oral tacrolimus 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 nanogram/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.  
Modigraf granules are an immediate-release formulation of tacrolimus for twice daily dosing. 
Following oral administration of Modigraf granules peak concentrations (Cmax) of tacrolimus in blood 
are on average achieved in approximately 2 to 2.5 hours. 
Absorption of tacrolimus is variable. Results of a single dose bioequivalence study with adult healthy 
volunteers showed that Modigraf granules were approximately 20% more bioavailable than the 
Prograf capsules. Mean oral bioavailability of tacrolimus (investigated with the Prograf capsules 
formulation) is in the range of 20 - 25% (individual range in adult patients 6 - 43%, in paediatric 
kidney transplant patients 3 - 77%). The oral bioavailability of tacrolimus was reduced when it was 
administered after a meal.  
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Modigraf 
granules may commence orally.  
In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a 
relatively flat absorption profile.  
 
The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of 
food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced 
after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.  
In stable liver transplant patients, the oral bioavailability of tacrolimus was reduced when it was 
administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and 
Cmax (50%), and an increase in tmax (173%) in whole blood were evident.  
In a study of stable renal transplant patients who were administered tacrolimus immediately after a 
standard continental breakfast the effect on oral bioavailability was less pronounced. Decreases in 
AUC (2 to 12%) and Cmax (15 to 38%), and an increase in tmax (38 to 80%) in whole blood were 
evident.  
A strong correlation exists between AUC and whole blood trough levels at steady-state for Modigraf. 
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 



 17 

of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to 
pharmacological activity of tacrolimus.  
 
Excretion  
Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance 
estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant 
patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as low 
haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or 
corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance 
rates observed following transplantation. 
 
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood 
was approximately 43 hours. In adult and paediatric liver transplant patients, it averaged 11.7 hours 
and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased 
clearance rates contribute to the shorter half-life observed in transplant recipients.  
 
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.  
 
Paediatric data  
In paediatric liver transplant patients the mean oral bioavailability of tacrolimus (investigated with the 
Modigraf granules) is 26%± 23% (individual range in paediatric liver transplant patients 4 - 80%). 
Data on oral bioavailability of Modigraf in other indications is not available.  
After oral administration (0.30 mg/kg/day) to paediatric liver transplant patients, steady-state 
concentrations of tacrolimus were achieved within 3 days in the majority of patients.  
In paediatric liver and kidney transplant patients, values for total body clearance of 
2.3 ± 1.2 ml/min/kg and 2.1 ± 0.6 ml/min/kg, respectively, have been observed. Highly variable age 
dependent total body clearance and half life were observed in limited paediatric clinical investigations, 
especially in early childhood.  
The half-life in paediatric transplant patients averages approximately 12 hours.  
 
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 nanogram/mL which is more than 6-fold higher than mean 
peak concentrations observed with Modigraf 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 
 
Lactose monohydrate 
Hypromellose (E464) 
Croscarmellose sodium (E468) 
 



 18 

6.2 Incompatibilities 
 
Tacrolimus is not compatible with PVC (polyvinylchloride) plastics. Materials used to prepare and 
administer the suspension, e.g. drinking vessels, cups, or tubing, must not contain PVC. 
 
6.3 Shelf life 
 
3 years. 
 
After preparation, the suspension should be administered immediately. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Sachets consisting of layers of polyethylene terephtalate (PET), aluminium (Al) and polyethylene 
(PE).  
 
Pack size: carton box containing 50 sachets.  
 
6.6 Special precautions for disposal and other handling 
 
No special requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V.  
Sylviusweg 62 
2333 BE Leiden 
Netherlands  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Modigraf 0.2 mg granules for oral suspension 
EU/1/09/523/001 
 
Modigraf 1 mg granules for oral suspension 
EU/1/09/523/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 May 2009 
Date of latest renewal: 17 Feb 2014 
 
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. 
 
