Envarsus

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Envarsus 0.75 mg prolonged-release tablets 
Envarsus 1 mg prolonged-release tablets 
Envarsus 4 mg prolonged-release tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Envarsus 0.75 mg prolonged-release tablets 
 
Each prolonged-release tablet contains 0.75 mg tacrolimus (as monohydrate). 
 
Excipient with known effect:  
Each tablet contains 41.7 mg lactose monohydrate. 
 
Envarsus 1 mg prolonged-release tablets 
 
Each prolonged-release tablet contains 1 mg tacrolimus (as monohydrate). 
 
Excipient with known effect:  
Each tablet contains 41.7 mg lactose monohydrate. 
 
Envarsus 4 mg prolonged-release tablets 
 
Each prolonged-release tablet contains 4 mg tacrolimus (as monohydrate). 
 
Excipient with known effect:  
Each tablet contains 104 mg lactose monohydrate.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release tablet. 
 
Envarsus 0.75 mg prolonged-release tablets 
 
Oval, white to off-white uncoated tablet, debossed with “0.75” on one side and “TCS” on the other 
side. 
 
Envarsus 1 mg prolonged-release tablets 
 
Oval, white to off-white uncoated tablet, debossed with “1” on one side and “TCS” on the other side. 
 
Envarsus 4 mg prolonged-release tablets 
 
Oval, white to off-white uncoated tablet, debossed with “4” on one side and “TCS” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Prophylaxis of transplant rejection in adult kidney or liver allograft recipients. 
 



3 

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal 
products in adult patients. 
 
4.2 Posology and method of administration 
 
Envarsus is a once-a-day oral formulation of tacrolimus. Tacrolimus therapy requires careful 
monitoring by adequately qualified and equipped personnel. This medicinal product should only be 
prescribed, and changes in immunosuppressive therapy be 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. Tacrolimus 
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.  
 
Envarsus 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. 
 
As tacrolimus is a substance with low clearance, adjustments to the 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. 
 
Envarsus doses are usually reduced in the post-transplant period. Post-transplant changes in the 
condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose 
adjustments. 
 
Missed dose 
A forgotten dose should be taken as soon as possible on the same day. A double dose should not be 
taken on the next day. 
 
Prophylaxis of kidney transplant rejection 
Envarsus therapy should commence at a dose of 0.17 mg/kg/day administered once daily in the 
morning. Administration should commence within 24 hours after the completion of surgery. 
 
Prophylaxis of liver transplant rejection 
Envarsus therapy should commence at a dose of 0.11–0.13 mg/kg/day administered once daily in the 
morning. Administration should commence within 24 hours after the completion of surgery.  
 
Conversion of Prograf- or Advagraf-treated patients to Envarsus - allograft transplant patients 
Envarsus is not interchangeable with other existing tacrolimus containing medicinal products 
(immediate-release or prolonged-release) on an equal dose by dose basis. 
Allograft transplant patients maintained on twice daily Prograf (immediate-release) or Advagraf (once 
daily) dosing requiring conversion to once daily Envarsus should be converted on a 1:0.7 (mg:mg) 



4 

total daily dose basis and the Envarsus maintenance dose should, therefore, be 30% less than the 
Prograf or Advagraf dose.  
 
In stable patients converted from tacrolimus immediate-release products (twice daily) to Envarsus 
(once daily) on a 1:0.7 (mg:mg) total daily dose basis, the mean systemic exposure to tacrolimus 
(AUC0-24) was similar to that of immediate-release tacrolimus. The relationship between tacrolimus 
trough levels (C24) and systemic exposure (AUC0-24) for Envarsus is similar to that of 
immediate-release tacrolimus. No studies have been conducted with conversion of patients from 
Advagraf to Envarsus; however, data from healthy volunteers would suggest that the same conversion 
rate is applicable as with the conversion from Prograf to Envarsus. 
 
When converting from tacrolimus immediate-release products (e.g. Prograf capsules) or from 
Advagraf prolonged-release capsules to Envarsus, trough levels should be measured prior to 
conversion and within two weeks after conversion. Dose adjustments should be made to ensure that 
similar systemic exposure is maintained after the switch. It should be noted that black patients may 
require a higher dose to achieve the targeted trough levels.  
 
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 to 
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 Envarsus may need to be 
reduced. 
 
Treatment of allograft rejection after kidney or liver transplantation 
For conversion from other immunosuppressants to once daily tacrolimus, treatment should begin with 
the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of 
transplant rejection. 
 
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 and systemic exposure (AUC0-24) is well correlated 
and is similar between the immediate-release formulation and Envarsus. 
 
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 
Envarsus, just prior to the next dose. Blood trough levels of tacrolimus should also be closely 
monitored following conversion from tacrolimus products, 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 Envarsus 
dose regimen it may take several days before the targeted steady state is achieved. 



5 

 
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 of 5-20 ng/mL in kidney transplant patients in the early 
post-transplant period, and 5-15 ng/mL during subsequent maintenance therapy. 
 
Special populations 
 
Elderly patients (> 65 years) 
There is no evidence currently available to indicate that dose should be adjusted in elderly patients. 
 
