Tracsus

Tracsus is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants.

Limitation of Use

Tracsus extended-release capsules are not interchangeable or substitutable with other tacrolimus extended-release or immediate-release products.

Tracsus is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants.

Limitation Of Use

Tracsus extended-release tablets are not interchangeable or substitutable with other tacrolimus extended-release or immediate-release products.

Tracsus therapy requires careful monitoring by adequately qualified and equipped personnel. The medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.

General considerations

The recommended initial dosages presented below are intended to act solely as a guideline. Tracsus dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below for recommended target whole blood trough concentrations). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

Tracsus can be administered intravenously or orally. In general, dosing may commence orally; if necessary, by administering the capsule contents suspended in water, via nasogastric tubing.

Tracsus is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The Tracsus dose may vary depending upon the immunosuppressive regimen chosen.

Method of administration

The concentrate should be used for intravenous infusion only after it is diluted with suitable carrier media.

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 - 500 ml.

The diluted solution should not be given as a bolus.

Duration of dosing

Patients should be converted from intravenous to oral medication as soon as individual circumstances permit. Intravenous therapy should not be continued for more than 7 days.

Dosage recommendations - Liver transplantation

Prophylaxis of transplant rejection - adults

Oral Tracsus therapy should commence at 0.10 - 0.20 mg/kg/day administered as two 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 should be initiated as a continuous 24-hour infusion.

Prophylaxis of transplant rejection - children

An initial oral dose of 0.30 mg/kg/day should be administered in two 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 should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and children

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

Rejection therapy - adults and children

Increased Tracsus 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 are noted the dose of Tracsus may need to be reduced.

For conversion to Tracsus, treatment should begin with the initial oral dose recommended for primary immunosuppression.

For information on conversion from ciclosporin to Tracsus, see below under “Dose adjustments in specific patient populations”.

Dosage recommendations - Kidney transplantation

Prophylaxis of transplant rejection - adults

Oral Tracsus therapy should commence at 0.20 - 0.30 mg/kg/day administered as two 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 should be initiated as a continuous 24-hour infusion.

Prophylaxis of transplant rejection - children

An initial oral dose of 0.30 mg/kg/day should be administered in two 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 should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and children

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

Rejection therapy - adults and children

Increased Tracsus 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 are noted the dose of Tracsus may need to be reduced.

For conversion to Tracsus, treatment should begin with the initial oral dose recommended for primary immunosuppression.

For information on conversion from ciclosporin to Tracsus, see below under “Dose adjustments in specific patient populations”.

Dosage recommendations - Heart transplantation

Prophylaxis of transplant rejection - adults

Tracsus can be used with antibody induction (allowing for delayed start of Tracsus therapy) or alternatively in clinically stable patients without antibody induction.

Following antibody induction, oral Tracsus therapy should commence at a dose of 0.075 mg/kg/day administered as two 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 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.

Prophylaxis of transplant rejection - children

Tracsus has been used with or without antibody induction in paediatric heart transplantation.

In patients without antibody induction, if Tracsus therapy is initiated intravenously, the recommended starting dose is 0.03 - 0.05 mg/kg/day as a continuous 24-hour infusion targeted to achieve tacrolimus whole blood concentrations of 15 - 25 ng/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 Tracsus therapy is initiated orally, the recommended starting dose is 0.10 - 0.30 mg/kg/day administered as two divided doses (e.g. morning and evening).

Dose adjustment during post-transplant period in adults and children

Tracsus 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.

Rejection therapy - adults and children

Increased Tracsus doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes.

In adult patients converted to Tracsus, an initial oral dose of 0.15 mg/kg/day should be administered in two divided doses (e.g. morning and evening).

In paediatric patients converted to Tracsus, an initial oral dose of 0.20 - 0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening).

For information on conversion from ciclosporin to Tracsus, see below under “Dose adjustments in specific patient populations”.

Dosage recommendations - Rejection therapy, other allografts

The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data. In lung-transplanted patients Tracsus has been used 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.

Dosage adjustments in specific patient populations

Patients with liver 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.

Patients with kidney impairment

As the pharmacokinetics of tacrolimus are unaffected by renal function, no dose adjustment should be 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).

Paediatric patients

In general, paediatric patients require doses 1½ - 2 times higher than the adult doses to achieve similar blood levels.

Older people

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

Conversion from ciclosporin

Care should be taken when converting patients from ciclosporin-based to Tracsus-based therapy. Tracsus 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, Tracsus 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.

Target whole blood trough concentration recommendations

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient.

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood including a semi-automated microparticle enzyme immunoassay (MEIA). 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.

Blood trough levels of tacrolimus should be monitored during the post-transplantation period. When dosed orally, blood trough levels should be drawn approximately 12 hours post-dosing, just prior to the next dose. The frequency of blood level monitoring should be based on clinical needs. As Tracsus is a medicinal product with low clearance, adjustments to the dosage regimen may take several days before changes in blood levels are apparent. Blood trough levels should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be monitored following dose adjustment, changes in the immunosuppressive regimen, or following co-administration of substances which may alter tacrolimus whole blood concentrations.

Clinical study analysis suggests 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. Subsequently, during maintenance therapy, blood concentrations have generally been in the range of 5 - 15 ng/ml in liver, kidney and heart transplant recipients.

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

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

Posology

Flare treatment

Tracsus can be used for short-term and intermittent long-term treatment. Treatment should not be continuous on a long-term basis.

Tracsus treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Tracsus 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.

Adults and adolescents (16 years of age and above)

Treatment should be started with Tracsus 0.1% twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Tracsus 0.1% should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Tracsus 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.

Older people

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 Tracsus 0.03 % ointment should be used in children from the age of 2 to 16 years.

Tracsus 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 Tracsus 0.1% ointment. Tracsus 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 Tracsus 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).

Older people

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

Paediatric population

Only Tracsus 0.03 % ointment should be used in children from the age of 2 to 16 years.

