Tacrolimus: prescribing information – dosing, contraindications, interactions, side effects

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.

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

Different oral formulations of tacrolimus should not be substituted without clinical supervision.
Inadvertent, unintentional or unsupervised switching between different oral formulations of tacrolimus with different release characteristics is unsafe. This can lead to graft rejection or increased incidence of adverse reactions, including under- or over-immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.4 and 4.8).
Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Advagraf is routinely administered in conjunction with other immunosuppressive agents in the initial post- operative period. The dose may vary depending upon the immunosuppressive regimen chosen.
Advagraf dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below under “Therapeutic drug monitoring”).
If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

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

To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.

Prophylaxis of kidney transplant rejection
Advagraf therapy should commence at a dose of 0.20 - 0.30 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant

changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Prophylaxis of liver transplant rejection
Advagraf therapy should commence at a dose of 0.10 - 0.20 mg/kg/day administered once daily in the morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Conversion of Prograf-treated patients to Advagraf
Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should be administered in the morning.

In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1 (mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC0-24) for Advagraf was approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) for Advagraf is similar to that of Prograf. When converting from Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary dose adjustments made to maintain similar systemic exposure. Dose adjustments should be made to ensure that similar systemic exposure is maintained.

Conversion from ciclosporin to tacrolimus
Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not recommended. Advagraf therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.

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

Treatment of allograft rejection after kidney or liver transplantation
For conversion from other immunosuppressants to once daily Advagraf, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection.

Treatment of allograft rejection after heart transplantation
In adult patients converted to Advagraf, an initial oral dose of 0.15 mg/kg/day should be administered once daily in the morning.

Treatment of allograft rejection after transplantation of other allografts
Although there is no clinical experience with Advagraf in lung-, pancreas- or intestine-transplanted patients, Prograf has been used in lung-transplanted patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.

Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods.
The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) is similar between the two formulations Advagraf and Prograf.

Blood trough levels of tacrolimus should be monitored during the post-transplantation period.
Tacrolimus blood trough levels should be determined approximately 24 hours post-dosing of Advagraf, just prior to the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored following conversion from Prograf to Advagraf, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Advagraf dose regimen it may take several days before the targeted steady state is achieved.

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

Special populations

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

Renal impairment
As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), no dose adjustment is required. However, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is recommended (including serial serum creatinine concentrations, calculation of creatinine clearance and monitoring of urine output).
Race
In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.

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

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

Paediatric population
The safety and efficacy of Advagraf in children under 18 years of age have not yet been established.
Limited data are available but no recommendation on a posology can be made.
Method of administration
Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be taken immediately following removal from the blister. Patients should be advised not to swallow the desiccant. The capsules should be swallowed whole with fluid (preferably water). Advagraf should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption (see section 5.2). A forgotten morning dose should be taken as soon as possible on the same day. A double dose should not be taken on the next morning.

In patients unable to take oral medicinal products during the immediate post-transplant period, tacrolimus therapy can be initiated intravenously (see Summary of Product Characteristics for Prograf 5 mg/ml concentrate for solution for infusion) at a dose approximately 1/5th of the recommended oral dose for the corresponding indication.

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

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.

The most commonly reported adverse reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre- existing infections may be aggravated. Both generalised and localised infections can occur.
Cases of CMV infection, BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Advagraf.

Neoplasms benign, malignant and unspecified (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, skin malignancies and Kaposi’s sarcoma 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, thrombotic microangiopathy rare:
thrombotic thrombocytopenic purpura, hypoprothrombinaemia not known:
pure red cell aplasia, agranulocytosis, haemolytic anaemia, febrile neutropenia

Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).

Endocrine disorders rare:
hirsutism

Metabolism and nutrition disorders very common:
diabetes mellitus, hyperglycaemic conditions, hyperkalaemia common:
metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, hypophosphataemia uncommon:
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia

Psychiatric disorders very common:
insomnia common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare uncommon:
psychotic disorder

Nervous system disorders very common:
headache, tremor common:
nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired uncommon:
encephalopathy, central nervous system haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia rare:
hypertonia very rare:
myasthenia not known:
posterior reversible encephalopathy syndrome (PRES)

Eye disorders common:
eye disorders, vision blurred, photophobia uncommon:
cataract rare:
blindness not known:
optic neuropathy

Ear and labyrinth disorders common:
tinnitus uncommon:
hypoacusis rare:
deafness neurosensory very rare:
hearing impaired

Cardiac disorders common:
ischaemic coronary artery disorders, tachycardia uncommon:
heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ventricular hypertrophy, palpitations rare:
pericardial effusion very rare:
Torsades de pointes

Vascular disorders very common:
hypertension common:
thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders uncommon:
venous thrombosis deep limb, shock, infarction

Respiratory, thoracic and mediastinal disorders common:
parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations uncommon:
respiratory failures, respiratory tract disorders, asthma rare:
acute respiratory distress syndrome

Gastrointestinal disorders very common:
diarrhoea, nausea common:
gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal pains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages, gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools uncommon:
acute and chronic pancreatitis, ileus paralytic, gastrooesophageal reflux disease, impaired gastric emptying

rare:
pancreatic pseudocyst, subileus

Hepatobiliary disorders common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice rare:
venoocclusive liver disease, hepatic artery thrombosis very rare:
hepatic failure

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

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

Renal and urinary disorders very common:
renal impairment common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms uncommon:
haemolytic uraemic syndrome, anuria very rare:
nephropathy, cystitis haemorrhagic

Reproductive system and breast disorders uncommon:
dysmenorrhoea and uterine bleeding

General disorders and administration site conditions common:
febrile disorders, pain and discomfort, asthenic conditions, oedema, body temperature perception disturbed uncommon:
influenza like illness, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance rare:
fall, ulcer, chest tightness, thirst very rare:
fat tissue increased

Investigations very common:
liver function tests abnormal common:
blood alkaline phosphatase increased, weight increased uncommon:
amylase increased, ECG investigations abnormal, heart rate and pulse investigations abnormal, weight decreased, blood lactate dehydrogenase increased very rare:
echocardiogram abnormal, electrocardiogram QT prolonged

Injury, poisoning and procedural complications common:
primary graft dysfunction

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

Description of selected adverse reactions
Pain in extremity has been described in a number of published case reports as part of Calcineurin- Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.

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.

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

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

For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients clinical data are not yet available for the prolonged-release formulation Advagraf.

For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for Advagraf.

During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.

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

CYP3A4 inhibitors
Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which could lead to serious adverse reactions, including nephrotoxicity, neurotoxicity and QT prolongation. It is recommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin)

with tacrolimus should be avoided. If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of co-administration, under the supervision of a transplant specialist, to adjust the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure.
Renal function, ECG including the QT interval, and the clinical condition of the patient should also be closely monitored.
Dose adjustment needs to be based upon the individual situation of each patient. An immediate dose reduction at the time of treatment initiation may be required (see section 4.5).

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

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

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

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

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

Other interactions
The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.5).

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

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

Vaccination
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.

Nephrotoxicity
Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairment without active intervention may progress to chronic renal impairment. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with drugs associated with nephrotoxicity (see section 4.5). Concurrent use of tacrolimus with drugs known to have

nephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus trough blood level and renal function should be monitored closely and dosage reduction should be considered if nephrotoxicity occurs.

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

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

Cardiac disorders
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed in Prograf treated patients on rare occasions and may also occur with Advagraf. Most cases have been reversible, occurring with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9 -12 months). If abnormalities develop, dose reduction of Advagraf, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may cause Torsades de pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see section 4.5).

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

A combination of immunosuppressives such as antilymphocytic antibodies (e.g. basiliximab, daclizumab) given concomitantly increases the risk of EBV-associated lymphoproliferative disorders.
EBV-Viral Capsid Antigen (VCA)-negative patients have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Advagraf. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

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

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

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

Infections including opportunistic infections
Patients treated with immunosuppressants, including Advagraf are at increased risk for infections including opportunistic infections (bacterial, fungal, viral and protozoal) such as CMV infection, 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 including graft rejection 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.

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

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

Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. 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
As Advagraf capsules contain lactose, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

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

Pharmacokinetics studies have indicated that the increase in tacrolimus blood levels when co- administered with inhibitors of CYP3A4 is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced.
It is recommended strongly to closely monitor tacrolimus blood levels under supervision of a transplant specialist, as well as, monitor for graft function, QT prolongation (with ECG), renal function and other side effects including neurotoxicity, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly, and to adjust or interrupt the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4). Similarly, patients should be closely monitored when using tacrolimus concomitantly with multiple substances that affect CYP3A4 as the effects on tacrolimus exposure may be enhanced or counteracted.