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. In clinical studies patients converted from twice daily Prograf were converted to 
Envarsus at 1:0.85 (mg:mg). 
 
Gender 
There is no evidence that male and female patients require different doses to achieve similar trough 
levels. 
 
Paediatric population 
The safety and efficacy of Envarsus in children below 18 years of age have not yet been established.  
No data are available. 
 
Method of administration 
 
Envarsus is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of 
Envarsus is administered once daily in the morning.  
The tablets should be swallowed whole with fluid (preferably water) immediately following removal 
from the blister. Envarsus should generally be taken on an empty stomach to achieve maximal 
absorption (see section 5.2).  
Patients should be advised not to swallow the desiccant. 
 
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 with tacrolimus. 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 



6 

regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 
and 4.8). 
 
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal 
products in adult patients clinical studies are not yet available for the prolonged-release formulation 
Envarsus.  
 
For prophylaxis of transplant rejection in adult heart, lung, pancreas, or intestine allograft recipients 
clinical data are not yet available for Envarsus. 
 
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 or 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) should be avoided when 
taking tacrolimus due to the risk of interactions that lead to a decrease in both blood concentrations 
and the therapeutic effect of tacrolimus (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.  
 
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. 
 



7 

Cardiac disorders 
 
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been 
observed in tacrolimus treated patients 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, 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 tacrolimus or 
change of treatment to another immunosuppressive agent should be considered. Tacrolimus may 
prolong the QT interval but at this time lacks substantial evidence for causing Torsades de Pointes. 
Caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome. 
 
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 
Envarsus. During treatment, careful monitoring with EBV-PCR (Polymerase-Chain-Reaction) 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. 
 
Infection including opportunistic infections 
 
Patients treated with immunosuppressants, including Envarsus, 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 (e.g. 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. 
 



8 

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 medicinal product 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 
 
Envarsus contains lactose. Patients with rare hereditary problems of galactose intolerance, total 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 renal function and 
other undesirable 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). 
 
Effect of other medicinal products on the metabolism of tacrolimus 
 
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), Hepatitis C Virus (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 and nefazodone. 
 
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 and (triacetyl)oleandomycin. 
Grapefruit juice has been reported to increase the blood level of tacrolimus and should, therefore, be 
avoided. 
Lansoprazol and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and, 
thereby, increase tacrolimus whole blood concentrations. 
 



9 

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: 
Interactions have been observed with rifampicin, phenytoin, and 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. 
 
Impact of DAA therapy  
The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA 
therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of 
tacrolimus is warranted to ensure continued efficacy. 
 
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 antipyrine.  
 
Mycophenolic acid 
Caution should be exercised when switching combination therapy from ciclosporin, which interferes 
with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as 
this might result in changes of mycophenolic acid exposure. Drugs which interfere with mycophenolic 
acid's enterohepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. 
Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from 
ciclosporin to tacrolimus or vice versa. 
 
Other interactions leading to clinically detrimental effects 
 
Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic 
effects may increase these effects (e.g. aminoglycosides, gyrase inhibitors, vancomycin, 
cotrimoxazole, NSAIDs, ganciclovir, or aciclovir). 
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and 
ibuprofen in conjunction with tacrolimus. 



10 

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). 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
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 events 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 potential adverse events of tacrolimus is 
recommended (in particular, effects on the kidneys). There is a risk for premature delivery (<37 week) 
(incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the newborns had 
normal birth weight for their gestational age) as well as for hyperkalaemia in the newborn (incidence 8 
of 111 neonates, i.e. 7.2 %) which, however normalises spontaneously. In rats and rabbits, tacrolimus 
caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3). 
 
Breast-feeding 
 
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the 
newborn cannot be excluded, women should not breast-feed whilst receiving Envarsus. 
 
Fertility 
 
A negative effect of tacrolimus on male fertility in the form of reduced sperm count and motility was 
observed in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Envarsus may have a minor influence on the ability to drive and use machines. Tacrolimus may cause 
visual and neurological disturbances. This effect may be enhanced if Envarsus is administered in 
association with alcohol. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most commonly reported adverse reactions for tacrolimus (occurring in >10% of patients) are 
tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, 
hypertension and insomnia. 
 



11 

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 
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. 
 
Neoplasms benign, malignant and unspecified (incl. 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. 
 
Immune system disorders 
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see 
section 4.4). 
 