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

Method of administration

Tracsus ointment should be applied as a thin layer to affected or commonly affected areas of the skin. Tracsus ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Tracsus ointment should not be applied under occlusion because this method of administration has not been studied in 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. Tracsus is a granular formulation of tacrolimus, for twice-a-day administration. Tracsus 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. Tracsus 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. Tracsus 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.).

Tracsus 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. 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 Tracsus 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 patients

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 Tracsus 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 patients

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

Tracsus 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 Tracsus 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 patients

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 Tracsus 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 Tracsus and Prograf tacrolimus formulations

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

Stable allograft recipients maintained on Tracsus 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 Tracsus granules, the total daily Tracsus 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 Tracsus should be rounded down to the nearest total daily dose possible with sachets 0.2 mg and 1 mg.

The total daily dose of Tracsus 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. Tracsus 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 Tracsus 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. 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 , the dose of Tracsus 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 Tracsus, 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 Tracsus, 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 (AUC_0-12) is similar between the 2 formulations Tracsus 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 Tracsus 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 Tracsus granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations. 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 Tracsus dose regimen before the targeted steady state is achieved.

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 , 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 patients

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 Tracsus granules suspended in water, via nasogastric tubing.

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

Tracsus 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.

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. 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.

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

Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of adverse reactions, including under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist. 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. Tracsus 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. Tracsus 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 AUC_0-24 of tacrolimus for Tracsus 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 Tracsus to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Tracsus 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

Tracsus 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.

Tracsus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Tracsus 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

Tracsus 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.

Tracsus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Tracsus 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 Tracsus

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

In stable patients converted from Prograf capsules (twice daily) to Tracsus (once daily) on a 1:1 (mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC_0-24) for Tracsus was approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C₂₄) and systemic exposure (AUC_0-24) for Tracsus is similar to that of Prograf. When converting from Prograf capsules to Tracsus, 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. The combined administration of ciclosporin and tacrolimus is not recommended. Tracsus 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 , the dose of Tracsus may need to be reduced.

Treatment of allograft rejection after kidney or liver transplantation

For conversion from other immunosuppressants to once daily Tracsus, 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 Tracsus, 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 Tracsus in lung-, pancreas- or intestine-transplanted patients, Prograf has been used in lung-transplanted patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.

Therapeutic drug monitoring

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

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship between tacrolimus trough levels (C₂₄) and systemic exposure (AUC _0-24) is similar between the two formulations Tracsus 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 Tracsus, 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 Tracsus, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations. The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Tracsus 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 , 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 patients

The safety and efficacy of Tracsus 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

Tracsus is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Tracsus be administered once daily in the morning. Tracsus 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). Tracsus 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. 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 1/5^th of the recommended oral dose for the corresponding indication.

Tracsus is a once-a-day oral formulation of tacrolimus. Tracsus 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. 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. Tracsus 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.

Tracsus 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 Tracsus 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.

Tracsus 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.

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

Tracsus 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

Tracsus 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 Tracsus - allograft transplant patients

Allograft transplant patients maintained on twice daily Prograf (immediate-release) or Advagraf (once daily) dosing requiring conversion to once daily Tracsus should be converted on a 1:0.7 (mg:mg) total daily dose basis and the Tracsus maintenance dose should, therefore, be 30% less than the Prograf or Advagraf dose. Tracsus should be administered in the morning.

In stable patients converted from tacrolimus immediate-release products (twice daily) to Tracsus (once daily) on a 1:0.7 (mg:mg) total daily dose basis, the mean systemic exposure to tacrolimus (AUC_0-24) was similar to that of immediate-release tacrolimus. The relationship between tacrolimus trough levels (C₂₄) and systemic exposure (AUC_0-24) for Tracsus is similar to that of immediate-release tacrolimus. No studies have been conducted with conversion of patients from Advagraf to Tracsus; however, data from healthy volunteers would suggest that the same conversion rate is applicable as with the conversion from Prograf to Tracsus.

When converting from tacrolimus immediate-release products (e.g. Prograf capsules) or from Advagraf prolonged-release capsules to Tracsus, 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. The combined administration of ciclosporin and tacrolimus is not recommended. Tracsus 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 , the dose of Tracsus may need to be reduced.

Treatment of allograft rejection after kidney or liver transplantation

For conversion from other immunosuppressants to once daily Tracsus, 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 (AUC_0-24) is well correlated and is similar between the immediate-release formulation and Tracsus.

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 Tracsus, 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. The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Tracsus 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

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 , 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 Tracsus at 1: 0.85 (mg:mg)

Gender

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

Elderly patients (> 65 years)

There is no evidence currently available to indicate that dose should be adjusted in elderly patients.

Paediatric population

The safety and efficacy of Tracsus in children below 18 years of age have not yet been established.

No data are available.

Method of administration

Tracsus is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Tracsus is administered once daily.

Patients should be advised not to swallow the desiccant. The tablets should be swallowed whole with fluid (preferably water) immediately following removal from the blister. Tracsus should generally be taken on an empty stomach to achieve maximal absorption.

Tracsus is not interchangeable with other existing tacrolimus containing medicines (immediate release or prolonged release) on an equal dose by dose basis.

Administration Instructions

• Take Tracsus consistently every morning at the same time (to ensure consistent and maximum possible drug exposure) on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
• Swallow Tracsus capsules whole with liquid; do not chew, divide, or crush the capsules.
• If a dose is missed, take the dose up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, take by 10:00 PM). Beyond the 14-hour time frame, wait until the usual scheduled time the following morning to take the next regular daily dose.
• Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking Tracsus.

Recommended Starting Dosage

Table 1 includes the recommended starting Tracsus dosages. Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require a lower starting dosage of Tracsus.

Table 1: Recommended Starting Dosage of Tracsus with or without Basiliximab Induction

Dosage Adjustments

Titrate the Tracsus dosage based on clinical assessments of rejection and tolerability and to achieve target trough concentration ranges (see Table 2).