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

Medicinal products which have effects on tacrolimus
Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration
Grapefruit or grapefruit juice May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].
Avoid grapefruit or grapefruit juice.
Ciclosporin
May increase tacrolimus whole blood trough concentrations. In addition, synergistic/additive nephrotoxic effects can occur.
The simultaneous use of ciclosporin and tacrolimus should be avoided [see section 4.4].
Products known to have nephrotoxic or neurotoxic effects:
aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen, cidofovir, foscarnet May enhance nephrotoxic or neurotoxic effects of tacrolimus.
Concurrent use of tacrolimus with drugs known to have nephrotoxic effects should be avoided. When co- administration cannot be avoided, monitor renal function and other side effects and adjust tacrolimus dose if needed.

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration
Strong CYP3A4 inhibitors:
antifungal agents (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), the macrolide antibiotics (e.g., telithromycin, troleandomycin, clarithromycin, josamycin), 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), nefazodone, the pharmacokinetic enhancer cobicistat, and the kinase inhibitors idelalisib, ceritinib.
Strong interactions have also been observed with the macrolide antibiotic erythromycin May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., nephrotoxicity, neurotoxicity, QT prolongation) which requires close monitoring [see section 4.4].
Rapid and sharp increases in tacrolimus levels may occur, as early as within 1-3 days after co- administration, despite immediate reduction of tacrolimus dose.
Overall tacrolimus exposure may increase > 5 fold. When ritonavir combinations are co-administered, tacrolimus exposure may increase > 50 fold. Nearly all patients may require a reduction in tacrolimus dose and temporary interruption of tacrolimus may also be necessary.
The effect on tacrolimus blood concentrations may remain for several days after co-administration is completed.
It is recommended that concomitant use should be avoided. If co-administration of a strong CYP3A4 inhibitor is unavoidable, consider omitting the dose of tacrolimus the day the strong CYP3A4 inhibitor is initiated. Reinitiate tacrolimus the next day at a reduced dose based on tacrolimus blood concentrations. Changes in both tacrolimus dose and/or dosing frequency should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re- evaluated on and after completion of the CYP3A4 inhibitor. Upon completion, appropriate dose and dosing frequency of tacrolimus should be guided by tacrolimus blood concentrations. Monitor renal function, ECG for QT prolongation, and other side effects closely.
Moderate or weak CYP3A4 inhibitors:
antifungal agents (e.g., fluconazole, isavuconazole, clotrimazole, miconazole), the macrolide antibiotics (e.g., azithromycin), calcium channel blockers (e.g., nifedipine, nicardipine, diltiazem, verapamil), amiodarone, danazol, ethinylestradiol, lansoprazole, omeprazole, the HCV antivirals elbasvir/grazoprevir and glecaprevir/pibrentasvir, the CMV antiviral letermovir, and the tyrosine kinase inhibitors nilotinib, crizotinib and imatinib and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4]. A rapid increase in tacrolimus level may occur.
Monitor tacrolimus whole blood trough concentrations frequently, starting within the first few days of co- administration. Reduce tacrolimus dose if needed [see section 4.2]. Monitor renal function, ECG for QT prolongation, and other side effects closely.

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration
In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism:
bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see section 4.2].
Monitor renal function, ECG for QT prolongation, and other side effects closely.
Strong CYP3A4 inducers:
rifampicin, phenytoin, carbamazepine, apalutamide, enzalutamide, mitotane, or
St. John’s wort (Hypericum perforatum)
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Maximal effect on tacrolimus blood concentrations may be achieved 1-2 weeks after co-administration. The effect may remain 1-2 weeks after completion of the treatment.

It is recommended that concomitant use should be avoided. If unavoidable, patients may require an increase in tacrolimus dose.
Changes in tacrolimus dose should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re- evaluated on and after completion of the CYP3A4 inducer. After use of the CYP3A4 inducer has ended, tacrolimus dose may need to be adjusted gradually. Monitor graft function closely.
Moderate CYP3A4 inducers:
metamizole, phenobarbital, isoniazid, rifabutin, efavirenz, etravirine, nevirapine; weak CYP3A4 inducers: flucloxacillin May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
Caspofungin
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection.
Mechanism of interaction has not been confirmed.
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
Cannabidiol (P-gp inhibitor)

There have been reports of increased tacrolimus blood levels during concomitant use of tacrolimus with cannabidiol. This may be due to inhibition of intestinal P-glycoprotein, leading to increased bioavailability of tacrolimus.
Tacrolimus and cannabidiol should be co-administered with caution, closely monitoring for side effects. Monitor tacrolimus whole blood trough concentrations and adjust the tacrolimus dose if needed [see sections 4.2 and 4.4].

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration
Products known to have high affinity for plasma proteins, e.g.: NSAIDs, oral anticoagulants, oral antidiabetics Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances known to have high affinity for plasma proteins should be considered.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see section 4.2].

Prokinetic agents:
metoclopramide, cimetidine and magnesium-aluminium- hydroxide
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).
Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see section 4.2].
Monitor closely for renal function, for QT prolongation with ECG, and for other side effects.
Maintenance doses of corticosteroids
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
High dose prednisolone or methylprednisolone
May have impact on tacrolimus blood levels (increase or decrease) when administered for the treatment of acute rejection.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.
Direct-acting antiviral
(DAA) therapy
May have impact on the pharmacokinetics of tacrolimus by changes in liver function during DAA therapy, related to clearance of hepatitis virus. A decrease in tacrolimus blood levels may occur.
However, the CYP3A4 inhibiting potential of some DAAs may counteract that effect or lead to increased tacrolimus blood levels.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed to ensure continued efficacy and safety.

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

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). Care should be taken when tacrolimus is co- administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Close monitoring of serum potassium is recommended.

Effect of tacrolimus on the metabolism of other medicinal products
Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal 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.

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).

Pregnancy
Data from women show that tacrolimus crosses the placenta. There is a risk for hyperkalaemia in the newborn (e.g. incidence in neonates of 7.2%, i.e., 8 of 111) which tends to normalise spontaneously.
Tacrolimus treatment can be considered in pregnant women, when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse events of tacrolimus is recommended (in particular effects on the kidneys).

Results from a non-interventional post-authorisation safety study [EUPAS37025]
A post-authorisation safety study analysed 2,905 pregnancies from the Transplant Pregnancy Registry International (TPRI), assessing outcomes in women treated with tacrolimus (383 reported prospectively, including 247 kidney and 136 liver transplant patients), and those on other immunosuppressants. Based on limited data (289 prospectively-reported pregnancies with 1st trimester tacrolimus exposure), study results did not indicate an increased risk of major malformations. A higher prevalence of spontaneous abortion was observed among women treated with tacrolimus compared with alternative immunosuppressants. Among kidney transplant patients there was also a higher prevalence of pre-eclampsia in women treated with tacrolimus. However, overall, there were insufficient evidence to conclude on the risk of these outcomes. Among kidney and liver transplant patients exposed to tacrolimus, 45% - 55% of their live births were premature, with 75% - 85% having a normal birth weight for gestational age. Similar results were observed for other immunosuppressants, although conclusions were hindered by limited evidence.

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3).
Breast-feeding
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Advagraf.
Fertility
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).

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 (Advagraf) on the ability to drive and use machines have been performed.

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

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02 Mechanism of action At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the expression of the interleukin-2 receptor.

Results from clinical trials performed with once-daily tacrolimus Advagraf

Liver transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared in 471 de novo liver transplant recipients. The event rate of biopsy confirmed acute rejection within the first 24 weeks after transplantation was 32.6% in the Advagraf group (N = 237) and 29.3% in the Prograf group (N = 234). The treatment difference (Advagraf – Prograf) was 3.3% (95% confidence interval [-5.7%, 12.3%]). The 12-month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female, 19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.

Kidney transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil (MMF) and corticosteroids, was compared in 667 de novo kidney transplant recipients. The event rate for biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the Advagraf group (N = 331) and 14.9% in the Prograf group (N = 336). The treatment difference (Advagraf-Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were 96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female,

7 male) and in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf and 92.8% for Prograf.

Absorption
In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract.
Available tacrolimus is generally rapidly absorbed. Advagraf is a prolonged-release formulation of tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood concentration (Cmax) of approximately 2 hours (tmax).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prograf formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral bioavailability of Advagraf was reduced when it was administered after a meal. Both the rate and extent of absorption of Advagraf were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf may commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Advagraf.
Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
Distribution
In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.
Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on whole blood averaged 47.6 l.
Biotransformation

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.