System Organ 
Class 

Frequency of adverse reactions 
 

 Very 
common 
 

Common 
 

Uncommon 
 

Rare 
 

Very rare 
 

Not known 
 

Blood and 
lymphatic system 
disorders 

 anaemia, 
thrombocyto-penia, 
leukopenia, red 
blood cell analyses 
abnormal, 
leukocytosis 

coagulo-pathies, 
pancytopenia, 
neutropenia, 
coagulation and 
bleeding 
analyses, 
abnormal 

thrombotic 
thrombo-
cytopenic 
purpura, 
hypopro-
thrombin-
aemia, 
thrombotic 
microangio-
pathy 

 pure red cell 
aplasia, 
agranulo-
cytosis, 
haemolytic 
anaemia 

Endocrine 
disorders 

   hirsutism   

Metabolism and 
nutrition disorders 

diabetes 
mellitus, 
hyper-
glycaemic 
conditions, 
hyper-
kalaemia 

anorexia, metabolic 
acidoses, other 
electrolyte ab-
normalities, 
hyponatraemia, 
fluid overload, 
hyperuricaemia, 
hypomagnes-
aemia, hypo-
kalaemia, 
hypocalcemia, 
appetite decreased, 
hypercholest-
erolaemia, 
hyperlipidaemia, 
hypertriglycerid-
aemia, hypophos-
phateaemia 

dehydration, 
hypo-glycaemia, 
hypoprotein-
aemia, 
hyperphos-
phataemia 

   



12 

System Organ 
Class 

Frequency of adverse reactions 
 

 Very 
common 
 

Common 
 

Uncommon 
 

Rare 
 

Very rare 
 

Not known 
 

Psychiatric 
disorders 

insomnia confusion and dis-
orientation, 
depression, anxiety 
symptoms, 
hallucination, 
mental disorders, 
depressed mood, 
mood disorders and 
disturbances, 
nightmare 

psychotic 
disorder 

   

Nervous system 
disorders 

headache, 
tremor 

nervous system 
disorders seizures, 
disturbances in 
consciousness, 
peripheral 
neuropathies, 
dizziness, 
paraesthesias and 
dysaesthesias, 
writing impaired 

encephalo-
pathy, central 
nervous system 
haemorrhages 
and cerebrovas-
cular accidents, 
coma, speech 
and language 
ab-normalities, 
paralysis and 
paresis, amnesia 

hypertonia myasthenia  

Eye disorders  eye disorders, 
vision blurred, 
photophobia 

cataract blindness  optic 
neuropathy 

Ear and labyrinth 
disorders 

 tinnitus hypoacusis deafness 
neurosensory 

hearing 
impaired 

 

Cardiac disorders  ischaemic coronary 
artery disorders, 
tachycardia 

heart failures, 
ventricular 
arrhythmias and 
cardiac arrest, 
supraventricular 
arrhythmias, 
cardiomyo-
pathies, 
ventricular 
hypertrophy, 
palpitations 

pericardial 
effusion 

  

Vascular disorders hypertension thromboembolic 
and ischaemic 
events, vascular 
hypotensive 
disorders, 
haemorrhage, 
peripheral vascular 
disorders 

venous 
thrombosis deep 
limb, shock, 
infarction 

   

Respiratory, 
thoracic and 
mediastinal 
disorders 

 parenchymal lung 
disorders, 
dyspnoea, pleural 
effusion, cough, 
pharyngitis, nasal 
congestion and 
inflammations 

respiratory 
failures, 
respiratory tract 
disorders, 
asthma 

acute 
respiratory 
distress 
syndrome 

  



13 

System Organ 
Class 

Frequency of adverse reactions 
 

 Very 
common 
 

Common 
 

Uncommon 
 

Rare 
 

Very rare 
 

Not known 
 

Gastrointestinal 
disorders 

diarrhoea, 
nausea 

gastrointestinal 
signs and 
symptoms, 
vomiting, gastro-
intestinal and 
abdominal pains, 
gastrointestinal 
inflammatory 
conditions, gastro-
intestinal haem-
orrhages, 
gastrointestinal 
ulceration and 
perforation, ascites, 
stomatitis and 
ulceration, 
constipation, 
dyspeptic signs and 
symptoms, 
flatulence, bloating 
and distension, 
loose stools 

acute and 
chronic 
pancreatitis, 
peritonitis, ileus 
paralytic, 
gastrooeso-
phageal reflux 
disease, 
impaired gastric 
emptying 

pancreatic 
pseudocyst, 
subileus 

  

Hepatobiliary 
disorders 

 bile duct disorders, 
hepatocellular 
damage and 
hepatitis, 
cholestasis and 
jaundice 

 veno-
occlusive liver 
disease, 
hepatic artery 
thrombosis 

hepatic 
failure 

 

Skin and 
subcutaneous 
tissue disorders 

 rash, pruritus, 
alopecias, acne, 
sweating increased 

dermatitis, 
photo-sensitivity 

toxic 
epidermal 
necrolysis 
(Lyell’s 
syndrome) 

Stevens 
Johnson 
syndrome 

 

Musculoskeletal 
and connective 
tissue disorders 

 arthralgia, back 
pain, muscle 
cramps, pain in 
limb 

joint disorders mobility 
decreased 

  

Renal and urinary 
disorders 

renal 
impairment 

renal failure, renal 
failure acute, 
nephropathy toxic, 
renal tubular 
necrosis, urinary 
abnormalities, 
oliguria, bladder 
and urethral 
symptoms 

haemolytic 
uraemic 
syndrome, 
anuria 

 nephropathy, 
cystitis 
haem-
orrhagic 

 

Reproductive 
system and breast 
disorders 

  dysmenorrhoea 
and uterine 
bleeding 

   