African-American patients, compared to Caucasian patients, may need to be titrated to higher Tracsus dosages to attain comparable trough concentrations.

Table 2: Recommended Target Tacrolimus Whole Blood Trough Concentrations in Kidney Transplant Patients

Therapeutic Drug Monitoring

Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors, or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the Tracsus dose.

Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.

Administration Instructions

• Take Tracsus on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
• Swallow Tracsus whole with fluid (preferably water); do not chew, divide, or crush the tablets.
• If a dose is missed, take it as soon as possible within 15 hours after missing the dose; beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose. Do not double the next dose.
• Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking Tracsus.
• African-American patients, compared to Caucasian patients, may need to be titrated to higher Tracsus dosages to attain comparable trough concentrations.

Conversion From Tacrolimus Immediate-Release Formulations

To convert from a tacrolimus immediate-release product to Tracsus, administer an Tracsus once daily dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole blood trough concentrations and titrate Tracsus dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/mL.

Therapeutic Drug Monitoring

Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the Tracsus dose.

Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.

Hypersensitivity to other macrolides.

Hypersensitivity to other macrolides

Hypersensitivity to other macrolides.

Tracsus is contraindicated in patients with known hypersensitivity to tacrolimus.

Tracsus is contraindicated in patients with known hypersensitivity to tacrolimus.

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

Substances with potential for interaction

When substances with a potential for interaction - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) - are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Herbal preparations containing St. John's wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Tracsus 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.

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.

High potassium intake or potassium-sparing diuretics should be avoided.

Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects.

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.

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 primarily in children 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 three months and then at 9-12 months). If abnormalities develop, dose reduction of Tracsus therapy, 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.

Lymphoproliferative disorders and malignancies

Patients treated with Tracsus have been reported to develop Epstein-Barr Virus (EBV)-associated lymphoproliferative disorders. Patients switched to Tracsus therapy should not receive anti-lymphocyte treatment concomitantly. Very young (< 2 years), EBV-VCA-negative children 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 Tracsus. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

As with other 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.

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 control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

Opportunistic infections

Patients treated with immunosuppressants, including Tracsus are at increased risk of opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in patients with deteriorating renal function or neurological symptoms.

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.

If administered accidentally either arterially or perivasally, the reconstituted Tracsus 5 mg/ml concentrate for solution for infusion may cause irritation at the injection site.

Excipients

Tracsus 5 mg/ml concentrate for solution for infusion contains polyoxyethylene hydrogenated castor oil, which has been reported to cause anaphylactoid reactions. Caution is therefore necessary in patients who have previously received preparations containing polyoxyethylene castor oil derivatives either by intravenous injection or infusion, and in patients with an allergenic predisposition. The risk of anaphylaxis may be reduced by slow infusion of reconstituted Tracsus 5 mg/ml concentrate for solution for infusion or by the prior administration of an antihistamine. Patients should be closely observed during the first 30 minutes of infusion for possible anaphylactoid reaction.

The ethanol content (638 mg per ml) of Tracsus 5 mg/ml concentrate for solution for infusion should be taken into account.

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 Tracsus ointment. 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. Tracsus 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 or cutaneous Graft Versus Host Disease. These skin conditions may increase systemic absorption of tacrolimus. Oral use of tacrolimus is also not recommended to treat these skin conditions. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.

Care should be exercised if applying Tracsus to patients with extensive skin involvement over an extended period of time, especially in children.

Patients, particularly paediatric patients should be continuously evaluated during treatment with Tracsus with respect to the response to treatment and the continuing need for treatment. After 12 months this evaluation should include suspension of Tracsus treatment in paediatric patients.

The potential for local immunosuppression (possibly resulting in infections or cutaneous malignancies) in the long term (i.e. over a period of years) is unknown.

Tracsus 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. In patients using tacrolimus ointment, cases of malignancies, including cutaneous (i.e. cutaneous T Cell lymphomas) and other types of lymphoma, and skin cancers have been reported. Tracsus should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.

Patients with atopic dermatitis treated with Tracsus have not been found to have significant systemic tacrolimus levels.

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. Transplant patients receiving immunosuppressive regimens (e.g. systemic tacrolimus) are at increased risk for developing lymphoma; therefore patients who receive Tracsus and who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. 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 Tracsus should be considered.

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

Emollients should not be applied to the same area within 2 hours of applying Tracsus 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 Tracsus 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.

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

Tracsus 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.

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

When substances with a potential for interaction - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) - are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Herbal preparations containing St. John's Wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Tracsus 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.

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.

High potassium intake or potassium-sparing diuretics should be avoided.

Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risks of these 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.

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 Tracsus, 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.

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been reported to develop Epstein-Barr Virus (EBV)-associated lymphoproliferative disorders. 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 Tracsus. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

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

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.

Opportunistic infections

Patients treated with immunosuppressants, including Tracsus, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

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 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.

Excipients

Tracsus granules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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.

Tracsus 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 Tracsus.

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

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

When substances with a potential for interaction - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) - are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Herbal preparations containing St. John's Wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Tracsus 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.

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.

High potassium intake or potassium-sparing diuretics should be avoided.

Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these 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.

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 Tracsus. 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 Tracsus, 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.

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been reported to develop Epstein-Barr-Virus (EBV)-associated lymphoproliferative disorders. 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 Tracsus. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

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

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.

Opportunistic infections

Patients treated with immunosuppressants, including Tracsus are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

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 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.

Excipients

Tracsus capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The printing ink used to mark Tracsus 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 Tracsus.

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.

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 Tracsus.

For prophylaxis of transplant rejection in adult heart, lung, pancreas, or intestine allograft recipients clinical data are not yet available for Tracsus.

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

When substances with a potential for interaction , particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or inducers of CYP3A4 (such as rifampicin or rifabutin), are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Herbal preparations containing St. John's Wort (Hypericum perforatum) should be avoided when taking Tracsus due to the risk of interactions that lead to a decrease in both blood concentrations and the therapeutic effect of tacrolimus.