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 over-immunosuppression, 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)

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.

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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypersensitivity to other macrolides.

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.

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 CMV infection, 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 and Kaposi’s sarcoma 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 microangio- pathy thrombotic thrombo- cytopenic purpura, hypopro- thrombin- aemia

pure red cell aplasia, agranulo- cytosis, haemolytic anaemia, febrile neutropenia Endocrine disorders

hirsutism

System Organ
Class
Frequency of adverse reactions

Very common
Common

Uncommon

Rare

Very rare

Not known

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

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 Posterior reversible encephalo- pathy syndrome (PRES) 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 Torsades de pointes

System Organ
Class
Frequency of adverse reactions

Very common
Common

Uncommon

Rare

Very rare

Not known

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

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

System Organ
Class
Frequency of adverse reactions

Very common
Common

Uncommon

Rare

Very rare

Not known

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

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

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.

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

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.

Substances with potential for interaction

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

CYP3A4 inhibitors
Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which could lead to serious adverse reactions, including nephrotoxicity, neurotoxicity and QT prolongation. It is recommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin) with tacrolimus should be avoided. If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of coadministration, under the supervision of a transplant specialist, to adjust the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure.
Renal function, ECG including the QT interval, and the clinical condition of the patient should also be closely monitored.
Dose adjustment needs to be based upon the individual situation of each patient. An immediate dose reduction at the time of treatment initiation may be required (see section 4.5).

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

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

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

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

Herbal preparations

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).

Other interactions

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 neurotoxic effects may increase the risk of these effects (see section 4.5).

Vaccination

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.

Nephrotoxicity

Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairment without active intervention may progress to chronic renal impairment. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with drugs associated with nephrotoxicity (see section 4.5). Concurrent use of tacrolimus with drugs known to have nephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus trough blood level and renal function should be monitored closely and dosage reduction should be considered if nephrotoxicity occurs.

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.

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

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

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

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 and other malignancies, including skin cancers and Kaposi's sarcoma (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.
Kaposi’s sarcoma, including cases with aggressive forms of disease and fatal outcomes, has been reported in patients receiving tacrolimus. In some cases, regression of Kaposi’s sarcoma has been observed after reducing the intensity of immunosuppression.
As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown.

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 CMV infection, 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 including graft rejection 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.

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.

Metabolic interactions

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

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

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

Medicinal products which have effects on tacrolimus are listed in the table below. The examples of drug-drug interactions are not intended to be inclusive or comprehensive and therefore the label of each drug that is co-administered with tacrolimus should be consulted for information related to the

route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.

Medicinal products which have effects on tacrolimus

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration
Grapefruit or grapefruit juice
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].
Avoid grapefruit or grapefruit juice.
Ciclosporin
May increase tacrolimus whole blood trough concentrations. In addition, synergistic/additive nephrotoxic effects can occur.
The simultaneous use of ciclosporin and tacrolimus should be avoided [see section 4.4].
Products known to have nephrotoxic or neurotoxic effects:
aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen, cidofovir, foscarnet May enhance nephrotoxic or neurotoxic effects of tacrolimus.
Concurrent use of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects should be avoided.
When co-administration cannot be avoided, monitor renal function and other side effects and adjust tacrolimus dose if needed.
Strong CYP3A4 inhibitors:
antifungal agents (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), the macrolide antibiotics (e.g., telithromycin, troleandomycin, clarithromycin, josamycin), 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), nefazodone, the pharmacokinetic enhancer cobicistat, and the kinase inhibitors idelalisib, ceritinib Strong interactions have also been observed with the macrolide antibiotic erythromycin May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., nephrotoxicity, neurotoxicity, QT prolongation) which requires close monitoring [see section 4.4].
Rapid and sharp increases in tacrolimus levels may occur, as early as within 1-3 days after co- administration, despite immediate reduction of tacrolimus dose.
Overall tacrolimus exposure may increase >5 fold. When ritonavir combinations are co-administered, tacrolimus exposure may increase >50 fold. Nearly all patients may require a reduction in tacrolimus dose and temporary interruption of tacrolimus may also be necessary.
The effect on tacrolimus blood concentrations may remain for several days after co-administration is completed.
It is recommended that concomitant use should be avoided. If co-administration of a strong CYP3A4 inhibitor is unavoidable, consider omitting the dose of tacrolimus the day the strong CYP3A4 inhibitor is initiated. Reinitiate tacrolimus the next day at a reduced dose based on tacrolimus blood concentrations. Changes in both tacrolimus dose and/or dosing frequency should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re- evaluated on and after completion of the CYP3A4 inhibitor. Upon completion, appropriate dose and dosing frequency of tacrolimus should be guided by tacrolimus blood

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration concentrations. Monitor renal function, ECG for QT prolongation, and other side effects closely.
Moderate or weak CYP3A4 inhibitors:
antifungal agents (e.g., fluconazole, isavuconazole, clotrimazole, miconazole), the macrolide antibiotics (e.g., azithromycin), calcium channel blockers (e.g., nifedipine, nicardipine, diltiazem, verapamil), amiodarone, danazol, ethinylestradiol, lansoprazole, omeprazole, the HCV antivirals elbasvir/grazoprevir and glecaprevir/pibrentasvir, the CMV antiviral letermovir, and the tyrosine kinase inhibitors nilotinib, crizotinib and imatinib and (Chinese) herbal preparations containing extracts of Schisandra sphenanthera May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4]. A rapid increase in tacrolimus level may occur.
Monitor tacrolimus whole blood trough concentrations frequently, starting within the first few days of co- administration. Reduce tacrolimus dose if needed [see section 4.2]. Monitor renal function, ECG for QT prolongation, and other side effects closely.

In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism:
bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see section 4.2].
Monitor renal function, ECG for QT prolongation, and other side effects closely.
Strong CYP3A4 inducers:
rifampicin, phenytoin, carbamazepine, apalutamide, enzalutamide, mitotane, or St.
John’s wort (Hypericum perforatum)
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Maximal effect on tacrolimus blood concentrations may be achieved 1-2 weeks after coadministration. The effect may remain 1-2 weeks after completion of the treatment.

It is recommended that concomitant use should be avoided. If unavoidable, patients may require an increase in tacrolimus dose.
Changes in tacrolimus dose should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re- evaluated on and after

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration completion of the CYP3A4 inducer. After use of the CYP3A4 inducer has ended, tacrolimus dose may need to be adjusted gradually. Monitor graft function closely.
Moderate CYP3A4 inducers:
metamizole, phenobarbital, isoniazid, rifabutin, efavirenz, etravirine, nevirapine

Weak CYP3A4 inducers:
flucloxacillin
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
Caspofungin
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection.
Mechanism of interaction has not been confirmed.
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
Products known to have high affinity for plasma proteins, e.g.: NSAIDs, oral anticoagulants, oral antidiabetics Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances known to have high affinity for plasma proteins should be considered.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see section 4.2].

Prokinetic agents:
metoclopramide, cisapride, cimetidine, and magnesium- aluminium-hydroxide
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).
Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see section 4.2].
Monitor closely for renal function, for QT prolongation with ECG, and for other side effects.
Maintenance doses of corticosteroids
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
High dose prednisolone or methylprednisolone
May have impact on tacrolimus blood levels (increase or decrease) when administered for the treatment of acute rejection.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co-administration
Direct-acting antiviral (DAA) therapy
May have impact on the pharmacokinetics of tacrolimus by changes in liver function during DAA therapy, related to clearance of hepatitis virus. A decrease in tacrolimus blood levels may occur.
However, the CYP3A4 inhibiting potential of some DAAs may counteract that effect or lead to increased tacrolimus blood levels.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed to ensure continued efficacy and safety.
Cannabidiol (P-gp inhibitor)
There have been reports of increased tacrolimus blood levels during concomitant use of tacrolimus with cannabidiol. This may be due to inhibition of intestinal P-glycoprotein, leading to increased bioavailability of tacrolimus.
Tacrolimus and cannabidiol should be co-administered with caution, closely monitoring for side effects. Monitor tacrolimus whole blood trough concentrations and adjust the tacrolimus dose if needed [see sections 4.2 and 4.4].

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

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). Care should be taken when tacrolimus is coadministered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium- sparing diuretic like amiloride. Close monitoring of serum potassium is recommended.

Effect of tacrolimus on the metabolism of other medicinal products

Tacrolimus is a known CYP3A4 inhibitor; thus, concomitant use of tacrolimus with medicinal 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

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.