14 

System Organ 
Class 

Frequency of adverse reactions 
 

 Very 
common 
 

Common 
 

Uncommon 
 

Rare 
 

Very rare 
 

Not known 
 

General disorders 
and administration 
site conditions 

 febrile disorders, 
pain and 
discomfort, 
asthenic conditions, 
oedema, body 
temperature 
perception 
disturbed 

influenza like 
illness, feeling 
jittery, feeling 
abnormal, multi-
organ failure, 
chest pressure 
sensation, 
temperature 
intolerance 

fall, ulcer, 
chest 
tightness, 
thirst 

fat tissue 
increased 

febrile 
neutropenia 

Investigations liver function 
tests 
abnormal 

blood alkaline 
phosphatase 
increased, weight 
increased 

amylase 
increased, ECG 
abnormal, heart 
rate and pulse 
investigations 
abnormal, 
weight 
decreased, blood 
lactate 
dehydrogenase 
increased 
 

 echo-
cardiogram 
abnormal,  

 

Injury, poisoning 
and procedural 
complications 

 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.  
 
In clinical studies in kidney transplant patients receiving Envarsus, the most frequent adverse reactions 
(at least in 2% of patients) were tremor, diabetes mellitus, blood creatinine increased, urinary tract 
infection, hypertension, BK virus infection, renal impairment, diarrhoea, toxicity to various agents, 
and toxic nephropathy all of which are known to occur in the respective patient population under 
immunosuppressive treatment. In all, there appears to be no significant difference in the pattern of 
adverse events suspected to be causally related to study drug between once daily Envarsus and 
tacrolimus immediate-release capsules (Prograf). 
Among the most frequent adverse reactions (at least in 2% of patients) in clinical studies in liver 
transplant patients receiving Envarsus were tremor, headache, fatigue, hyperkalaemia, hypertension, 
renal failure, blood creatinine increased, dizziness, hepatitis C, muscle spasms, tinea infection, 
leukopenia, sinusitis, and upper respiratory tract infections (URTI), all of which are known to occur in 
the respective patient population under immunosuppressive treatment. As in kidney transplant 
recipients, there appears to be no meaningful difference in the pattern of suspected adverse drug 
reactions between once daily Envarsus and tacrolimus immediate-release capsules (Prograf). 
 
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. 
 

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


15 

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. 
It should be noted however, that there has been no direct experience with Envarsus in overdose. 
 
 
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. 
 
Pharmacodynamic effects 
 
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. 
 
Clinical efficacy and safety 
 
Results from clinical studies performed with once-daily tacrolimus 
 
Kidney transplantation 
The efficacy and safety of Envarsus and Prograf, both in combination with mycophenolate mofetil 
(MMF), corticosteroids and IL-2 receptor antagonist as per the standard of care were compared in a 
randomised, double-blind, double-dummy study, in 543 de novo kidney transplant recipients.  
The percentage of patients with one or greater than one episode of clinically-suspected and treated 
rejections during the 360-day study was 13.8% for the Envarsus group (N=268) and 15.6% for the 
Prograf group (N=275). The event rate for centrally read, biopsy-confirmed acute rejection (BPAR) 
during the 360-day study was 13.1% in the Envarsus group (N=268) and 13.5% in the Prograf group 
(N=275). The efficacy failure rate as measured by the composite endpoint of death, graft loss, 
centrally read BPAR and loss to follow-up was 18.3% in the Envarsus group and 19.6% in the Prograf 
group. The treatment difference (Envarsus-Prograf) was -1.35% (95% confidence interval [-7.94%, 
5.27%]). Treatment-emergent fatal adverse events occurred in 1.8% of Envarsus patients and 2.5% of 
Prograf patients. 
 



16 

The efficacy and safety of Envarsus and Prograf, both in combination with mycophenolate mofetil 
(MMF) or mycophenolate sodium (MPS) and corticosteroids, were compared in 324 stable kidney 
transplant recipients. The event rate for locally read BPAR during the 360-day study was 1.2% in the 
Envarsus group (N=162) post conversion from Prograf at a dose ratio of 1:0.7 (mg:mg) and 1.2% in 
the group maintained on Prograf (N=162). The efficacy failure rate as measured by the composite 
endpoint of death, graft loss, locally read BPAR and loss to follow-up was 2.5% in both the Envarsus 
and Prograf groups. The treatment difference (Envarsus-Prograf) was 0% (95% confidence interval [-
4.21%, 4.21%]). The treatment failure rate using the same composite end-point with centrally read 
BPAR was 1.9% in the Envarsus group and 3.7% in the Prograf group (95% confidence interval [-
6.51%, 2.31%]). Treatment emergent fatal adverse events occurred in 1.2% of Envarsus patients and 
0.6% of Prograf patients. 
 