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.

High potassium intake or potassium-sparing diuretics should be avoided.

Certain combinations of tacrolimus with substances known to have nephrotoxic or neurotoxic effects may increase the risk of these 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.

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 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 preexisting 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 Tracsus 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 EBV-associated lymphoproliferative disorders. 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 Tracsus. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

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

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.

Patients treated with immunosuppressants, including Tracsus are at increased risk for opportunistic infections (bacterial, fungal, viral, and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

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.

Excipients

Tracsus contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Paediatric population

Tracsus is not recommended for use in children below 18 years of age due to the limited data on safety and/or efficacy

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lymphoma And Other Malignancies

Immunosuppressants, including Tracsus, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light.

Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in patients who are EBV seronegative. Monitor EBV serology during treatment.

Serious Infections

Immunosuppressants, including Tracsus, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

• Polyomavirus-associated nephropathy (especially due to BK virus infection),
• JC virus-associated progressive multifocal leukoencephalopathy (PML), and
• Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection.

Increased Mortality In Female Liver Transplant Patients

In a clinical trial of 471 liver transplant patients randomized to Tracsus or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with Tracsus compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. Tracsus is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.

Graft Rejection And Other Serious Adverse Reactions Due To Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and Tracsus (tacrolimus extended-release capsules) were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus. Tracsus is not interchangeable or substitutable with tacrolimus immediate-release products or tacrolimus extended-release products. Instruct patients and caregivers to recognize the appearance of Tracsus capsules.

New Onset Diabetes After Transplant

Tracsus caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately.

Nephrotoxicity Due To Tracsus And Drug Interactions

Tracsus, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range.

The risk for nephrotoxicity may increase when Tracsus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

Neurotoxicity

Tracsus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of Tracsus if neurotoxicity occurs.

Hyperkalemia

Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including Tracsus. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia. Monitor serum potassium levels periodically during treatment.

Hypertension

Hypertension is a common adverse reaction of Tracsus therapy and may require antihypertensive therapy. Some antihypertensive drugs can increase the risk for hyperkalemia. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of Tracsus.

Risk Of Rejection With Strong CYP3A Inducers And Risk Of Serious Adverse Reactions With Strong CYP3A Inhibitors

The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). Therefore, adjust Tracsus dose and monitor tacrolimus whole blood trough concentrations when coadministering Tracsus with strong CYP3A inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin).

QT Prolongation

Tracsus may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid Tracsus in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).

When coadministering Tracsus with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in Tracsus dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with Tracsus.

Avoid the use of live attenuated vaccines during treatment with Tracsus (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with Tracsus.

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of Tracsus.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration

Advise patients to:

• Inspect their Tracsus medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for Tracsus.
• Take Tracsus at the same time every day to achieve consistent blood concentrations.
• Take Tracsus in the morning, preferably at least 1 hour before or at least 2 hours after breakfast to achieve maximum possible blood concentrations of the drug.
• Swallow capsule whole with liquid. Do not chew, divide or crush capsule.
• Avoid alcoholic beverage, grapefruit and grapefruit juice while on Tracsus.
• Take a missed dose of Tracsus as soon as possible but not more than 14 hours after the scheduled time (i.e., for a missed 8 AM dose, take by 10 PM). Beyond the 14-hour timeframe, instruct the patient to wait until the usual scheduled time the following morning to take the next scheduled dose. Do not take 2 doses at the same time.

Development of Lymphoma and Other Malignancies

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor.

Increased Risk of Infection

Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection.

New Onset Diabetes After Transplant

Inform patients that Tracsus can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger.

Nephrotoxicity

Inform patients that Tracsus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team.

Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors.

Hyperkalemia

Inform patients that Tracsus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia.

Hypertension

Inform patients that Tracsus can cause high blood pressure which may require treatment with anti-hypertensive therapy.

Drug Interactions

Instruct patients to tell their healthcare providers when they start or stop taking any concomitant medications, including prescription and non-prescription medicines, herbal and dietary supplements. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of Tracsus.

Immunizations

Inform patients that Tracsus can interfere with the usual response to immunizations and that they should avoid live vaccines.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3 mg/kg/day (0.49 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) and in the rat was 5 mg/kg/day (0.14 times the AUC at the maximum clinical dose of 0.2 mg/kg/day).

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m²/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.4-fold the human exposure in stable adult renal transplant patients > 6 months post transplant). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system's ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus given orally at 1 mg/kg (0.8 times the maximum clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.6 times the maximum clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction.

Tacrolimus given orally to pregnant rabbits at 0.5 times the maximum clinical dose and pregnant rats at 0.8 times the maximum clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Tracsus should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.5 and 1.6 times the maximum clinical dose based on body surface area, respectively) was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (2.6 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (0.8 and 2.6 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

Nursing Mothers

Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ASTAGRAF XL, a decision should be made whether to discontinue nursing or to discontinue Tracsus, taking into account the importance of drug to the mother.

Pediatric Use

The safety and effectiveness of Tracsus in pediatric patients less than 16 years of age have not been established.

Geriatric Use

Clinical studies of Tracsus did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In Studies 1 and 2, 29 patients were 65 years of age and older, and 3 patients were 75 years of age and over. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated.

Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy subjects with normal hepatic function. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

Race

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lymphoma And Other Malignancies

Immunosuppressants, including Tracsus, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light.

Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in those individuals who are EBV seronegative. Monitor EBV serology during treatment.

Serious Infections

Immunosuppressants, including Tracsus, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

• Polyomavirus-associated nephropathy (especially due to BK virus infection),
• JC virus-associated progressive multifocal leukoencephalopathy (PML), and
• Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection.

Graft Rejection And Other Serious Adverse Reactions Due To Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus. Tracsus is not interchangeable or substitutable with tacrolimus immediate-release products or other tacrolimus extended-release products. Instruct patients and caregivers to recognize the appearance of Tracsus tablet.