Pregnancy

Data from women show that tacrolimus crosses the placenta. There is a risk for hyperkalaemia in the newborn (e.g. incidence in neonates of 7.2%, i.e., 8 of 111) which tends to normalise spontaneously.
Tacrolimus treatment can be considered in pregnant women when there is no safer alternative, 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).
Results from a non-interventional post-authorisation safety study [EUPAS37025]
A post-authorisation safety study analysed 2,905 pregnancies from the Transplant Pregnancy Registry International (TPRI), assessing outcomes in women treated with tacrolimus (383 reported prospectively, including 247 kidney and 136 liver transplant patients), and those on other immunosuppressants. Based on limited data (289 prospectively-reported pregnancies with 1st trimester tacrolimus exposure), study results did not indicate an increased risk of major malformations. A higher prevalence of spontaneous abortion was observed among women treated with tacrolimus compared with alternative immunosuppressants. Among kidney transplant patients there was also a higher prevalence of pre-eclampsia in women treated with tacrolimus. However, overall, there were insufficient evidence to conclude on the risk of these outcomes. Among kidney and liver transplant patients exposed to tacrolimus, 45% - 55% of their live births were premature, with 75% - 85% having a normal birth weight for gestational age. Similar results were observed for other immunosuppressants, although conclusions were hindered by limited evidence.

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated 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).

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.

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

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.

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.

Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult and paediatric patients.

This medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients. Modigraf is a granular formulation of tacrolimus, for twice-a-day administration. Modigraf therapy requires careful monitoring by adequately qualified and equipped personnel.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Modigraf is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The dose may vary depending upon the immunosuppressive regimen chosen.
Modigraf dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below under “Therapeutic drug monitoring”).
If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks post-transplant to ensure adequate exposure to the active substance in the immediate post-transplant period. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before steady state is achieved (see below under “Therapeutic drug monitoring” and section 5.2).

Modigraf should not be switched with the prolonged-release capsules (Advagraf) as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. In general, inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of undesirable effects, including under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

Prophylaxis of kidney transplant rejection
Adults
Oral Modigraf therapy should commence at 0.20 - 0.30 mg/kg/day administered as 2 divided doses (e.g. morning and evening). Administration should commence within 24 hours after the completion of surgery.
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.05 - 0.10 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be initiated as a continuous 24-hour infusion.

Paediatric population
An initial oral dose of 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 0.075 - 0.100 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and paediatric patients
Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to tacrolimus-based dual therapy.
Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Prophylaxis of liver transplant rejection
Adults
Oral Modigraf therapy should commence at 0.10 - 0.20 mg/kg/day administered as 2 divided doses (e.g. morning and evening). Administration should commence approximately 12 hours after the completion of surgery.
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.01 - 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be initiated as a continuous 24-hour infusion.

Paediatric population
An initial oral dose of 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and paediatric patients
Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to tacrolimus monotherapy.
Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Prophylaxis of heart transplant rejection
Adults
Modigraf can be used with antibody induction (allowing for delayed start of tacrolimus therapy) or alternatively in clinically stable patients without antibody induction.
Following antibody induction, oral Modigraf therapy should commence at a dose of 0.075 mg/kg/day administered as 2 divided doses (e.g. morning and evening). Administration should commence within 5 days after the completion of surgery as soon as the patient's clinical condition is stabilised. If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.01 to 0.02 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be initiated as a continuous 24-hour infusion.
An alternative strategy was published where oral tacrolimus was administered within 12 hours post transplantation. This approach was reserved for patients without organ dysfunction (e.g. renal dysfunction). In that case, an initial oral tacrolimus dose of 2 to 4 mg per day was used in combination with mycophenolate mofetil and corticosteroids or in combination with sirolimus and corticosteroids.

Paediatric population
Tacrolimus has been used with or without antibody induction in paediatric heart transplantation.
In patients without antibody induction, if tacrolimus therapy is initiated intravenously, the recommended starting dose is 0.03 - 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) as a continuous 24-hour infusion targeted to achieve tacrolimus whole blood concentrations of 15 - 25 nanogram/ml. Patients should be converted to oral therapy as soon as clinically practicable. The first dose of oral therapy should be 0.30 mg/kg/day starting 8 to 12 hours after discontinuing intravenous therapy.
Following antibody induction, if Modigraf therapy is initiated orally, the recommended starting dose is 0.10 - 0.30 mg/kg/day administered as 2 divided doses (e.g. morning and evening).

Dose adjustment during post-transplant period in adults and paediatric patients
Tacrolimus doses are usually reduced in the post-transplant period. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Conversion between Modigraf and Prograf tacrolimus formulations
In healthy subjects the systemic exposure to tacrolimus (AUC) for Modigraf was approximately 18% higher than that for Prograf capsules when administered as single doses. There are no safety data available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in critically ill patients.

Stable allograft recipients maintained on Modigraf granules, requiring conversion to Prograf capsules, should be converted on a 1:1 mg:mg total daily dose basis. If equal doses are not possible, the total daily dose of Prograf should be rounded-up to the nearest amount possible, with the higher dose given in the morning and the lower dose in the evening.

Similarly, for conversion of patients from Prograf capsules to Modigraf granules, the total daily Modigraf dose should preferably be equal to the total daily Prograf dose. If conversion on the basis of equal quantities is not possible, the total daily dose of Modigraf should be rounded down to the nearest total daily dose possible with sachets 0.2 mg and 1 mg.
The total daily dose of Modigraf granules should be administered in 2 equal doses. If equal doses are not possible, then the higher dose should be administered in the morning and the lower dose in the evening. Modigraf sachets must not be used partially.

Example: Total daily dose Prograf capsules given as 1 mg in the morning and 0.5 mg in the evening.
Then give a total daily dose of Modigraf 1.4 mg divided as 0.8 mg in the morning and 0.6 mg in the evening.

Tacrolimus trough levels should be measured prior to conversion and within 1 week after conversion.
Dose adjustments should be made to ensure that similar systemic exposure is maintained.

Conversion from ciclosporin to tacrolimus
Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not recommended. Tacrolimus therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.

Treatment of allograft rejection
Increased tacrolimus doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity such as severe adverse reactions are noted (see section 4.8), the dose of Modigraf may need to be reduced.

Treatment of allograft rejection after kidney or liver transplantation – adults and paediatric patients For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with the initial oral dose recommended for primary immunosuppression.

Treatment of allograft rejection after heart transplantation therapy – adults and paediatric patients In adult patients converted to Modigraf, an initial oral dose of 0.15 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening).
In paediatric patients converted to tacrolimus, an initial oral dose of 0.20 - 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening).

Treatment of allograft rejection after transplantation of other allografts
The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data with the Prograf formulation. Prograf has been used in lung-transplanted patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.

Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods.
The relationship between tacrolimus trough levels (C12) and systemic exposure (AUC0-12) is similar between the 2 formulations Modigraf granules and Prograf capsules.

Blood trough levels of tacrolimus should be monitored during the post-transplantation period.
Tacrolimus blood trough levels should be determined approximately 12 hours post-dosing of Modigraf granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels should be monitored at least twice weekly during the early post-transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored when clinical signs of toxicity or acute rejection are observed, following conversion between Modigraf granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).

Data from clinical studies suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 nanogram/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood

trough levels have generally been in the range 5 - 20 nanogram/ml in liver transplant recipients and 10 - 20 nanogram/ml in kidney and heart transplant patients in the early post-transplant period. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 - 15 nanogram/ml in liver, kidney and heart transplant recipients.

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

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

Race
In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.

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

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

Paediatric population
In general, paediatric patients require doses 1½ - 2 times higher than the adult doses to achieve similar blood levels.
Method of administration
Tacrolimus therapy is generally initiated by the oral route. If necessary, tacrolimus dosing may commence by administering Modigraf granules suspended in water, via nasogastric tubing.

It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).

Modigraf granules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption (see section 5.2).

The required dose is calculated from the weight of the patient, using the minimum number of sachets possible. 2 ml of water (at room temperature) should be used per 1 mg tacrolimus to produce a suspension (up to a maximum of 50 ml, depending on body weight) in a cup. Materials containing polyvinyl chloride (PVC) should not be used (see section 6.2). Granules are added to the water and stirred. It is not advised to use any liquids or utensils to empty the sachets. The suspension can be drawn up via a syringe or swallowed directly by the patient. Thereafter the cup is rinsed once with the same quantity of water and the rinsings consumed by the patient. The suspension should be administered immediately after preparation.

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

Summary of the safety profile
The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.

The most commonly reported adverse reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.

List of adverse reactions
The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not

known (cannot be estimated from the available data). Within each frequency grouping adverse reactions are presented in order of decreasing seriousness.

Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.
Cases of CMV infection, BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Modigraf.

Neoplasms benign, malignant and unspecified (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, skin malignancies and Kaposi’s sarcoma 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, thrombotic microangiopathy rare:
thrombotic thrombocytopenic purpura, hypoprothrombinaemia not known:
pure red cell aplasia, agranulocytosis, haemolytic anaemia, febrile neutropenia

Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).

Endocrine disorders rare:
hirsutism

Metabolism and nutrition disorders very common:
diabetes mellitus, hyperglycaemic conditions, hyperkalaemia common:
metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, hypophosphataemia uncommon:
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia

Psychiatric disorders very common:
insomnia common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare uncommon:
psychotic disorder

Nervous system disorders very common:
headache, tremor common:
nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired uncommon:
encephalopathy, central nervous system haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia rare:
hypertonia very rare:
not known:
myasthenia posterior reversible encephalopathy syndrome (PRES)

Eye disorders common:
eye disorders, vision blurred, photophobia uncommon:
cataract rare:
not known:
blindness optic neuropathy

Ear and labyrinth disorders common:
tinnitus uncommon:
hypoacusis rare:
deafness neurosensory very rare:
hearing impaired

Cardiac disorders common:
ischaemic coronary artery disorders, tachycardia uncommon:
heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ventricular hypertrophy, palpitations rare:
pericardial effusion very rare:
Torsades de pointes

Vascular disorders very common:
hypertension common:
thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders uncommon:
venous thrombosis deep limb, shock, infarction

Respiratory, thoracic and mediastinal disorders common:
parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations uncommon:
respiratory failures, respiratory tract disorders, asthma rare:
acute respiratory distress syndrome

Gastrointestinal disorders very common:
diarrhoea, nausea common:
gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal pains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages, gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools uncommon:
acute and chronic pancreatitis, ileus paralytic, gastrooesophageal reflux disease, impaired gastric emptying rare:
pancreatic pseudocyst, subileus

Hepatobiliary disorders common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice rare:
venoocclusive liver disease, hepatic artery thrombosis very rare:
hepatic failure

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

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

rare:
mobility decreased

Renal and urinary disorders very common:
renal impairment common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms uncommon:
haemolytic uraemic syndrome, anuria very rare:
nephropathy, cystitis haemorrhagic

Reproductive system and breast disorders uncommon:
dysmenorrhoea and uterine bleeding

General disorders and administration site conditions common:
febrile disorders, pain and discomfort, asthenic conditions, oedema, body temperature perception disturbed uncommon:
influenza like illness, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance rare:
fall, ulcer, chest tightness, thirst very rare:

fat tissue increased
Investigations very common:
liver function tests abnormal common:
blood alkaline phosphatase increased, weight increased uncommon:
amylase increased, ECG investigations abnormal, heart rate and pulse investigations abnormal, weight decreased, blood lactate dehydrogenase increased very rare:
echocardiogram abnormal, electrocardiogram QT prolonged

Injury, poisoning and procedural complications common:
primary graft dysfunction

Description of selected adverse reactions
Pain in extremity has been described in a number of published case reports as part of Calcineurin- Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There are no safety data available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in critically ill patients.

Modigraf should not be switched with Advagraf as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse reactions, including graft rejection, or other adverse reactions which could be a consequence of either under- or over-exposure to tacrolimus.
Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulations or regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8).

During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.

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

CYP3A4 inhibitors
Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which could lead to serious adverse reactions, including nephrotoxicity, neurotoxicity and QT prolongation. It is recommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin) with tacrolimus should be avoided. If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of co-administration, under the supervision of a transplant specialist, to adjust the tacrolimus dose if appropriate, in order to maintain similar tacrolimus exposure. Renal function, ECG including the QT interval, and the clinical condition of the patient should also be closely monitored.
Dose adjustment needs to be based upon the individual situation of each patient. An immediate dose reduction at the time of treatment initiation may be required. (see section 4.5).

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

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

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

P-glycoprotein
Caution should be observed when co-administering tacrolimus with drugs that inhibit P-glycoprotein,

as an increase in tacrolimus levels may occur. Tacrolimus whole blood levels and the clinical condition of the patient should be monitored closely. An adjustment of the tacrolimus dose may be required (see section 4.5).

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

Other interactions
The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.5).

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

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

Vaccination
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.

Nephrotoxicity
Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairment without active intervention may progress to chronic renal impairment. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with drugs associated with nephrotoxicity (see section 4.5). Concurrent use of tacrolimus with drugs known to have nephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus trough blood level and renal function should be monitored closely and dosage reduction should be considered if nephrotoxicity occurs.

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

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

Cardiac disorders
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients, particularly young children and those receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9-12 months). If abnormalities develop, dose reduction of Modigraf, or change of treatment to another immunosuppressive agent should be considered.
Tacrolimus may prolong the QT interval and may cause Torsades de pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities.
Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the

QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see section 4.5).

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

A combination of immunosuppressives such as antilymphocytic antibodies (e.g. basiliximab, daclizumab) given concomitantly increases the risk of EBV-associated lymphoproliferative disorders.
EBV-Viral Capsid Antigen (VCA)-negative patients have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Modigraf. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

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

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

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

Infections including opportunistic infections
Patients treated with immunosuppressants, including Modigraf, are at increased risk for infections including opportunistic infections (bacterial, fungal, viral and protozoal) such as CMV infection, 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 including graft rejection 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.

Thrombotic microangiopathy (TMA) (including haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)) The diagnosis of TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, should be considered

in patients presenting with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological manifestation, renal impairment, and fever. If TMA is diagnosed, prompt treatment is required, and discontinuation of tacrolimus should be considered at the discretion of the treating physician.
The concomitant administration of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, everolimus) may increase the risk of thrombotic microangiopathy (including haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura).

Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. 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
As Modigraf granules contain lactose, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’.

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

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

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

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

Medicinal products which have effects on tacrolimus
Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co- administration
Grapefruit or grapefruit juice
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].
Avoid grapefruit or grapefruit juice.
Ciclosporin
May increase tacrolimus whole blood trough concentrations. In addition, synergistic/additive nephrotoxic effects can occur.
The simultaneous use of ciclosporin and tacrolimus should be avoided [see section 4.4].
Products known to have nephrotoxic or neurotoxic effects:
aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen cidofovir, foscarnet May enhance nephrotoxic or neurotoxic effects of tacrolimus.
Concurrent use of tacrolimus with drugs known to have nephrotoxic effects should be avoided. When co-administration cannot be avoided, monitor renal function and other side effects and adjust tacrolimus dose if needed.
Strong CYP3A4 inhibitors:
antifungal agents (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), the macrolide antibiotics (e.g., telithromycin, troleandomycin, clarithromycin, josamycin), 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), nefazodone, the pharmacokinetic enhancer cobicistat and the kinase inhibitors idelalisib, ceritinib.
Strong interactions have also been observed with the macrolide antibiotic erythromycin May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., nephrotoxicity, neurotoxicity, QT prolongation) which requires close monitoring [see section 4.4].
Rapid and sharp increases in tacrolimus levels may occur, as early as within 1-3 days after co-administration, despite immediate reduction of tacrolimus dose. Overall tacrolimus exposure may increase > 5 fold. When ritonavir combinations are co-administered, tacrolimus exposure may increase > 50 fold.
Nearly all patients may require a reduction in tacrolimus dose and temporary interruption of tacrolimus may also be necessary.
It is recommended that concomitant use should be avoided. If co-administration of a strong CYP3A4 inhibitor is unavoidable, consider omitting the dose of tacrolimus the day the strong CYP3A4 inhibitor is initiated. Reinitiate tacrolimus the next day at a reduced dose based on tacrolimus blood concentrations. Changes in both tacrolimus dose and/or dosing frequency should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re-evaluated on and after completion of the CYP3A4 inhibitor. Upon completion, appropriate dose and dosing frequency of tacrolimus should be guided by tacrolimus blood concentrations. Monitor renal function, ECG for QT prolongation, and other side effects closely.

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co- administration
The effect on tacrolimus blood concentrations may remain for several days after co-administration is completed.

Moderate or weak CYP3A4 inhibitors:
antifungal agents (e.g., fluconazole, isavuconazole, clotrimazole, miconazole), the macrolide antibiotics (e.g., azithromycin), calcium channel blockers (e.g., nifedipine, nicardipine, diltiazem, verapamil), amiodarone, danazol, ethinylestradiol, lansoprazole, omeprazole, the HCV antivirals elbasvir/grazoprevir and glecaprevir/pibrentasvir, the CMV antiviral letermovir, and the tyrosine kinase inhibitors nilotinib, crizotinib and imatinib and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4]. A rapid increase in tacrolimus level may occur.
Monitor tacrolimus whole blood trough concentrations frequently, starting within the first few days of co-administration. Reduce tacrolimus dose if needed [see section 4.2]. Monitor renal function, ECG for QT prolongation, and other side effects closely.