Liver transplantation 
The pharmacokinetics, efficacy and safety of Envarsus and tacrolimus immediate-release capsules, 
both in combination with corticosteroids were compared in 117 liver transplant recipients, of whom 
88 received treatment with Envarsus. In the de novo liver transplant study, 29 subjects were treated 
with Envarsus. The event rate of biopsy-confirmed acute rejection within the 360-day study period 
was not significantly different between the Envarsus group and the tacrolimus immediate-release 
group. The overall incidence of fatal treatment emergent adverse events for the combined de novo and 
stable liver transplant population was not significantly different between the Envarsus group and the 
tacrolimus immediate-release group.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
The oral bioavailability of Envarsus was decreased when the medicinal product was administered after 
a meal; the extent of absorption was decreased by 55% and the maximum plasma concentration was 
decreased by 22% when taken directly after a high-fat meal. Therefore, Envarsus should generally be 
taken on an empty stomach to achieve maximal absorption. 
 
In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. 
Available tacrolimus is generally rapidly absorbed. Envarsus 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 6 hours (tmax) at steady state.  
 
Absorption is variable and the mean oral bioavailability of tacrolimus is in the range of 20%-25% 
(individual range in adult patients 6%-43%). The oral bioavailability is approximately 40% higher for 
Envarsus as compared to the same dose of tacrolimus immediate-release formulation (Prograf) in 
kidney transplant patients.  
 
Higher Cavg (~50%), reduced peak trough fluctuation (Cmax/Cmin) and a longer Tmax were seen for 
Envarsus when compared with both, tacrolimus immediate-release formulation (Prograf) and a 
tacrolimus once daily formulation (Advagraf). Mean values for Cmax, percentage degree of fluctuation 
and percentage degree of swing were significantly lower with administration of Envarsus tablets. 
 
A strong correlation exists between AUC and whole blood trough levels at steady-state for Envarsus. 
Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure. 
 
In vitro test results indicate that there is no risk of in vivo dose dumping related to alcohol intake.  
 
Distribution 
 
In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic. 
 



17 

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 1,300 L (healthy subjects). Corresponding data based on 
whole blood averaged 47.6 L. 
 
Biotransformation 
 
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.  
 
Elimination 
 
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 30 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. 
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 count and motility was 
observed in rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Hypromellose 
Lactose monohydrate 
Macrogol 6000 
Poloxamer 188 
Magnesium stearate 
Tartaric acid (E334) 
Butylated hydroxytoluene (E321) 
Dimethicone 350 
 



18 

6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
30 months. 
 
After opening the aluminium foil wrapper: 45 days.  
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
Store in the original aluminium foil wrapper in order to protect from light. 
 
6.5 Nature and contents of container 
 
PVC/alu blisters containing 10 prolonged-release tablets. 3 blisters are packed together in an 
aluminium foil wrapper containing a desiccant. 
 
Pack sizes of 30, 60 and 90 prolonged-release tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Chiesi Farmaceutici S.p.A. 
Via Palermo, 26/A 
43122 Parma 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Envarsus 0.75 mg prolonged-release tablets 
 
EU/1/14/935/001 
EU/1/14/935/002 
EU/1/14/935/003 
 
Envarsus 1 mg prolonged-release tablets 
 
EU/1/14/935/004 
EU/1/14/935/005 
EU/1/14/935/006 
 
Envarsus 4 mg prolonged-release tablets 
 
EU/1/14/935/007 
EU/1/14/935/008 
EU/1/14/935/009 
 



19 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 July 2014 
Date of latest renewal: 06 June 2019 
 
 
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/


20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



21 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Chiesi Farmaceutici S.p.A. 
Via San Leonardo 96 
43122 Parma 
Italy 
 
Rottendorf Pharma GmbH 
Ostenfelder Strasse 51-61 
D-59320 Ennigerloh 
Germany 
 
Chiesi Pharmaceuticals GmbH 
Gonzagagasse 16/16 
1010 Wien 
Austria 
 
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  
 
The requirements for submission of periodic safety update reports 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 
 
• Risk Management Plan (RMP) 
 
The 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.  

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



22 

• Additional risk minimisation measures  
 
Prior to launch in each Member State, the Marketing Authorisation Holder MAH shall agree the 
content and format of the educational programme with the national competent authority. The 
Marketing Authorisation Holder should ensure that, at launch, all Healthcare Professionals who are 
expected to prescribe or dispense Envarsus are provided with an Educational pack.  
The educational pack should contain the following: 
• Summary of Product Characteristics and Patient Information Leaflet  
• Educational material for Healthcare Professionals 
• Patient cards to be given to patients with the product 
 
The educational material for Healthcare Professionals should include information on the following key 
elements: 
- The authorised indications  
- The need for prescribing and dispensing with attention to pharmaceutical form 

(prolonged-release) and posology (once daily administration).  
- The importance of avoiding inadvertent switching between tacrolimus containing products and 

the risk of under and overdosing if monitoring is inadequate.  
- The clinical risks associated with over- and under-dosing. 
- The need for specialist supervision and monitoring if there is a clinical decision to switch a 

patient to another tacrolimus containing products. 
- The role of the patient card in ensuring that patients are aware of the product they are taking and 

the recommendations for safe and effective use in particular once daily dose and the importance 
of avoiding switching between other tacrolimus containing products except under the advice 
and supervision of your doctor  

 
The patient card should include information on the following key elements: 
- The product name 
- That the dose is once daily 
- The importance of avoiding switching between other tacrolimus containing products except 

under the advice and supervision of physicians. 
 