New Onset Diabetes After Transplant

Tracsus caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately.

Nephrotoxicity Due To Tracsus And Drug Interactions

Tracsus, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when Tracsus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

Neurotoxicity

Tracsus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of Tracsus if neurotoxicity occurs.

Hyperkalemia

Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including Tracsus. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia. Monitor serum potassium levels periodically during treatment.

Hypertension

Hypertension is a common adverse reaction of Tracsus therapy and may require antihypertensive therapy. Some antihypertensive drugs can increase the risk for hyperkalemia. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of Tracsus.

Risk Of Rejection With Strong CYP3A Inducers And Risk Of Serious Adverse Reactions With Strong CYP3A Inhibitors

The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) Therefore, adjust Tracsus dose and monitor tacrolimus whole blood trough concentrations when coadministering Tracsus with strong CYP3A inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin).

QT Prolongation

Tracsus may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid Tracsus in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).

When coadministering Tracsus with other substrates and/or inhibitors of CYP3A, a reduction in Tracsus dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with Tracsus.

Avoid the use of live attenuated vaccines during treatment with Tracsus (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with Tracsus.

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of Tracsus.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration

Advise patients to:

• Inspect their Tracsus medicine when they receive a new prescription and before taking it. If the appearance of the tablet is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that you have the right medicine. Other tacrolimus products cannot be substituted for Tracsus.
• Take once-daily Tracsus at the same time every day (preferably in the morning) on an empty stomach to ensure consistent and maximum possible drug concentrations in the blood.
• Swallow tablet whole with liquid, preferably water. Do not chew, divide or crush tablet.
• Avoid alcohol, grapefruit, and grapefruit juice while on Tracsus.
• Take a missed dose as soon as possible but not more than 14 hours after the scheduled time. Beyond the 14-hour timeframe, instruct the patient to wait until the usual scheduled time the following morning to take the next regularly scheduled dose. Do not take two doses at the same time..

Development of Lymphoma and Other Malignancies

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor.

Increased Risk of Infection

Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection.

New Onset Diabetes After Transplant

Inform patients that Tracsus can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger.

Nephrotoxicity

Inform patients that Tracsus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team.

Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors.

Hyperkalemia

Inform patients that Tracsus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia.

Hypertension

Inform patients that Tracsus can cause high blood pressure which may require treatment with anti-hypertensive therapy.

Drug Interactions

Instruct patients to tell their health care providers when they start or stop taking any concomitant medications, including prescription and non-prescription medicines, herbal and dietary supplements. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of Tracsus.

Immunizations

Inform patients that Tracsus can interfere with the usual response to immunizations and that they should avoid live vaccines.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.84 times the AUC at the maximum clinical dose of 0.14 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.24 times the AUC at the maximum clinical dose of 0.14 mg/kg/day).

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%-3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/ m²/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.5-fold the human exposure in stable adult renal transplant patients converted from tacrolimus immediate-release product to Tracsus). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system's ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus given orally at 1.0 mg/kg (1.2 times the maximum clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (3.7 times the maximum clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction.

Tacrolimus given orally to pregnant rabbits at 0.7 times the maximum clinical dose and pregnant rats at 1.1 times the maximum clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Tracsus should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.7 and 2.3 times the maximum clinical dose based on body surface area, respectively) was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (3.7 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (1.2 and 3.7 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

Nursing Mothers

Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ENVARSUS XR, a decision should be made whether to discontinue nursing or to discontinue Tracsus, taking into account the importance of drug to the mother.

Pediatric Use

The safety and effectiveness of Tracsus in pediatric patients have not been established.

Geriatric Use

Clinical studies of Tracsus did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the stable kidney transplant study, there were 17 patients 65 years of age and older, and no patients were over 75 years. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated.

Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy subjects with normal hepatic function. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

Race

African-American patients may need to be titrated to higher Tracsus dosages to attain comparable trough concentrations compared to Caucasian patients

Not relevant.

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

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

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

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

Tracsus 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 Tracsus is administered in association with alcohol.

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

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

Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Infections and infestations

As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.

Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Tracsus.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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.

* The adverse reaction has been reported during post-marketing experience

Post-marketing

Cases of malignancies, including cutaneous (i.e. cutaneous T Cell lymphomas) and other types of lymphoma, and skin cancers, have been reported in patients using tacrolimus ointment.

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

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

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

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

List of adverse reactions

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

Infections and infestations

As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.

Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Tracsus.

Neoplasms benign, malignant and unspecified (inl. cysts and polyps)

Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

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

Infections and infestations

As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.

Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Tracsus.

Neoplasms benign, malignant and unspecified

Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 for tacrolimus (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, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.

Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including tacrolimus.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.

Immune system disorders

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus.

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 Tracsus, 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 Tracsus 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 Tracsus were tremor, headache, fatigue, hyperkalaemia, hypertension, renal failure, blood creatinine increased, dizziness, hepatitis C, muscle spasms, tinea infection, leukopenia, sinusitis , and 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 Tracsus 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 Yellow Card Scheme in the UK, Website: www.mhra.gov.uk/yellowcard or in Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: [email protected].

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney transplant patients were treated with Tracsus (N=214) or tacrolimus immediate-release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S. patients (Study 1). The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2 [non-U.S. trial in kidney transplant patients treated with Tracsus (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants].

In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the Tracsus and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation in Tracsus-treated patients were related to infections or renal/urinary disorders.

Infections

The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the Tracsus or tacrolimus immediate-release product in Study 1 are shown in Table 3.

Table 3: Percentage of Patients with Infections in Study 1^a Through One Year Post-Renal Transplant

New Onset Diabetes After Transplant (NODAT)

The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were > 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA1C ≥ 6.5%) is summarized in Table 4 below for Study 1 through one year post-transplant.

Table 4: Percentage of Patients with NODAT Through 1 Year Post-Renal Transplant in Study 1^a

Hyperkalemia

In Study 1 , 73 out of 214 (34.1% ) patients on Tracsus had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L.