In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism:
bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see section 4.2].
Monitor renal function, ECG for
QT prolongation, and other side effects closely.
Strong CYP3A4 inducers:
rifampicin, phenytoin carbamazepine, apalutamide, enzalutamide, mitotane or St.
John’s wort (Hypericum perforatum)
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Maximal effect on tacrolimus blood concentrations may be achieved 1-2 weeks after co- administration. The effect may remain 1-2 weeks after completion of the treatment.

It is recommended that concomitant use should be avoided. If unavoidable, patients may require an increase in tacrolimus dose. Changes in tacrolimus dose should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re-evaluated on and after completion of the CYP3A4 inducer. After use of the CYP3A4 inducer has ended, tacrolimus

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co- administration dose may need to be adjusted gradually. Monitor graft function closely.
Moderate CYP3A4 inducers:
metamizole, phenobarbital, isoniazid rifabutin, efavirenz, etravirine, nevirapine; weak CYP3A4 inducers:
flucloxacillin
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
Caspofungin
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection.
Mechanism of interaction has not been confirmed.
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2]. Monitor graft function closely.
Cannabidiol (P-gp inhibitor)

There have been reports of increased tacrolimus blood levels during concomitant use of tacrolimus with cannabidiol. This may be due to inhibition of intestinal P- glycoprotein, leading to increased bioavailability of tacrolimus.
Tacrolimus and cannabidiol should be co-administered with caution, closely monitoring for side effects. Monitor tacrolimus whole blood trough concentrations and adjust the tacrolimus dose if needed [see sections 4.2 and 4.4].

Products known to have high affinity for plasma proteins, e.g.: NSAIDs, oral anticoagulants, oral antidiabetics Tacrolimus is extensively bound to plasma proteins.
Possible interactions with other active substances known to have high affinity for plasma proteins should be considered.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see section 4.2].

Prokinetic agents:
metoclopramide, cimetidine and magnesium-aluminium- hydroxide
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).
Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see section 4.2].
Monitor closely for renal function, for QT prolongation with ECG, and for other side effects.
Maintenance doses of corticosteroids
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see section 4.4].
Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed [see section 4.2].
Monitor graft function closely.
High dose prednisolone or methylprednisolone
May have impact on tacrolimus blood levels
(increase or decrease) when administered for the treatment of acute rejection.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.

Drug/Substance Class or
Name
Drug interaction effect
Recommendations concerning co- administration
Direct-acting antiviral (DAA) therapy
May have impact on the pharmacokinetics of tacrolimus by changes in liver function during DAA therapy, related to clearance of HCV virus. A decrease in tacrolimus blood levels may occur. However, the CYP3A4 inhibiting potential of some DAAs may counteract that effect or lead to increased tacrolimus blood levels.
Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed to ensure continued efficacy and safety.

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

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). Care should be taken when tacrolimus is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Close monitoring of serum potassium is recommended.

Effect of tacrolimus on the metabolism of other medicinal products
Tacrolimus is a known CYP3A4 inhibitor; thus, concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.4).
Tacrolimus has been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.
Limited knowledge of interactions between tacrolimus and statins is available. Clinical data suggest that the pharmacokinetics of statins are largely unaltered by the co-administration of tacrolimus.
Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and phenazone.

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

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).

Pregnancy
Data from women show that tacrolimus crosses the placenta. There is a risk for hyperkalaemia in the newborn (e.g. incidence in neonates of 7.2%, i.e., 8 of 111) which tends to normalise spontaneously.
Tacrolimus treatment can be considered in pregnant women, when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse events of tacrolimus is recommended (in particular effects on the kidneys).

Results from a non-interventional post-authorisation safety study [EUPAS37025]
A post-authorisation safety study analysed 2,905 pregnancies from the Transplant Pregnancy Registry International (TPRI), assessing outcomes in women treated with tacrolimus (383 reported prospectively, including 247 kidney and 136 liver transplant patients), and those on other immunosuppressants. Based on limited data (289 prospectively-reported pregnancies with 1st trimester tacrolimus exposure), study results did not indicate an increased risk of major malformations. A higher prevalence of spontaneous abortion was observed among women treated with tacrolimus compared with alternative immunosuppressants. Among kidney transplant patients there was also a higher prevalence of pre-eclampsia in women treated with tacrolimus. However, overall, there were insufficient evidence to conclude on the risk of these outcomes. Among kidney and liver transplant patients exposed to tacrolimus, 45%-55% of their live births were premature, with 75%-85% having a normal birth weight for gestational age. Similar results were observed for other immunosuppressants, although conclusions were hindered by limited evidence.

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

Breast-feeding
Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving tacrolimus.
Fertility
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).

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

No studies on the effects of tacrolimus (Modigraf) on the ability to drive and use machines have been performed.

Several cases of accidental overdose have been reported with tacrolimus; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy and increases in blood urea nitrogen, serum creatinine concentrations and alanine aminotransferase levels.
No specific antidote to tacrolimus therapy is available. If overdose occurs, general supportive measures and symptomatic treatment should be conducted.
Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with very high plasma levels, haemofiltration or diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02 Mechanism of action and pharmacodynamic effects At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of lymphokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the expression of the interleukin-2 receptor.
Clinical efficacy and safety of tacrolimus administered twice daily in other primary organ transplantation In prospective published studies oral tacrolimus (given as Prograf capsules) was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of oral tacrolimus in these published studies appeared to be similar to what was reported in the large studies, where tacrolimus was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.

Lung transplantation
The interim analysis of a recent multicentre study discussed 110 patients who underwent 1:1 randomisation to either tacrolimus or ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.01 to 0.03 mg/kg/day and oral tacrolimus was administered at a dose of 0.05 to 0.3 mg/kg/day. A lower incidence of acute rejection episodes for tacrolimus- versus ciclosporin-treated patients (11.5% versus 22.6%) and a lower incidence of chronic rejection, the bronchiolitis obliterans syndrome (2.86% versus 8.57%), was reported within the first year after transplantation. The 1-year patient survival rate was 80.8% in the tacrolimus and 83% in the ciclosporin group.

Another randomised study included 66 patients on tacrolimus versus 67 patients on ciclosporin.

Absorption
In man, tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract.
Available tacrolimus is generally rapidly absorbed.
Modigraf granules are an immediate-release formulation of tacrolimus for twice daily dosing.
Following oral administration of Modigraf granules peak concentrations (Cmax) of tacrolimus in blood are on average achieved in approximately 2 to 2.5 hours.
Absorption of tacrolimus is variable. Results of a single dose bioequivalence study with adult healthy volunteers showed that Modigraf granules were approximately 20% more bioavailable than the Prograf capsules. Mean oral bioavailability of tacrolimus (investigated with the Prograf capsules formulation) is in the range of 20 - 25% (individual range in adult patients 6 - 43%, in paediatric kidney transplant patients 3 - 77%). The oral bioavailability of tacrolimus was reduced when it was administered after a meal.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Modigraf granules may commence orally.
In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a relatively flat absorption profile.

The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.
In stable liver transplant patients, the oral bioavailability of tacrolimus was reduced when it was administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and Cmax (50%), and an increase in tmax (173%) in whole blood were evident.

Protopic 0.03% ointment is indicated in adults, adolescents and children from the age of 2 years.

Flare treatment
Adults and adolescents (16 years of age and above)
Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.

Children (2 years of age and above)
Treatment of moderate to severe atopic dermatitis in children who failed to respond adequately to conventional therapies such as topical corticosteroids.

Maintenance treatment
Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).

Protopic 0.1 % ointment is indicated in adults and adolescents (16 years of age and above)

Flare treatment
Adults and adolescents (16 years of age and above)
Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.

Maintenance treatment
Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).

Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.

Protopic is available in two strengths, Protopic 0.03% and Protopic 0.1% ointment.

Posology

Flare treatment
Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be continuous on a long-term basis.
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected.
eDoc-000593873 - Version 19. 0

Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.

Adults and adolescents (16 years of age and above)
Treatment should be started with Protopic 0.1% twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Protopic 0.03% ointment if the clinical condition allows.

Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered.

Elderly
Specific studies have not been conducted in older people. However, the clinical experience available in this patient population has not shown the necessity for any dosage adjustment.