  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
  



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTERS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Envarsus 0.75 mg prolonged-release tablets 
tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each prolonged-release tablet contains 0.75 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release tablets 
60 prolonged-release tablets 
90 prolonged-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Once daily. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP 
Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping. 
 
 



26 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original aluminium foil wrapper in order to protect from light. 
 
 
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 
 
Chiesi Farmaceutici S.p.A. 
Via Palermo 26/A 
43122 Parma 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/935/001 
EU/1/14/935/002 
EU/1/14/935/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Envarsus 0.75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



27 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Envarsus 0.75 mg prolonged-release tablets 
tacrolimus 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Chiesi 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Once daily 
 



28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
ALUMINIUM FOIL WRAPPER 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Envarsus 0.75 mg prolonged-release tablets 
tacrolimus 
For oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 tablets 
 
 
6. OTHER 
 
Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping. 
Store in the original aluminium foil wrapper in order to protect from light. 
Once daily. 
 
Chiesi  
 
  



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTERS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Envarsus 1 mg prolonged-release tablets 
tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each prolonged-release tablet contains 1 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release tablets 
60 prolonged-release tablets 
90 prolonged-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Once daily. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP 
Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping. 
 
 



30 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original aluminium foil wrapper in order to protect from light. 
 
 
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 
 
Chiesi Farmaceutici S.p.A. 
Via Palermo 26/A 
43122 Parma 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/935/004 
EU/1/14/935/005 
EU/1/14/935/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Envarsus 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



31 

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



32 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
ALUMINIUM FOIL WRAPPER 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Envarsus 1 mg prolonged-release tablets 
tacrolimus 
For oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 tablets 
 
 
6. OTHER 
 
Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping. 
Store in the original aluminium foil wrapper in order to protect from light. 
Once daily. 
 
Chiesi 
 
  



33 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTERS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Envarsus 4 mg prolonged-release tablets 
tacrolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each prolonged-release tablet contains 4 mg tacrolimus (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release tablets 
60 prolonged-release tablets 
90 prolonged-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Once daily. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP 
Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping. 
 
 



34 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original aluminium foil wrapper in order to protect from light. 
 
 
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 
 
Chiesi Farmaceutici S.p.A. 
Via Palermo 26/A 
43122 Parma 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/935/007 
EU/1/14/935/008 
EU/1/14/935/009 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Envarsus 4 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



35 

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



36 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
ALUMINIUM FOIL WRAPPER 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Envarsus 4 mg prolonged-release tablets 
tacrolimus 
For oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 tablets 
 
 
6. OTHER 
 
Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping. 
Store in the original aluminium foil wrapper in order to protect from light. 
Once daily. 
 
Chiesi 
 

  



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



38 

Package leaflet: Information for the patient 
 

Envarsus 0.75 mg prolonged-release tablets 
Envarsus 1 mg prolonged-release tablets 
Envarsus 4 mg prolonged-release tablets 

 
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 Envarsus is and what it is used for 
2. What you need to know before you take Envarsus 
3. How to take Envarsus 
4. Possible side effects 
5. How to store Envarsus 
6. Contents of the pack and other information 
 
 
1. What Envarsus is and what it is used for 
 
Envarsus contains the active substance tacrolimus. It is an immunosuppressant. Following your kidney 
or liver transplant, your body’s immune system will try to reject the new organ.  
 
Envarsus is used to control your body’s immune response, enabling your body to accept the 
transplanted organ. 
 
You may also be given Envarsus 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. 
 
Envarsus is used in adults. 
 
 
2. What you need to know before you take Envarsus 
 
Do not take Envarsus: 
- 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  
Envarsus contains the active substance tacrolimus presented in a prolonged release formulation. 
Envarsus is taken once daily and is not interchangeable with other existing medicines containing 
tacrolimus (immediate release or prolonged release) on an equal dose by dose basis. 
 



39 

Talk to your doctor before taking Envarsus: 
- if you have, or have had, liver problems. 
- if you have diarrhoea for more than one day. 
- if you are taking any medicines mentioned below under “Other medicines and Envarsus”. 
- 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. 
- if you feel strong abdominal pain accompanied or not with other symptoms, such as chills, 

fever, nausea or vomiting  
- an infection, leading to problems with your kidney or neurological symptoms 
- headache, altered mental status, seizures and visual disturbances 
- weakness, change in skin or eye colour, easy bruising, infection, cough, anaemia 
 
Your doctor may need to adjust your dose of Envarsus or will decide to stop treatment with 
tacrolimus. 
 
You should keep in regular contact with your doctor. From time to time, your doctor may need to do 
blood, urine, heart, or eye tests, to set the right dose of Envarsus. 
 
You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Envarsus. 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 Envarsus is not recommended in children and adolescents under 18 years. 
 
Other medicines and Envarsus 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines, including medicines obtained without a prescription and herbal preparations. 
 
It is not recommended that Envarsus is taken with ciclosporin (another medicine used for the 
prevention of transplant organ rejection). 
 