Common Adverse Reactions

The most common ( ≥ 30%) adverse reactions observed with Tracsus in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The incidence of adverse reactions that occurred in ≥ 15% of Tracsus-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 5.

Table 5: Adverse Reactions ( ≥ 15%) in Kidney Transplant Patients Through One Year Post Transplant in Study 1^a

Less Frequently Reported Adverse Reactions ( < 15% in Tracsus-treated patients) by System Organ Class

The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with Tracsus, MMF, and steroids (Studies 1 and 2).

Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy

Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia

Ear Disorders: Tinnitus

Eye Disorders: Vision blurred, conjunctivitis

Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease

General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia

Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity

Infections and Infestations: Condyloma acuminatum, tinea versicolor

Injury: Fall

Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme

Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis

Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis

Neoplasms: Kaposi's sarcoma

Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy

Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare

Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy

Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough

Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash

Vascular Disorders: Deep vein thrombosis, flushing

Postmarketing Experience

The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, pancytopenia, pure red cell aplasia , coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen

Cardiac Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsade de Pointes, QT prolongation

Ear Disorders: Hearing loss

Eye Disorders: Blindness, optic atrophy, photophobia

Gastrointestinal Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia

Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice

Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Immune System Disorders: Graft versus host disease (acute and chronic)

Investigations: Increased international normalized ratio

Metabolism and Nutrition Disorders: Hypoproteinaemia

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis

Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD , leukemia, melanoma

Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal , posterior reversible encephalopathy syndrome (PRES) , coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence

Psychiatric Disorders: Mental status changes

Renal and Urinary Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence

Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups

Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity

Vascular Disorders: Hemorrhage

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

In an open label, randomized, multinational conversion study, stable kidney transplant patients on a tacrolimus immediate-release product and concomitant immunosuppressants were randomized to treatment with ENVARSUS XR (N=162) or to continued treatment on the tacrolimus immediate-release product (N=162) and treated for a duration of 12 months.

The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the Tracsus and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the Tracsus treatment group was cardiac arrest (2 events).

Infections

The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidney transplant recipients treated with Tracsus or tacrolimus immediate-release product are shown in Table 1.

Table 1: Percentage of Stable Patients with Infections Through One Year Post-Treatment in the Conversion Study^a

New Onset Diabetes After Transplantation (NODAT)

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥ 126 mg/dL, 2-hour postprandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on 2 or more consecutive occasions post baseline, insulin requirement for ≥ 31 days, an oral hypoglycemic agent use ≥ 31 days, or HbA1c ≥ 6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for the stable kidney transplant study through one year post-transplant is summarized in Table 2 below.

Table 2: Percentage of Stable Patients with NODAT Through 1 Year Post-Treatment in the Conversion Study^a

Common Adverse Reactions

The incidence of adverse reactions that occurred in ≥ 5% of Tracsus-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in Table 3.

Table 3: Adverse Reactions ( ≥ 5%) in Stable Kidney Transplant Patients Through 1 Year Post-Treatment in the Conversion Study^a

Postmarketing Experience

The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia , thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Cardiac Disorders: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial hypertrophy, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, supraventricular extrasystoles, supraventricular tachycardia, Torsade de Pointes, deep limb venous thrombosis, ventricular fibrillation

Ear Disorders: Hearing loss including deafness

Eye Disorders: Blindness, photophobia, optic atrophy

Gastrointestinal Disorders: Colitis, dysphagia, gastrointestinal perforation, impaired gastric emptying, intestinal obstruction, mouth ulceration, peritonitis, stomach ulcer

Hepatobiliary Disorders: Bile duct stenosis, cholangitis, cirrhosis, fatty liver, hepatic cytolysis, hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, hemorrhagic pancreatitis, necrotizing pancreatitis, venoocclusive liver disease

Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Immune System Disorders: Graft versus host disease (acute and chronic)

Metabolism and Nutrition Disorders: Glycosuria, increased amylase, pancreatitis

Musculoskeletal and Connective Tissue Disorders: Myalgia, polyarthritis, rhabdomyolysis

Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, PTLD ; leukemia

Nervous System Disorders: Carpal tunnel syndrome, cerebral infarction, coma, dysarthria, flaccid paralysis, hemiparesis, mental disorder, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) , progressive multifocal leukoencephalopathy (PML) sometimes fatal , quadriplegia, speech disorder, status epilepticus, syncope

Renal and Urinary Disorder: Acute renal failure, hemorrhagic cystitis, hemolytic uremic syndrome, micturition disorder

Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, pulmonary hypertension, respiratory distress, respiratory failure

Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity

Experience with overdosage is limited. Several cases of accidental overdosage have been reported; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy, increased blood urea nitrogen and elevated serum creatinine concentrations, and increase in alanine aminotransferase levels.

No specific antidote to Tracsus therapy is available. If overdosage 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.

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.

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.

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.

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 Tracsus in overdose.

Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:

• nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence)
• gastrointestinal disturbances (nausea, vomiting, and diarrhea)
• abnormal renal function (increased blood urea nitrogen and elevated serum creatinine)
• urticarial
• hypertension
• peripheral edema, and
• infections [one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release) overdose].

Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:

• nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence)
• gastrointestinal disturbances (nausea, vomiting, and diarrhea)
• abnormal renal function (increased blood urea nitrogen and elevated serum creatinine)
• urticaria
• hypertension
• peripheral edema, and
• infections [one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release capsules) overdose].

Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

Pharmacotherapeutic group: 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.

Results from published data in other primary organ transplantation

Tracsus has evolved into an accepted treatment as primary immunosuppressive medicinal product following pancreas, lung and intestinal transplantation. In prospective published studies tacrolimus 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 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 (Treede et al., 3^rd ICI San Diego, US, 2004;Abstract 22).

Another randomised study included 66 patients on tacrolimus versus 67 patients on ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 ng/ml. The 1-year patient survival was 83% in the tacrolimus and 71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p = 0.025). Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated patients to ciclosporin (n = 2) (p = 0.02) (Keenan et al., Ann Thoracic Surg 1995;60:580).