 

http://www.ema.europa.eu/


 19 

 
 
 
 
 
 
 
 
 
 
 
 
 
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 

 



 20 

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

 
 

 
 

 
 
 
 
 
  



 21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III  
 

LABELLING AND PACKAGE LEAFLET 
 
 
 
  



 22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

A. LABELLING 
 
  



 23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Modigraf 0.2 mg granules for oral suspension  
tacrolimus  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 0.2 mg tacrolimus (as monohydrate).  
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See package leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
50 sachets containing granules for oral suspension.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
Suspend the granules in water.  
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 
 
 
8. EXPIRY DATE 
 
EXP:  
 
After preparation, the suspension should be administered immediately.  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 24 

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)  
 
 
13. BATCH NUMBER 
 
Batch:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
modigraf 0.2 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



 25 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET FOIL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Modigraf 0.2 mg granules for oral suspension  
tacrolimus  
oral use  
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use.  
 
 
3. EXPIRY DATE 
 
EXP:  
 
 
4. BATCH NUMBER 
 
Batch:  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 
  



 26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Modigraf 1 mg granules for oral suspension 
tacrolimus  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 1 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See package leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
50 sachets containing granules for oral suspension.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
Suspend the granules in water.  
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 
 
 
8. EXPIRY DATE 
 
EXP:  
 
After preparation, the suspension should be administered immediately.  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 27 

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)  
 
 
13. BATCH NUMBER 
 
Batch:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
modigraf 1 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



 28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET FOIL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Modigraf 1 mg granules for oral suspension  
tacrolimus  
oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use.  
 
 
3. EXPIRY DATE 
 
EXP:  
 
 
4. BATCH NUMBER 
 
Batch:  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 
  



 29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 30 

Package leaflet: Information for the user 
 

Modigraf 0.2 mg, granules for oral suspension 
Modigraf 1 mg, granules for oral suspension 

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

section 6).  
-  If you are allergic to sirolimus (another substance used to prevent rejection of your transplanted 

organ) or to any macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Modigraf  
 
-  if you have or have had liver problems.  
-  if you have diarrhoea for more than one day.  
- 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”. 
 



 31 

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 Modigraf.  
 
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 Modigraf.  
 
You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Modigraf. This is 
because immunosuppressants like Modigraf could increase the risk of skin cancer. In case of sun 
exposure, wear appropriate protective clothing and use a sunscreen with a high sun protection factor.  
 
Other medicines and Modigraf 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
It is not recommended that Modigraf is taken with ciclosporin (another medicine used for the 
prevention of transplant organ rejection).  
 
Modigraf blood levels can be affected by other medicines you take, and blood levels of other 
medicines can be affected by taking Modigraf, which may require interruption, an increase or a 
decrease in Modigraf 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)  
-  anti-emetics, used to treat nausea and vomiting (e.g. metoclopramide)  
-  cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn  
-  the contraceptive pill, hormone treatments with ethinylestradiol, or hormone treatments with 

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

diltiazem and verapamil)  
-  anti-arrhythmic medicines (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  
- 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 Modigraf.  
 



 32 

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 Modigraf.  
 
If you need to have any vaccinations, please tell your doctor before.  
 
Modigraf with food and drink 
You should generally take Modigraf on an empty stomach or at least 1 hour before or 2 to 3 hours 
after a meal. Grapefruit and grapefruit juice should be avoided while taking Modigraf, since it can 
affect its levels in the blood.  
 
Pregnancy and breast-feeding 
If you take Modigraf during pregnancy, it may pass into your baby through the placenta. It could 
potentially influence the health of the baby or adversely influence the course of the pregnancy. 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine.  
Modigraf passes into breast milk. Therefore, you should not breast-feed whilst using Modigraf.  
 
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 Modigraf. These effects are more frequent if you also drink alcohol.  
 
Modigraf contains lactose and sodium 
Modigraf 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 sachet, that is to say essentially ‘sodium-
free’. 
 
 
3.  How to take Modigraf 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. Modigraf should be prescribed by doctors trained to treat transplant patients and 
experienced in the use of medicines that control the body’s immune system (immunosuppressants). 
 
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 twice a day. If the physical appearance  has changed from the normal 
white granules, or if dose 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 doses just after transplantation will generally be in 
the range of 0.075 - 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 medicines you 
are taking.  
 
Children and adolescents 
Children and adolescents will receive doses of Modigraf calculated in the same way as adults. In 
general children need higher doses per kg of body weight to achieve the same effective levels in the 
blood as adults. 
 



 33 

Following the initiation of your treatment with Modigraf, frequent blood tests will be taken by your 
doctor to define the correct dose and to adjust the dose from time to time. Your doctor will usually 
reduce your Modigraf dose once your condition has stabilised. Your doctor will tell you exactly how 
many sachets to take. 
 
You will need to take Modigraf every day as long as you need immunosuppression to prevent rejection 
of your transplanted organ. You should keep in regular contact with your doctor.  
 
Modigraf is taken orally twice daily, usually in the morning and evening. Take Modigraf on an empty 
stomach or 2 to 3 hours after a meal. Wait at least 1 hour until the next meal.  
 
How to prepare the Modigraf sachets for use?  
Your doctor will advise you on the number of sachets that you need to open and the volume of water 
that is required to make a suspension. For accurate measuring the volume of water you can use a 
syringe or graduated cylinder.  
 
Pour the prescribed volume of water (at room temperature) into a glass or cup, up to a maximum of 
50 ml. Place the cup with water on a stable surface. Do not use cups or spoons that are made of PVC 
(polyvinylchloride) to take Modigraf because the active substance in Modigraf may stick to PVC.  
Carefully open the prescribed number of sachets, e.g. with a pair of scissors  at the point indicated 
with an arrow. Hold the opened sachet between thumb and index finger above the cup with the open 
side of the sachet facing downwards. Gently tap on the closed end of the sachet and pour the contents 
of each sachet into the glass or cup containing the water. Do not use any utensils or liquids to empty 
the sachet. If you follow these instructions, you will get the right amount of granules from the sachet. 
It is normal that some granules stay behind; the sachet was designed that way.  
Stir, or swirl gently until the granules have been suspended completely. The suspension can be drawn 
up with a syringe or swallowed directly by the patient. The liquid has a sweet taste. Rinse the glass or 
cup once with the same amount of water and drink this, too. The liquid should be drunk immediately 
after preparation.  
 
If you take more Modigraf than you should 
If you have accidentally taken too much Modigraf, contact your doctor or nearest hospital emergency 
department immediately.  
 
If you forget to take Modigraf 
Do not take a double dose to make up for forgotten individual doses.  
If you have forgotten to take your Modigraf, wait until it is time for the next dose, and then continue as 
before. 
 
If you stop taking Modigraf 
Stopping your treatment with Modigraf 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, this medicine can cause side effects, although not everybody gets them.  
 
Modigraf 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 Modigraf.  
 
Severe effects may occur, including allergic and anaphylactic reactions (a very serious type of allergic 
reaction with fainting and difficulty breathing, which needs immediate medical attention). Benign and 
malignant tumours have been reported following Modigraf treatment.  
 



 34 

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  
 
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, changes in the lung tissue, collection of liquid around the lung, 

inflammation of the throat, 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  



 35 

-  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  
-  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) 

 
Children and adolescents 
Children and adolescents may experience the same side effects as adults. 
 
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 Modigraf 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and sachet after EXP. The 
expiry date refers to the last day of that month. 
 
This medicine does not require any special temperature storage conditions.  
 
After preparation, the suspension should be taken immediately.  
 
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 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 36 

What Modigraf contains 
-  The active substance is tacrolimus.  

Each sachet of Modigraf 0.2 mg granules contains 0.2 mg of tacrolimus (as monohydrate).  
Each sachet of Modigraf 1 mg granules contains 1 mg of tacrolimus (as monohydrate).  

-  The other ingredients are: lactose monohydrate, hypromellose (E464) and croscarmellose 
sodium (E468).  

 
What Modigraf looks like and contents of the pack 
Modigraf granules for oral suspension are white granules supplied in sachets. 
Packs containing 50 sachets are available. 
 
Marketing Authorisation Holder 
Astellas Pharma Europe B.V.  
Sylviusweg 62 
2333 BE Leiden 
Netherlands  
 
Manufacturer 
Astellas Ireland Co. Ltd.  
Killorglin  
County Kerry  
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 UAB 
Tel: +370 37 408 681 
 

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 
 

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 OÜ 
Tel: +372 6 056 014 
 

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 
 



 37 

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 02 921381 
 

Suomi/Finland 
Astellas Pharma  
Puh/Tel: + 358 (0)9 85606000 
 

Κύπρος 
Astellas Pharmaceuticals AEBE 
Ελλάδα 
Τηλ: +30 210 8189900 
 

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: 
 
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 REQUIREMENT 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