Tell your doctor if you have hepatitis C. Your liver function may change with treatment of hepatitis C 
and this may affect the levels of tacrolimus in your blood. Your doctor may need to closely monitor 
tacrolimus blood levels and make adjustments to the dose after you start treatment for hepatitis C. 
 
Envarsus blood levels can be affected by other medicines you take, and blood levels of other 
medicines can be affected by taking Envarsus, which may require interruption, an increase or a 
decrease in Envarsus 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, isoniazid 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  
- 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 



40 

- 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 substances (e.g. 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 
- prednisolone and methylprednisolone, belonging to the class of corticosteroids and used to treat 

inflammations or suppress the immune system (e.g. in transplant rejection) 
- carbamazepine, used to prevent and control seizures 
- metamizole, used to treat pain and high fever 
- nefazodone, used to treat depression 
- herbal preparations containing St. John’s Wort (Hypericum perforatum) 
 
Tell your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation and 
pain), amphotericin B (used to treat fungal infections), antibiotics (used to treat bacterial infections, 
e.g. aminoglycosides, vancomycin or clotrimazole) or antivirals (used to treat viral infections, e.g. 
aciclovir). These may worsen kidney or nervous system problems when taken together with Envarsus. 
 
While you take Envarsus 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), nonsteroidal anti-inflammatory substances (NSAIDs, e.g. ibuprofen) used for fever, 
inflammation and pain, anticoagulants (blood thinners), or oral medicines for diabetes. 
 
If you need to have any vaccinations, please tell your doctor before. 
 
Envarsus with food and drink 
Avoid grapefruit (also as juice) while on treatment with Envarsus, since it can affect its levels in the 
blood. 
 
Pregnancy and breast-feeding 
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. 
Tacrolimus passes into breast milk. Therefore, you should not breast-feed whilst taking Envarsus. 
 
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 Envarsus. These effects are more frequent if you also drink alcohol. 
 
Envarsus contains lactose 
Envarsus contains lactose (milk sugar).  
• Envarsus 0.75 mg tablets:  41.7 mg 
• Envarsus 1 mg tablets:  41.7 mg 
• Envarsus 4 mg tablets:  104 mg 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 
3. How to take Envarsus 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
This medicine should only be prescribed for you by a doctor with experience in the treatment of 
transplant patients. 
 

https://www.webmd.com/epilepsy/understanding-seizures-basics


41 

Important information 
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 doe instructions have changed, speak to your doctor or pharmacist as soon as possible to make 
sure that you have the right medicine. 
 
How much Envarsus do I have to take 
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: 
0.11 - 0.17 mg per kg body weight per day 
depending on the transplanted organ. When treating rejection, the same doses may be used. 
 
Your dose depends on your general condition and on which other immunosuppressive medicines you 
are taking. Following the initiation of your treatment with this medicine, 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 Envarsus dose once your condition has stabilised.  
 
How should I take the Envarsus tablets 
Envarsus is taken orally once daily, generally on an empty stomach.  
 
Take the tablets immediately following removal from the blister. The tablets should be swallowed 
whole with a glass of water. Do not swallow the desiccant contained in the foil wrapper. 
 
How long should I take the Envarsus tablets 
You will need to take Envarsus every day as long as you need immunosuppression to prevent rejection 
of your transplanted organ. You should keep in regular contact with your doctor. 
 
If you take more Envarsus than you should 
If you have accidentally taken too much Envarsus, contact your doctor or nearest hospital emergency 
department immediately. 
 
If you forget to take Envarsus 
Do not take a double dose to make up for a forgotten tablet. Take the tablet as soon as possible on the 
same day.  
 
If you stop taking Envarsus  
Stopping your treatment with Envarsus 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. 
 
Tacrolimus 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 Envarsus. 
Please contact your doctor immediately, should you experience severe effects. 
Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant 
tumours have been reported following Envarsus treatment. 
 



42 

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, loss of 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 or back, muscle cramps 
- 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 
- psychotic behaviour, such as delusions, hallucinations, and confusion 
- 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, partial or total inability to hear 
- 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 
- acute or chronic inflammation of the pancreas, inflammation of the lining of the inner wall of 

the abdomen, obstruction of the gut, increased blood level of the enzyme amylase, reflux of 
stomach contents in your throat, delayed emptying of the stomach 

- inflammation of the skin, burning sensation in the sunlight 
- joint disorders 



43 

- 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, pre-stage of a blockage in your bowel  
- 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 
- Impaired hearing 
- Abnormal heart scan 
- Liver failure 
- Painful urination with blood in the urine 
- Increase of fat tissue 
 
Unknown side effects (frequency not known): 
- 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)  
- Febrile neutropenia (a decrease in the type of white blood cells which fight infection, 

accompanied by fever) 
- 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 Envarsus 
 
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, blister and wrapper after 
‘EXP’. The expiry date refers to the last day of that month. 
 
Do not store above 25°C. 
Store in the original aluminium foil wrapper in order to protect from light. 
 
Use all the prolonged-release tablets within 45 days 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. 
 
 

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


44 

6. Contents of the pack and other information 
 
What Envarsus contains  
- The active substance is tacrolimus. 