In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%) (Treede et al., J Heart Lung Transplant 2001;20:511).

The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.

Pancreas transplantation

A multicentre study included 205 patients undergoing simultaneous pancreas-kidney transplantation who were randomised to tacrolimus (n=103) or to ciclosporin (n=102). The initial oral per protocol dose of tacrolimus was 0.2 mg/kg/day with subsequent dose adjustments to target trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/mL after Month 6. Pancreas survival at 1 year was significantly superior with tacrolimus: 91.3% versus 74.5% with ciclosporin (p < 0.0005), whereas renal graft survival was similar in both groups. In total 34 patients switched treatment from ciclosporin to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy (Bechstein et al., Transplantation 2004;77:1221).

Intestinal transplantation

Published clinical experience from a single centre on the use of tacrolimus for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was 0.3 mg/kg/day. Results continuously improved with increasing experience over the course of 11 years. A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15 ng/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time (Abu-Elmagd et al., Ann Surg 2001;234:404).

Pharmacotherapeutic group: Other dermatologicals, 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 Tracsus 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 = 0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck

§§ higher values = greater improvement

The incidence and nature of most adverse events were similar in the two treatment groups. Skin burning, herpes simplex, alcohol intolerance (facial flushing or skin sensitivity after alcohol intake), skin tingling, hyperaesthesia, acne and fungal dermatitis occurred more often in the tacrolimus treatment group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the study.

In the second trial, children aged from 2 to 15 years with moderate to severe atopic dermatitis received twice daily treatment for three weeks of 0.03% tacrolimus ointment, 0.1% tacrolimus ointment or 1% hydrocortisone acetate ointment. The primary endpoint was the area-under-the-curve (AUC) of the mEASI as a percentage of baseline averaged over the treatment period. The results of this multicentre, double-blind, randomised trial showed that tacrolimus ointment, 0.03% and 0.1%, is significantly more effective (p<0.001 for both) than 1% hydrocortisone acetate ointment (Table 2).

Table 2 Efficacy at week 3

§ lower values = greater improvement

The incidence of local skin burning was higher in the tacrolimus treatment groups than in the hydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in the hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the clinical trial.

The purpose of the third multicentre, double-blind, randomised study was the assessment of efficacy and safety of 0.03% tacrolimus ointment applied once or twice a day relative to twice daily administration of 1% hydrocortisone acetate ointment in children with moderate to severe atopic dermatitis. Treatment duration was for up to three weeks.

Table 3 Efficacy at week 3

§ higher values = greater improvement

The primary endpoint was defined as the percentage decrease in mEASI from the baseline to end of treatment. A statistically significant better improvement was shown for once daily and twice daily 0.03% tacrolimus ointment compared to twice daily hydrocortisone acetate ointment (p<0.001 for both). Twice daily treatment with 0.03% tacrolimus ointment was more effective than once daily administration (Table 3). The incidence of local skin burning was higher in the tacrolimus treatment groups than in the hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the study.

In the fourth trial, approximately 800 patients (aged > 2 years) received 0.1% tacrolimus ointment intermittently or continuously in an open-label, long-term safety study for up to four years, with 300 patients receiving treatment for at least three years and 79 patients receiving treatment for a minimum of 42 months. Based on changes from baseline in EASI score and body surface area affected, patients regardless of age had improvement in their atopic dermatitis at all subsequent time points. In addition, there was no evidence of loss of efficacy throughout the duration of the clinical trial. The overall incidence of adverse events tended to decrease as the study progressed for all patients independent of age. The three most common adverse events reported were flu-like symptoms (cold, common cold, influenza, upper respiratory infection, etc.), pruritus and skin burning. No adverse events previously unreported in shorter duration and/or previous studies were observed in this long-term study.

The efficacy and safety of tacrolimus ointment in maintenance treatment of mild to severe atopic dermatitis was assessed in 524 patients in two Phase III multicentre clinical trials of similar design, one in adult patients (> 16 years) and one in paediatric patients (2-15 years). In both studies, patients with active disease entered an open-label period (OLP) during which they treated affected lesions with tacrolimus ointment twice daily until improvement had reached a predefined score (Investigator's Global Assessment [IGA] ≤ 2, i.e. clear, almost clear or mild disease) for a maximum of 6 weeks. Thereafter, patients entered a double-blind disease control period (DCP) for up to 12 months. Patients were randomised to receive either tacrolimus ointment (0.1% adults; 0.03% children) or vehicle, once a day twice weekly on Mondays and Thursdays. If a disease exacerbation occurred, patients were treated with open-label tacrolimus ointment twice daily for a maximum of 6 weeks until the IGA score returned to ≤ 2.

The primary endpoint in both studies was the number of disease exacerbations requiring a “substantial therapeutic intervention” during the DCP, defined as an exacerbation with an IGA of 3-5 (i.e. moderate, severe and very severe disease) on the first day of the flare, and requiring more than 7 days treatment. Both studies showed significant benefit with twice weekly treatment with tacrolimus ointment with regard to the primary and key secondary endpoints over a period of 12 months in a pooled population of patients with mild to severe atopic dermatitis. In a subanalysis of a pooled population of patients with moderate to severe atopic dermatitis these differences remained statistically significant (Table 4). No adverse events not reported previously were observed in these studies.

Table 4 Efficacy (moderate to severe subpopulation)

DE: disease exacerbation

P<0.001 in favour of tacrolimus ointment 0.1% (adults) and 0.03% (children) for the primary and key secondary endpoints

A seven-month, double blind, randomised parallel group study of paediatric patients (2-11 years) with moderate to severe atopic dermatitis was performed. In one arm patients received Tracsus 0.03% ointment (n=121) twice a day for 3 weeks and thereafter once a day until clearance. In the comparator arm patients received 1% hydrocortisone acetate ointment (HA) for head and neck and 0.1% hydrocortisone butyrate ointment for trunk and limbs (n=111) twice a day for 2 weeks and subsequently HA twice a day to all affected areas. During this period all patients and control subjects (n=44) received a primary immunisation and a rechallenge with a protein-conjugate vaccine against Neisseria menigitidis serogroup C.