Paediatric population
Children (2 years of age and above) should use the lower strength Protopic 0.03% ointment.
Treatment should be started twice a day for up to three weeks. Afterwards the frequency of application should be reduced to once a day until clearance of the lesion (see section 4.4).

Protopic ointment should not be used in children aged below 2 years until further data are available.

Maintenance treatment
Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions cleared, almost cleared or mildly affected) are suitable for maintenance treatment.

Adults and adolescents (16 years of age and above)
Adult patients should use Protopic 0.1% ointment.
Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.

After 12 months treatment, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months.

If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment section above).

Elderly
Specific studies have not been conducted in older people (see flare treatment section above).

Paediatric population
Children (2 years of age and above) should use the lower strength Protopic 0.03% ointment.
Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.
The review of the child`s condition after 12 months treatment should include suspension of treatment to assess the need to continue this regimen and to evaluate the course of the disease.

Protopic ointment should not be used in children aged below 2 years until further data are available.

Method of administration
Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin.
Protopic ointment may be used on any part of the body, including face, neck and flexure areas, except eDoc-000593873 - Version 19. 0

on mucous membranes. Protopic ointment should not be applied under occlusion because this method of administration has not been studied in patients (see section 4.4).

Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.

Protopic is available in two strengths, Protopic 0.03 % and Protopic 0.1 % ointment.

Posology

Flare treatment
Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be continuous on a long-term basis.
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected.
Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.

eDoc-000593873 - Version 19. 0

Adults and adolescents (16 years of age and above)
Treatment should be started with Protopic 0.1% twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Protopic 0.03% ointment if the clinical condition allows.

Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered.

Elderly
Specific studies have not been conducted in older people. However, the clinical experience available in this patient population has not shown the necessity for any dosage adjustment.

Paediatric population
Only Protopic 0.03 % ointment should be used in children from the age of 2 to 16 years.
Protopic ointment should not be used in children aged below 2 years until further data are available.

Maintenance treatment
Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions cleared, almost cleared or mildly affected) are suitable for maintenance treatment.

Adults and adolescents (16 years of age and above)
Adult patients (16 years of age and above) should use Protopic 0.1% ointment. Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.

After 12 months treatment, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months.

If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment section above).

Elderly
Specific studies have not been conducted in older people (see flare treatment section above).

Paediatric population
Only Protopic 0.03 % ointment should be used in children from the age of 2 to 16 years.
Protopic ointment should not be used in children aged below 2 years until further data are available.

Method of administration
Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin.
Protopic ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Protopic ointment should not be applied under occlusion because this method of administration has not been studied in patients (see section 4.4).

Hypersensitivity to the active substance, macrolides in general, or to any of the excipients listed in section 6.1.

In clinical studies approximately 50% of patients experienced some type of skin irritation adverse reaction at the site of application. Burning sensation and pruritus were very common, usually mild to moderate in severity and tended to resolve within one week of starting treatment. Erythema was a common skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site of application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage) was common.
Patients may be at an increased risk of folliculitis, acne and herpes viral infections.

Adverse reactions with suspected relationship to treatment are listed below by system organ class.
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ
Class
Very Common
≥1/10
Common
≥1/100,
<1/10
Uncommon
≥1/1000,
<1/100
Not known
(cannot be estimated from the available data)
Infections and infestations

Local skin infection regardless of specific aetiology including but not limited to:
Eczema herpeticum,
Folliculitis,
Herpes simplex,
Herpes virus infection,
Kaposi’s varicelliform eruption*

Ophthalmic
Herpes
Infection*
Metabolism and nutrition disorders

Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage)

Nervous system disorders

Paraesthesias and dysaesthesias
(hyperaesthesia, burning sensation)

Skin and subcutaneous tissue disorders

Pruritus

Acne*
Rosacea*
Lentigo*
General disorders and administration site conditions
Application site burning,
Application site pruritus
Application site warmth,
Application site erythema,
Application site pain,
Application site irritation,
Application site paraesthesia,
Application site rash

Application site oedema* eDoc-000593873 - Version 19. 0

Investigations

Drug level increased*
(see section
4.4)
*The adverse reaction has been reported during post-marketing experience

Maintenance treatment
In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and severe atopic dermatitis the following adverse events were noted to occur more frequently than in the control group: application site impetigo (7.7% in children) and application site infections (6.4% in children and 6.3% in adults).

Paediatric population
Frequency, type and severity of adverse reactions in children are similar to those reported in adults.

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.

In clinical studies approximately 50% of patients experienced some type of skin irritation adverse reaction at the site of application. Burning sensation and pruritus were very common, usually mild to moderate in severity and tended to resolve within one week of starting treatment. Erythema was a common skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site of eDoc-000593873 - Version 19. 0

application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage) was common.
Patients may be at an increased risk of folliculitis, acne and herpes viral infections.

Adverse reactions with suspected relationship to treatment are listed below by system organ class.
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ
Class
Very Common
≥1/10
Common
≥1/100,
<1/10
Uncommon
≥1/1000,
<1/100
Not known
(cannot be estimated from the available data)
Infections and infestations

Local skin infection regardless of specific aetiology including but not limited to:
Eczema herpeticum,
Folliculitis,
Herpes simplex,
Herpes virus infection,
Kaposi’s varicelliform eruption*

Ophthalmic
Herpes
Infection*
Metabolism and nutrition disorders

Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage)

Nervous system disorders

Paraesthesias and dysaesthesias
(hyperaesthesia, burning sensation)

Skin and subcutaneous tissue disorders

Pruritus

Acne*
Rosacea*
Lentigo*
General disorders and administration site conditions
Application site burning,
Application site pruritus
Application site warmth,
Application site erythema,
Application site pain,
Application site irritation,
Application site paraesthesia,
Application site rash

Application site oedema*
Investigations

Drug level increased*
(see section
4.4)
*The adverse reaction has been reported during post-marketing experience

Maintenance treatment
In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and severe atopic dermatitis the following adverse events were noted to occur more frequently than in the control group: application site impetigo (7.7% in children) and application site infections (6.4% in children and 6.3% in adults).

Reporting of suspected adverse reactions eDoc-000593873 - Version 19. 0

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.

Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided during use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that are considered to be potentially malignant or pre-malignant. The development of any new change different from previous eczema within a treated area should be reviewed by the physician.

The use of tacrolimus ointment is not recommended in patients with a skin barrier defect, such as Netherton’s syndrome, lamellar ichthyosis, generalized erythroderma, pyoderma gangrenosum or cutaneous Graft Versus Host Disease. These skin conditions may increase systemic absorption of tacrolimus. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions. Protopic should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.

Care should be exercised if applying Protopic to patients with extensive skin involvement over an extended period of time, especially in children (see section 4.2). Patients, particularly paediatric patients should be continuously evaluated during treatment with Protopic with respect to the response to treatment and the continuing need for treatment. After 12 months this evaluation should include suspension of Protopic treatment in paediatric patients (see section 4.2). The effect of treatment with Protopic ointment on the developing immune system of children aged below 2 years has not been established (see section 4.1).

Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies. Patients with atopic dermatitis treated with Protopic have not been found to have significant systemic tacrolimus levels and the role of local immunosuppression is unknown.
Based on the results of long-term studies and experience, a link between Protopic ointment treatment and development of malignancies has not been confirmed, but definitive conclusions cannot be drawn.
It is recommended to use tacrolimus ointment at the lowest strength and the lowest frequency for the shortest duration necessary as determined by the physician’s evaluation of the clinical condition (see section 4.2).

Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic therapy. Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Protopic should be considered. Patients who develop lymphadenopathy during treatment should be monitored to ensure that the lymphadenopathy resolves.

Patients with atopic dermatitis are predisposed to superficial skin infections. Protopic ointment has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis.
Before commencing treatment with Protopic ointment, clinical infections at treatment sites should be cleared. Treatment with Protopic is associated with an increased risk of folliculitis and herpes viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi’s eDoc-000593873 - Version 19. 0

varicelliform eruption) (see section 4.8). In the presence of these infections, the balance of risks and benefits associated with Protopic use should be evaluated.

Emollients should not be applied to the same area within 2 hours of applying Protopic ointment.
Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.

Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.

The use of Protopic ointment under occlusion has not been studied in patients. Occlusive dressings are not recommended.

As with any topical medicinal product, patients should wash their hands after application if the hands are not intended for treatment.

Tacrolimus is extensively metabolised in the liver and although blood concentrations are low following topical therapy, the ointment should be used with caution in patients with hepatic failure (see section 5.2).

Excipients warnings
Protopic ointment contains butylhydroxytoluene (E321) as an excipient, which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided during use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sun eDoc-000593873 - Version 19. 0

protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that are considered to be potentially malignant or pre-malignant. The development of any new change different from previous eczema within a treated area should be reviewed by the physician.

The use of tacrolimus ointment is not recommended in patients with a skin barrier defect, such as Netherton’s syndrome, lamellar ichthyosis, generalized erythroderma, pyoderma gangrenosum or cutaneous Graft Versus Host Disease. These skin conditions may increase systemic absorption of tacrolimus. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions. Protopic should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.

Care should be exercised if applying Protopic to patients with extensive skin involvement over an extended period of time, especially in children (see section 4.2). Patients, particularly paediatric patients should be continuously evaluated during treatment with Protopic with respect to the response to treatment and the continuing need for treatment. After 12 months this evaluation should include suspension of Protopic treatment in paediatric patients (see section 4.2).

Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies. Patients with atopic dermatitis treated with Protopic have not been found to have significant systemic tacrolimus levels and the role of local immunosuppression is unknown.
Based on the results of long-term studies and experience, a link between Protopic ointment treatment and development of malignancies has not been confirmed, but definitive conclusions cannot be drawn.
It is recommended to use tacrolimus ointment at the lowest strength and the lowest frequency for the shortest duration necessary as determined by the physician’s evaluation of the clinical condition (see section 4.2).

Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic therapy. Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Protopic should be considered. Patients who develop lymphadenopathy during treatment should be monitored to ensure that the lymphadenopathy resolves.

Patients with atopic dermatitis are predisposed to superficial skin infections. Protopic ointment has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis.
Before commencing treatment with Protopic ointment, clinical infections at treatment sites should be cleared. Treatment with Protopic is associated with an increased risk of folliculitis and herpes viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi’s varicelliform eruption) (see section 4.8). In the presence of these infections, the balance of risks and benefits associated with Protopic use should be evaluated.

Emollients should not be applied to the same area within 2 hours of applying Protopic ointment.
Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.

Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.

The use of Protopic ointment under occlusion has not been studied in patients. Occlusive dressings are not recommended.

As with any topical medicinal product, patients should wash their hands after application if the hands are not intended for treatment.
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Tacrolimus is extensively metabolised in the liver and although blood concentrations are low following topical therapy, the ointment should be used with caution in patients with hepatic failure (see section 5.2).

Excipients warnings
Protopic ointment contains butylhydroxytoluene (E321) as an excipient, which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Formal topical drug interaction studies with tacrolimus ointment have not been conducted.

Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous interactions that could affect the metabolism of tacrolimus.

Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4).
Systemic exposure from topical application of tacrolimus ointment is low (<1.0 ng/ml) and is unlikely to be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, the possibility of interactions cannot be ruled out and the concomitant systemic administration of known CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread and/or erythrodermic disease should be done with caution.

Paediatric population
An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C has been investigated in children aged 2-11 years. No effect on immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity has been observed (see section 5.1).

Formal topical drug interaction studies with tacrolimus ointment have not been conducted.

Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous interactions that could affect the metabolism of tacrolimus.

Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4).
Systemic exposure from topical application of tacrolimus ointment is low (< 1.0 ng/ml) and is unlikely to be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, the possibility of interactions cannot be ruled out and the concomitant systemic administration of known CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread and/or erythrodermic disease should be done with caution.

Paediatric population
An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C has been investigated in children aged 2-11 years. No effect on immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity has been observed (see section 5.1).

Pregnancy
There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see section 5.3). The potential risk for humans is unknown.

Protopic ointment should not be used during pregnancy unless clearly necessary.

Breast-feeding
Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk.
Although clinical data have shown that systemic exposure from application of tacrolimus ointment is low, breast-feeding during treatment with Protopic ointment is not recommended.
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Fertility
There are no fertility data available.

Pregnancy
There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see section 5.3). The potential risk for humans is unknown.

Protopic ointment should not be used during pregnancy unless clearly necessary.

Breast-feeding
Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk.
Although clinical data have shown that systemic exposure from application of tacrolimus ointment is low, breast-feeding during treatment with Protopic ointment is not recommended.

Fertility
There are no fertility data available.

Protopic ointment has no or negligible influence on the ability to drive and use machines.

Overdosage following topical administration is unlikely.
If ingested, general supportive measures may be appropriate. These may include monitoring of vital signs and observation of clinical status. Due to the nature of the ointment vehicle, induction of vomiting or gastric lavage is not recommended.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Agents for dermatitis, excluding corticosteroids, ATC code: D11AH01

Mechanism of action and pharmacodynamic effects
The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known.
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium- dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ.
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory mediators from skin mast cells, basophils and eosinophils.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis in humans.

Clinical efficacy and safety eDoc-000593873 - Version 19. 0

The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus ointment in Phase I to Phase III clinical trials. Data from six major trials are presented here.

In a six-month multicentre double-blind randomised trial, 0.1% tacrolimus ointment was administered twice-a-day to adults with moderate to severe atopic dermatitis and compared to a topical corticosteroid based regimen (0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck). The primary endpoint was the response rate at month 3 defined as the proportion of patients with at least 60% improvement in the mEASI (modified Eczema Area and Severity Index) between baseline and month 3. The response rate in the 0.1% tacrolimus group (71.6%) was significantly higher than that in the topical corticosteroid based treatment group (50.8%; p<0.001; Table 1). The response rates at month 6 were comparable to the 3-month results.

Table 1: Efficacy at month 3

Topical corticosteroid regimen§
(N=485)
Tacrolimus 0.1%
(N=487)
Response rate of ≥ 60% improvement in mEASI (Primary
Endpoint)§§
50.8%
71.6%
Improvement ≥ 90% in Physician’s
Global Evaluation
28.5%
47.7%
§ Topical corticosteroid regimen = 0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck §§ higher values = greater improvement

Pharmacotherapeutic group: Agents for dermatitis, excluding corticosteroids, ATC code: D11AH01

Mechanism of action and pharmacodynamic effects
The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known.
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium- dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ.
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory mediators from skin mast cells, basophils and eosinophils.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis in humans.

Clinical efficacy and safety
The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus ointment in Phase I to Phase III clinical trials. Data from six major trials are presented here.

In a six-month multicentre double-blind randomised trial, 0.1% tacrolimus ointment was administered twice-a-day to adults with moderate to severe atopic dermatitis and compared to a topical corticosteroid based regimen (0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck). The primary endpoint was the response rate at month 3 defined as the proportion of patients with at least 60% improvement in the mEASI (modified Eczema Area and Severity Index) between baseline and month 3. The response rate in the 0.1% tacrolimus group (71.6%) was significantly higher than that in the topical corticosteroid based treatment group (50.8%; p<0.001; Table 1). The response rates at month 6 were comparable to the 3-month results.

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Table 1: Efficacy at month 3

Topical corticosteroid regimen§
(N=485)
Tacrolimus 0.1%
(N=487)
Response rate of ≥ 60% improvement in mEASI (Primary
Endpoint)§§
50.8%
71.6%
Improvement ≥ 90% in Physician’s
Global Evaluation
28.5%
47.7%
§ Topical corticosteroid regimen = 0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck §§ higher values = greater improvement

Clinical data have shown that tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.

Absorption
Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimus following single or repeated topical application of tacrolimus ointment.
Target trough concentrations for systemic immunosuppression for oral tacrolimus are 5-20 ng/mL in transplant patients. Most atopic dermatitis patients (adults and children) treated with single or repeated application of tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment (0.03%) had blood concentrations < 1.0 ng/mL. When observed, blood concentrations exceeding 1.0 ng/mL were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus from Protopic ointment is approximately 30-fold less than that seen eDoc-000593873 - Version 19. 0

with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to one year) with tacrolimus ointment.

Distribution
As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to plasma proteins is considered not to be clinically relevant.
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin with minimal diffusion into the systemic circulation.

Biotransformation
Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is extensively metabolised in the liver via CYP3A4.

Clinical data have shown that tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.

Absorption
Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimus following single or repeated topical application of tacrolimus ointment.
Target trough concentrations for systemic immunosuppression for oral tacrolimus are 5-20 ng/mL in transplant patients. Most atopic dermatitis patients (adults and children) treated with single or repeated application of tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment (0.03%) had blood concentrations < 1.0 ng/mL. When observed, blood concentrations exceeding 1.0 ng/mL were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus from Protopic ointment is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to one year) with tacrolimus ointment.

Distribution
As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to plasma proteins is considered not to be clinically relevant.
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin with minimal diffusion into the systemic circulation.

Biotransformation
Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is extensively metabolised in the liver via CYP3A4.
eDoc-000593873 - Version 19. 0