 
Envarsus 0.75 mg prolonged-release tablets 
Each prolonged-release tablet contains 0.75 mg tacrolimus (as monohydrate). 
 
Envarsus 1 mg prolonged-release tablets 
Each prolonged-release tablet contains 1.0 mg tacrolimus (as monohydrate). 
 
Envarsus 4 mg prolonged-release tablets 
Each prolonged-release tablet contains 4.0 mg tacrolimus (as monohydrate). 
 

- The other excipients are hypromellose, lactose monohydrate, macrogol 6000, poloxamer 188, 
magnesium stearate, tartaric acid (E334), butylated hydroxytoluene (E321), dimethicone 350. 

 
What Envarsus looks like and contents of the pack 
Envarsus 0.75 mg prolonged-release tablets are oval, white to off-white uncoated tablet, debossed with 
“0.75” on one side and “TCS” on the other side. 
Envarsus 1 mg prolonged-release tablets are oval, white to off-white uncoated tablet, debossed with “1” 
on one side and “TCS” on the other side  
Envarsus 4 mg prolonged-release tablets are oval, white to off-white uncoated tablet, debossed with “4” 
on one side and “TCS” on the other side. 
 
Envarsus is supplied in PVC/alu blisters containing 10 tablets. 3 blisters are packed together within a 
protective aluminium foil wrapper, including a desiccant. Packs of 30, 60 and 90 prolonged-release 
tablets are available. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Chiesi Farmaceutici S.p.A. 
Via Palermo, 26/A 
43122 Parma 
Italy 
 
Manufacturer 
Rottendorf Pharma GmbH 
Ostenfelder Straβe 51 - 61 
59320 Ennigerloh 
Germany 
or 
Chiesi Farmaceutici S.p.A. 
Via San Leonardo 96 
43122 Parma 
Italy 
or 
Chiesi Pharmaceuticals GmbH 
Gonzagagasse 16/16 
1010 Wien 
Austria 
 



45 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Chiesi sa/nv 
Tél/Tel: +32 (0)2 788 42 00 
 

Lietuva 
Chiesi Pharmaceuticals GmbH  
Tel: +43 1 4073919 
 

България 
Chiesi Bulgaria EOOD  
Teл.: +359 29201205 
 

Luxembourg/Luxemburg 
Chiesi sa/nv 
Tél/Tel: +32 (0)2 788 42 00 
 

Česká republika 
Chiesi CZ s.r.o. 
Tel: +420 261221745 
 

Magyarország 
Chiesi Hungary Kft. 
Tel.: +36-1-429 1060 
 

Danmark 
Chiesi Pharma AB 
Tlf: +46 8 753 35 20 
 

Malta 
Chiesi Farmaceutici S.p.A. 
Tel: +39 0521 2791 
 

Deutschland 
Chiesi GmbH 
Tel: +49 40 89724-0 
 

Nederland 
Chiesi Pharmaceuticals B.V. 
Tel: +31 0 88 5016400 
 

Eesti 
Chiesi Pharmaceuticals GmbH 
Tel: +43 1 4073919 
 

Norge 
Chiesi Pharma AB 
Tlf: +46 8 753 35 20 
 

Ελλάδα 
Chiesi Hellas AEBE 
Τηλ: +30 210 6179763 
 

Österreich 
Chiesi Pharmaceuticals GmbH  
Tel: +43 1 4073919 
 

España 
Chiesi España, S.A.U. 
Tel: +34 93 494 8000 
 

Polska 
Chiesi Poland Sp. z.o.o. 
Tel.: +48 22 620 1421 
 

France 
Chiesi S.A.S  
Tél: +33 1 47688899 
 

Portugal 
Chiesi Farmaceutici S.p.A. 
Tel: +39 0521 2791 
 

Hrvatska 
Chiesi Pharmaceuticals GmbH 
Tel: +43 1 4073919 
 

România 
Chiesi Romania S.R.L. 
Tel: +40 212023642 
 

Ireland 
Chiesi Farmaceutici S.p.A. 
Tel: +39 0521 2791 

Slovenija 
Chiesi Slovenija d.o.o. 
Tel: +386-1-43 00 901 
 

Ísland 
Chiesi Pharma AB 
Tlf: +46 8 753 35 20 
 

Slovenská republika 
Chiesi Slovakia s.r.o. 
Tel: +421 259300060 
 

Italia 
Chiesi Farmaceutici S.p.A. 
Tel: +39 0521 2791 
 

Suomi/Finland 
Chiesi Pharma AB 
Puh/Tel: +46 8 753 35 20 
 



46 

Κύπρος 
Chiesi Farmaceutici S.p.A. 
Τηλ: +39 0521 2791 
 

Sverige 
Chiesi Pharma AB 
Tlf: +46 8 753 35 20 
 

Latvija 
Chiesi Pharmaceuticals GmbH  
Tel: +43 1 4073919 
 

United Kingdom 
Chiesi Ltd  
Tel: +44 0161 4885555 
 

 
This leaflet was last revised in. 
 
 
Other sources of information 
 
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. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET