Tacforius

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Tacforius 0.5 mg prolonged-release hard capsules 
Tacforius 1 mg prolonged-release hard capsules 
Tacforius 3 mg prolonged-release hard capsules 
Tacforius 5 mg prolonged-release hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Tacforius 0.5 mg prolonged-release hard capsules 
Each prolonged-release hard capsule contains 0.5 mg tacrolimus (as monohydrate). 
Excipient with known effect 
Each capsule contains 53.725 mg lactose. 
 
Tacforius 1 mg prolonged-release hard capsules 
Each prolonged-release hard capsule contains 1 mg tacrolimus (as monohydrate). 
Excipient with known effect 
Each capsule contains 107.45 mg lactose. 
 
Tacforius 3 mg prolonged-release hard capsules 
Each prolonged-release hard capsule contains 3 mg tacrolimus (as monohydrate). 
Excipient with known effect 
Each capsule contains 322.35 mg lactose. 
 
Tacforius 5 mg prolonged-release hard capsules 
Each prolonged-release hard capsule contains 5 mg tacrolimus (as monohydrate). 
Excipients with known effect 
Each capsule contains 537.25 mg lactose and 0.0154 mg ponceau 4R. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release hard capsule 
 
Tacforius 0.5 mg prolonged-release hard capsules 
Gelatin capsules imprinted with “TR” on the light yellow capsule cap and “0.5 mg” on the light orange 
capsule body. 
 
Tacforius 1 mg prolonged-release hard capsules 
Gelatin capsules imprinted with “TR” on the white capsule cap and “1 mg” on the light orange capsule 
body. 
 
Tacforius 3 mg prolonged-release hard capsules 
Gelatin capsules imprinted with “TR” on the light orange capsule cap and “3 mg” on the light orange 
capsule body. 
 
Tacforius 5 mg prolonged-release hard capsules 
Gelatin capsules imprinted with “TR” on the greyish red capsule cap and “5 mg” on the light orange 
capsule body. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 



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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 
 
Tacforius is a once-a-day oral formulation of tacrolimus. Tacforius therapy requires careful 
monitoring by adequately qualified and equipped personnel. This medicinal product should only be 
prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in 
immunosuppressive therapy and the management of transplant patients. 
 
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations 
of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of adverse reactions, 
including under- or overimmunosuppression, due to clinically relevant differences in systemic 
exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the 
corresponding daily dosing regimen; alterations in formulation or regimen should only take place 
under the close supervision of a transplant specialist (see 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. Tacforius 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. 
Tacforius 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 the prolonged-release 
capsules on Day 1 was 30% and 50% lower respectively, when compared with that for the immediate 
release capsules 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 
Tacforius to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a 
substance with low clearance, adjustments to the Tacforius dose regimen may take several days before 
steady state is achieved. 
 
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the 
duration of oral therapy can be given. 
 
Prophylaxis of kidney transplant rejection 
 
Tacforius 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. 
 
Tacforius doses are usually reduced in the post-transplant period. It is possible in some cases to 
withdraw concomitant immunosuppressive therapy, leading to Tacforius 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 
 



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Tacforius 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. 
 
Tacforius doses are usually reduced in the post-transplant period. It is possible in some cases to 
withdraw concomitant immunosuppressive therapy, leading to Tacforius monotherapy. Post-transplant 
improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may 
necessitate further dose adjustments. 
 
Conversion of tacrolimus immediate release capsules-treated patients to Tacforius 
 
Allograft transplant patients maintained on twice daily immediate release capsules dosing requiring 
conversion to once daily Tacforius should be converted on a 1:1 (mg:mg) total daily dose basis. 
Tacforius should be administered in the morning. 
 
In stable patients converted from tacrolimus immediate release capsules (twice daily) to tacrolimus 
prolonged-release capsules (once daily) on a 1:1 (mg:mg) total daily dose basis, the systemic exposure 
to tacrolimus (AUC0-24) for tacrolimus prolonged-release capsules was approximately 10% lower than 
that for tacrolimus immediate release capsules. The relationship between tacrolimus trough levels 
(C24) and systemic exposure (AUC0-24) for tacrolimus prolonged-release capsules is similar to that of 
tacrolimus immediate release capsules. When converting from tacrolimus immediate release capsules 
to Tacforius prolonged-release capsules, 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. Tacforius 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 Tacforius may need to be 
reduced. 
 
Treatment of allograft rejection after kidney or liver transplantation 
For conversion from other immunosuppressants to once daily Tacforius, 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 Tacforius, an initial oral dose of 0.15 mg/kg/day should be administered 
once daily in the morning. 
 
Treatment of allograft rejection after transplantation of other allografts 
Although there is no clinical experience with tacrolimus prolonged-release capsules in lung-, 
pancreas- or intestine-transplanted patients, tacrolimus immediate release capsules have been used in 
lung-transplanted patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted 



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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 (AUC0-24) is similar 
between the two formulations of tacrolimus prolonged-release capsules and tacrolimus immediate 
release capsules. 
 
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 
Tacforius, 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 tacrolimus 
immediate release capsules to Tacforius, 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 Tacforius 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. 
 
Elderly 
There is no evidence currently available to indicate that dosing should be adjusted in the elderly. 



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Paediatric population 
The safety and efficacy of Tacforius 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 
 
Tacforius is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of 
Tacforius be administered once daily in the morning. Tacforius 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). 
Tacforius 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 
tacrolimus 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 the active substance, 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). 
 
Tacforius 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 of 
tacrolimus. 
 
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet 
available for the prolonged-release formulation of tacrolimus. 
 
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 tacrolimus 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 substances 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 patients treated with immediate release tacrolimus on rare occasions and may also occur 
with prolonged-release tacrolimus. 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 Tacforius, 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 
Tacforius. 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. 
 



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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 tacrolimus 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 
 
Tacforius 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. 
Tacforius 5 mg capsules contain ponceau 4R. This may cause allergic reactions. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 



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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, 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 



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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 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. Active 
substances 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 reactions 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 Tacforius. 
 



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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 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. 
 
Tabulated 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 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 tacrolimus prolonged-release capsules. 
 
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 
 



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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 
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 



13 

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: veno-occlusive 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). 



14 

 
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 
 
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 prolonged-release capsules 
 
Liver transplantation 
 
The efficacy and safety of tacrolimus prolonged-release capsules and tacrolimus immediate release 
capsules, 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 

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


15 

transplantation was 32.6% in the tacrolimus prolonged-release capsules group (N=237) and 29.3% in 
the tacrolimus immediate release capsules group (N=234). The treatment difference (tacrolimus 
prolonged-release capsules – tacrolimus immediate release capsules) was 3.3% (95% confidence 
interval [-5.7%, 12.3%]).The 12-month patient survival rates were 89.2% for tacrolimus prolonged-
release capsules and 90.8% for tacrolimus immediate release capsules; in the tacrolimus prolonged-
release capsules arm 25 patients died (14 female, 11 male) and in the tacrolimus immediate release 
capsules arm 24 patients died (5 female, 19 male). 12-month graft survival was 85.3% for tacrolimus 
prolonged-release capsules and 85.6% for tacrolimus immediate release capsules. 
 
Kidney transplantation 
 
The efficacy and safety of tacrolimus prolonged-release capsules and tacrolimus immediate release 
capsules, 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 tacrolimus prolonged-release capsules group 
(N=331) and 14.9% in the tacrolimus immediate release capsules group (N=336). The treatment 
difference (tacrolimus prolonged-release capsules - tacrolimus immediate release capsules) was 3.8% 
(95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were 96.9% for 
tacrolimus prolonged-release capsules and 97.5% for tacrolimus immediate release capsules; in the 
tacrolimus prolonged-release capsules arm 10 patients died (3 female, 7 male) and in the tacrolimus 
immediate release capsules arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% 
for tacrolimus prolonged-release capsules and 92.8% for tacrolimus immediate release capsules. 
 
The efficacy and safety of tacrolimus immediate release capsules, ciclosporin and tacrolimus 
prolonged-release capsules, 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 tacrolimus prolonged-release capsules group (N=214), 15.1% in the tacrolimus 
immediate release capsules group (N=212) and 17.0% in the ciclosporin group (N=212). The 
treatment difference was -3.0% (tacrolimus prolonged-release capsules - ciclosporin) (95.2% 
confidence interval [-9.9%, 4.0%]) for tacrolimus prolonged-release capsules vs. ciclosporin and -
1.9% (tacrolimus immediate release capsules - ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) 
for tacrolimus immediate release capsules vs. ciclosporin. The 12 - month patient survival rates were 
98.6% for tacrolimus prolonged-release capsules, 95.7% for tacrolimus immediate release capsules 
and 97.6% for ciclosporin; in the tacrolimus prolonged-release capsules arm 3 patients died (all male), 
in the tacrolimus immediate release capsules 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 tacrolimus 
prolonged-release capsules, 92.9% for tacrolimus immediate release capsules and 95.7% for 
ciclosporin. 
 
Clinical efficacy and safety of tacrolimus immediate release capsules bid in primary organ 
transplantation 
 
In prospective studies oral tacrolimus immediate release 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 
immediate release capsules in these published studies appeared to be similar to what was reported in 
the large studies, where tacrolimus immediate release capsules 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 tacrolimus immediate release capsules 
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 



16 

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 tacrolimus immediate release capsules included 205 patients 
undergoing simultaneous pancreas-kidney transplantation who were randomised to tacrolimus (n = 
103) or to ciclosporin (n = 102). The initial oral per protocol dose of tacrolimus was 0.2 mg/kg/day 
with subsequent dose adjustments to target trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/ml 
after Month 6. Pancreas survival at 1 year was significantly superior with tacrolimus: 91.3% versus 
74.5% with ciclosporin (p < 0.0005), whereas renal graft survival was similar in both groups. In total 
34 patients switched treatment from ciclosporin to tacrolimus, whereas only 6 tacrolimus patients 
required alternative therapy. 
 
Intestinal transplantation 
 
Published clinical experience from a single centre on the use of oral tacrolimus immediate release 
capsules 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. 



17 

Available tacrolimus is generally rapidly absorbed. Tacforius 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 (immediate release capsules 
formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral 
bioavailability of tacrolimus prolonged-release capsules was reduced when it was administered after a 
meal. Both the rate and extent of absorption of tacrolimus prolonged-release capsules were reduced 
when administered with food. 
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Tacforius may 
commence orally. 
 
A strong correlation exists between AUC and whole blood trough levels at steady-state for tacrolimus 
prolonged-release capsules. 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. 
 
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. 



18 

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 tacrolimus prolonged-release capsules 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 
Ethylcellulose 
Hypromellose 2910 
Lactose monohydrate 
Magnesium stearate 
 
Capsule shell 
Tacforius 0.5 mg / 1 mg / 3 mg prolonged-release hard capsules 
Red iron oxide (E172) 
Yellow iron oxide (E172) 
Titanium dioxide (E171) 
Gelatin 
Tacforius 5 mg prolonged-release hard capsules 
Red iron oxide (E172) 
Yellow iron oxide (E172) 
Titanium dioxide (E171) 
Black iron oxide (E172) 
Ponceau 4R (E124) 
Gelatin 
 
Printing ink 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment 
used to prepare a suspension of Tacforius capsule contents must not contain PVC. 
 
6.3 Shelf life 
 
Tacforius 0.5 mg / 1 mg prolonged-release hard capsules 
2 years 
 
Tacforius 3 mg / 5 mg prolonged-release hard capsules 
30 months 
 
After opening the aluminium wrapper: 1 year 
 
6.4 Special precautions for storage 



19 

 
Store in the original package in order to protect from light and moisture. 
This medicinal product does not require any special temperature storage conditions. 
 
6.5 Nature and contents of container 
 
Transparent PVC/PVDC aluminium blister or perforated unit-dose blister wrapped in an aluminium 
pouch with a desiccant containing 10 capsules per blister. 
 
Tacforius 0.5 mg / 3 mg / 5 mg prolonged-release hard capsules 
Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30x1, 50x1 and 100x1 
prolonged-release hard capsules in perforated unit-dose blisters. 
 
Tacforius 1 mg prolonged-release hard capsules 
Pack sizes: 30, 50, 60 and 100 prolonged-release hard capsules in blisters or 30x1, 50x1, 60x1 and 
100x1 prolonged-release hard capsules in perforated unit-dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Tacforius 0.5 mg prolonged-release hard capsules 
EU/1/17/1244/001 
EU/1/17/1244/002 
EU/1/17/1244/003 
EU/1/17/1244/004 
EU/1/17/1244/005 
EU/1/17/1244/006 
 
Tacforius 1 mg prolonged-release hard capsules 
EU/1/17/1244/007 
EU/1/17/1244/008 
EU/1/17/1244/009 
EU/1/17/1244/010 
EU/1/17/1244/011 
EU/1/17/1244/012 
EU/1/17/1244/013 
EU/1/17/1244/014 
 
Tacforius 3 mg prolonged-release hard capsules 
EU/1/17/1244/015 
EU/1/17/1244/016 
EU/1/17/1244/017 



20 

EU/1/17/1244/018 
EU/1/17/1244/019 
EU/1/17/1244/020 
 
Tacforius 5 mg prolonged-release hard capsules 
EU/1/17/1244/021 
EU/1/17/1244/022 
EU/1/17/1244/023 
EU/1/17/1244/024 
EU/1/17/1244/025 
EU/1/17/1244/026 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 8 December 2017 
 
 
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/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS 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 

 



22 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Merckle GmbH 
Ludwig-Merckle-Strasse 3 
89143 Blaubeuren 
Germany 
 
PLIVA Hrvatska d.o.o. 
Prilaz baruna Filipovica 25 
10 000 Zagreb 
Croatia 
 
TEVA Czech Industries s.r.o. 
Ostravská 29, č.p. 305 
Opava - Komárov 
747 70 
Czech Republic 
 
Teva Operations Poland Sp. z o.o. 
ul. Mogilska 80 
31-546 Krakow 
Poland 
 
Teva Pharma S.L.U. 
C/C, n. 4, Poligono Industrial Malpica 
ES-50016 Zaragoza 
Spain 
 
Teva Pharmaceutical Works Private Limited Company 
Pallagi Ut 13 
4042 Debrecen 
Hungary 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
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 (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



23 

 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required 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. 

 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tacforius 0.5 mg prolonged-release hard capsules 
Tacforius 1 mg prolonged-release hard capsules 
Tacforius 3 mg prolonged-release hard capsules 
Tacforius 5 mg prolonged-release hard capsules 
tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 0.5 mg tacrolimus (as monohydrate). 
Each capsule contains 1 mg tacrolimus (as monohydrate). 
Each capsule contains 3 mg tacrolimus (as monohydrate). 
Each capsule contains 5 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
0.5 mg, 1 mg, 3 mg 
Contains lactose. See package leaflet for further information. 
 
5 mg 
Contains lactose and ponceau 4R. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release hard capsules 
30x1 prolonged-release hard capsules 
50 prolonged-release hard capsules 
50x1 prolonged-release hard capsules 
60 prolonged-release hard capsules 
60x1 prolonged-release hard capsules 
100 prolonged-release hard capsules 
100x1 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. 
 



27 

 
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. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light and 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 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1244/001 30 capsules 
EU/1/17/1244/002 30x1 capsules 
EU/1/17/1244/003 50 capsules 
EU/1/17/1244/004 50x1 capsules 
EU/1/17/1244/005 100 capsules 
EU/1/17/1244/006 100x1 capsules 
EU/1/17/1244/007 30 capsules 
EU/1/17/1244/008 30x1 capsules 
EU/1/17/1244/009 50 capsules 
EU/1/17/1244/010 50x1 capsules 
EU/1/17/1244/011 60 capsules 
EU/1/17/1244/012 60x1 capsules 
EU/1/17/1244/013 100 capsules 
EU/1/17/1244/014 100x1 capsules 
EU/1/17/1244/015 30 capsules 
EU/1/17/1244/016 30x1 capsules 
EU/1/17/1244/017 50 capsules 
EU/1/17/1244/018 50x1 capsules 
EU/1/17/1244/019 100 capsules 
EU/1/17/1244/020 100x1 capsules 
EU/1/17/1244/021 30 capsules 
EU/1/17/1244/022 30x1 capsules 
EU/1/17/1244/023 50 capsules 
EU/1/17/1244/024 50x1 capsules 



28 

EU/1/17/1244/025 100 capsules 
EU/1/17/1244/026 100x1 capsules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tacforius 0.5 mg 
Tacforius 1 mg 
Tacforius 3 mg 
Tacforius 5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tacforius 0.5 mg prolonged-release capsules 
Tacforius 1 mg prolonged-release capsules 
Tacforius 3 mg prolonged-release capsules 
Tacforius 5 mg prolonged-release capsules 
tacrolimus 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Once daily. 
 
  



30 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ALUMINIUM POUCH 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tacforius 0.5 mg prolonged-release capsules 
Tacforius 1 mg prolonged-release capsules 
Tacforius 3 mg prolonged-release capsules 
Tacforius 5 mg prolonged-release capsules 
tacrolimus 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date. 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Once daily. 
 
 
  



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



32 

Package leaflet: Information for the patient 
 

Tacforius 0.5 mg prolonged-release hard capsules 
Tacforius 1 mg prolonged-release hard capsules 
Tacforius 3 mg prolonged-release hard capsules 
Tacforius 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 Tacforius is and what it is used for 
2. What you need to know before you take Tacforius 
3. How to take Tacforius 
4. Possible side effects 
5. How to store Tacforius 
6. Contents of the pack and other information 
 
 
1. What Tacforius is and what it is used for 
 
Tacforius 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. Tacforius is 
used to control your body’s immune response, enabling your body to accept the transplanted organ. 
 
You may also be given Tacforius 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. 
 
Tacforius is used in adults. 
 
 
2. What you need to know before you take Tacforius 
 
Do not take Tacforius 
- 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 or to any macrolide-antibiotic (e.g. erythromycin, clarithromycin, 

josamycin). 
 
Warnings and precautions 
Tacrolimus immediate release capsules (e.g, Tacni) and Tacforius prolonged-release capsules both 
contain the active substance, tacrolimus. However, Tacforius prolonged-release capsules are taken 
once daily, whereas the immediate release capsules are taken twice daily. This is because Tacforius 
capsules allow for a prolonged-release (more slow release over a longer period) of tacrolimus. 
Tacforius prolonged-release capsules and tacrolimus immediate release capsules are not 
interchangeable. 
 



33 

Tell your doctor if any of the following apply to you: 
- if you are taking any medicines mentioned below under “Other medicines and Tacforius”. 
- 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”. 
 
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 Tacforius. 
 
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 Tacforius. 
 
You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Tacforius. 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 Tacforius is not recommended in children and adolescents under 18 years. 
 
Other medicines and Tacforius 
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other 
medicines. 
 
It is not recommended that Tacforius is taken with ciclosporin (another medicine used for the 
prevention of transplant organ rejection). 
 
Tacforius blood levels can be affected by other medicines you take, and blood levels of other 
medicines can be affected by taking Tacforius, which may require interruption, an increase or a 
decrease in Tacforius 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 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 



34 

- 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 Tacforius. 
 
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 medicines (NSAIDs, e.g. ibuprofen) used for fever, inflammation and 
pain, anticoagulants (blood thinners), or oral medicines for diabetes, while you take Tacforius. 
 
If you need to have any vaccinations, please tell your doctor before. 
 
Tacforius with food and drink 
Avoid grapefruit (also as juice) while on treatment with Tacforius, since it can affect its levels in the 
blood. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. 
Tacrolimus passes into breast milk. Therefore, you should not breast-feed whilst using Tacforius. 
 
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 Tacforius. These effects are more frequent if you also drink alcohol. 
 
Tacforius contains lactose 
Tacforius 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. 
 
Tacforius 5 mg capsules contains ponceau 4R 
Tacforius 5 mg capsules contain ponceau 4R. This may cause allergic reactions. 
 
 
3. How to take Tacforius 
 
Always take this medicine 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 



35 

 
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 Tacforius, 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 
Tacforius dose once your condition has stabilised. Your doctor will tell you exactly how many 
capsules to take. 
 
You will need to take Tacforius every day as long as you need immunosuppression to prevent 
rejection of your transplanted organ. You should keep in regular contact with your doctor. 
 
Tacforius is taken orally once daily in the morning. Take Tacforius 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 pouch. 
 
If you take more Tacforius than you should 
If you have accidentally taken too many capsules, contact your doctor or nearest hospital emergency 
department immediately. 
 
If you forget to take Tacforius 
If you have forgotten to take your 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 Tacforius 
Stopping your treatment with Tacforius 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. 
 
Tacforius 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 Tacforius. 
 
Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant 
tumours have been reported following Tacforius 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 



36 

- 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, 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 



37 

- 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) 
 
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 Tacforius 
 
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 blister after “EXP”. 
The expiry date refers to the last day of that month. 
 
Store in the original package in order to protect from light and moisture. 
This medicinal product does not require any special temperature storage conditions. 
 
Use all the prolonged-release hard capsules within 1 year of opening the aluminium wrapping. 
 
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 Tacforius contains 
 
- The active substance is tacrolimus. 

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

- The other ingredients are: 
Capsule content 
Hypromellose 2910, ethylcellulose, lactose, magnesium stearate. 
Capsule shell 
Tacforius 0.5 mg / 1 mg / 3 mg prolonged-release hard capsules: red iron oxide (E172), yellow 
iron oxide (E172), titanium dioxide (E171), gelatin. 

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


38 

Tacforius 5 mg prolonged-release hard capsules: red iron oxide (E172), yellow iron oxide 
(E172), titanium dioxide (E171), black iron oxide (E172), ponceau 4R (E124), gelatin. 
Printing Ink 
Shellac, propylene glycol, black iron oxide (E172), potassium hydroxide. 
 

What Tacforius looks like and contents of the pack 
 
Tacforius 0.5 mg prolonged-release hard capsules 
Hard gelatin capsules imprinted with “TR” on the light yellow capsule cap and “0.5 mg” on the light 
orange capsule body. 
Tacforius 1 mg prolonged-release hard capsules 
Hard gelatin capsules imprinted with “TR” on the white capsule cap and “1 mg” on the light orange 
capsule body. 
Tacforius 3 mg prolonged-release hard capsules 
Hard gelatin capsules imprinted with “TR” on the light orange capsule cap and “3 mg” on the light 
orange capsule body. 
Tacforius 5 mg prolonged-release hard capsules 
Hard gelatin capsules imprinted with “TR” on the greyish red capsule cap and “5 mg” on the light 
orange capsule body. 
 
Tacforius 0.5 mg / 3 mg / 5 mg prolonged-release hard capsules 
Supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil 
pouch, including a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules are available in 
blisters and packs of 30x1, 50x1 and 100x1 prolonged-release capsules are available in perforated 
unit-dose blisters. 
 
Tacforius 1 mg prolonged-release hard capsules 
Supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil 
pouch, including a desiccant. Packs of 30, 50, 60 and 100 prolonged-release capsules are available in 
blisters and packs of 30x1, 50x1, 60x1 and 100x1 prolonged-release capsules are available in 
perforated unit-dose blisters. 
 
Marketing Authorisation Holder 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands 
 
Manufacturer 
 
Merckle GmbH 
Ludwig-Merckle-Strasse 3 
89143 Blaubeuren 
Germany 
 
PLIVA Hrvatska d.o.o. 
Prilaz baruna Filipovica 25 
10 000 Zagreb 
Croatia 
 
TEVA Czech Industries s.r.o. 
Ostravská 29, č.p. 305 
Opava - Komárov 
747 70 
Czech Republic 
 
Teva Operations Poland Sp. z o.o. 



39 

ul. Mogilska 80 
31-546 Krakow 
Poland 
 
Teva Pharma S.L.U. 
C/C, n. 4, Poligono Industrial Malpica 
ES-50016 Zaragoza 
Spain 
 
Teva Pharmaceutical Works Private Limited Company 
Pallagi Ut 13 
4042 Debrecen 
Hungary 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Teva Pharma Belgium N.V./S.A./AG 
Tél/Tel: +32 38207373 
 

Lietuva 
UAB Teva Baltics 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Тел: +359 24899585 
 

Luxembourg/Luxemburg 
ratiopharm GmbH 
Allemagne/Deutschland 
Tél/Tel: +49 73140202 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Teva Pharmaceuticals Ireland 
L-Irlanda 
Tel: +353 19630330 
 

Deutschland 
TEVA GmbH 
Tel: +49 73140208 
 

Nederland 
Teva Nederland B.V. 
Tel: +31 8000228400 
 

Eesti 
UAB Teva Baltics Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 2118805000 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Teva Pharma, S.L.U. 
Tel: + 34 913873280 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 
 

France 
Teva Santé 
Tél: +33 155917800 
 

Portugal 
Teva Pharma - Produtos Farmacêuticos, Lda. 
Tel: +351 214767550 
 

Hrvatska 
Pliva Hrvatska d.o.o. 

România 
Teva Pharmaceuticals S.R.L 



40 

Tel: + 385 13720000 
 

Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Pharmaceuticals Iceland ehf. 
Sími: +354 5503300 

Slovenská republika 
Teva Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Teva Italia S.r.l. 
Tel: +39 028917981 
 

Suomi/Finland 
Teva Finland Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Teva Ελλάς Α.Ε. 
Ελλάδα 
Τηλ: +30 2118805000 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Teva Baltics filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1977628500 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS 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