The primary endpoint of this study was the response rate to vaccination, defined as the percentage of patients with a serum bactericidal antibody (SBA) titre > 8 at the week 5 visit. Analysis of the response rate at week 5 showed equivalence between the treatment groups (hydrocortisone 98.3%, tacrolimus ointment 95.4%; 7-11 years: 100% in both arms). The results in the control group were similar.

The primary response to vaccination was not affected.

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. Tacrolimus was started as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 nanogram/ml. The 1-year patient survival was 83% in the tacrolimus and 71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p = 0.025). Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated patients to ciclosporin (n = 2) (p = 0.02).

In an additional 2-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 nanogram/ml. The 1-year survival rates were 73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).

The 3 studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all 3 studies and one of the studies reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.

Pancreas transplantation

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

Intestinal transplantation

Published clinical experience from a single centre on the use of oral tacrolimus for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was 0.3 mg/kg/day. Results continuously improved with increasing experience over the course of 11 years. A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15 nanogram/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.

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 Tracsus

Liver transplantation

The efficacy and safety of Tracsus 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 Tracsus group (N=237) and 29.3% in the Prograf group (N=234). The treatment difference (Tracsus - Prograf) was 3.3% (95% confidence interval [-5.7%, 12.3%]).The 12‑month patient survival rates were 89.2% for Tracsus and 90.8% for Prograf; in the Tracsus 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 Tracsus and 85.6% for Prograf.

Kidney transplantation

The efficacy and safety of Tracsus 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 Tracsus group (N=331) and 14.9% in the Prograf group (N=336). The treatment difference (Tracsus-Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12‑month patient survival rates were 96.9% for Tracsus and 97.5% for Prograf; in the Tracsus 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 Tracsus and 92.8% for Prograf.

The efficacy and safety of Prograf, ciclosporin and Tracsus, all in combination with basiliximab antibody induction, MMF and corticosteroids, was compared in 638 de novo kidney transplant recipients. The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute rejection, or lost to follow-up) was 14.0% in the Tracsus group (N=214), 15.1% in the Prograf group (N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (Tracsus-ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Tracsus vs. ciclosporin and -1.9% (Prograf-ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient survival rates were 98.6% for Tracsus, 95.7% for Prograf and 97.6% for ciclosporin; in the Tracsus arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Tracsus, 92.9% for Prograf and 95.7% for ciclosporin.

Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation

In prospective studies oral Prograf was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of oral Prograf in these published studies appeared to be similar to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.

Lung transplantation

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

Another randomised study included 66 patients on tacrolimus versus 67 patients on ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 ng/ml. The 1-year patient survival was 83% in the tacrolimus and 71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p = 0.025). Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated patients to ciclosporin (n = 2) (p = 0.02) (Keenan et al., Ann Thoracic Surg 1995;60:580).

In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).

The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.

Pancreas transplantation

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

Intestinal transplantation

Published clinical experience from a single centre on the use of oral Prograf for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was 0.3 mg/kg/day. Results continuously improved with increasing experience over the course of 11 years. A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15 ng/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.

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 effect

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 trials performed with once-daily tacrolimus, Tracsus

Kidney transplantation

The efficacy and safety of Tracsus and Prograf, both in combination with Mycophenolate Mofetil (MMF) corticosteroids, and IL-2 receptor antagonist as per the standard of care was 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 episodes of clinically-suspected and treated rejections during the 360-day study was 13.8% for the Tracsus 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 Tracsus 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 Tracsus group and 19.6% in the Prograf group. The treatment difference (Tracsus-Prograf) was -1.35% (95% confidence interval [-7.94%,5.27%]). Treatment-emergent fatal adverse events occurred in 1.8% of Tracsus patients and 2.5% of Prograf patients.

The efficacy and safety of Tracsus and Prograf, both in combination with mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) and corticosteroids, was compared in 324 stable kidney transplant recipients. The event rate for locally read biopsy-confirmed acute rejection (BPAR) during the 360 day study was 1.2% in the Tracsus group (N=162) post conversion from Prograf at a dose ratio of 1: 0.7 (mg:mg) and 1.2% in the group maintained on Prograf (N=162). The efficacy failure rate as measured by the composite endpoint of death, graft loss, locally read BPAR and loss to follow-up was 2.5% in both the Tracsus and Prograf groups. The treatment difference (Tracsus - Prograf) was 0% (95% confidence interval [-4.21%, 4.21%]). The treatment failure rate using the same composite end-point with centrally read BPAR was 1.9% in the Tracsus group and 3.7% in the Prograf group (95% confidence interval [-6.51%, 2.31%]). Treatment emergent fatal adverse events occurred in 1.2% of Tracsus patients and 0.6% of Prograf patients.

Liver transplantation

The pharmacokinetics, efficacy and safety of Tracsus and tacrolimus immediate-release capsules , both in combination with corticosteroids was compared in 117 liver transplant recipients, of whom 88 received treatment with Tracsus. In the de novo liver transplant study, 29 subjects were treated with Tracsus. The event rate of biopsy-confirmed acute rejection within the 360 day study period was not significantly different between the Tracsus group and the tacrolimus immediate-release group. The overall incidence of fatal treatment emergent adverse events for the combined de novo and stable liver transplant population was not significantly different between the Tracsus group and the tacrolimus immediate-release group

Absorption

In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Following oral administration of Tracsus capsules peak concentrations (C_max) of tacrolimus in blood are achieved in approximately 1 - 3 hours. In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a relatively flat absorption profile. The mean oral bioavailability of tacrolimus is in the range of 20% - 25%.

After oral administration (0.30 mg/kg/day) to liver transplant patients, steady-state concentrations of Tracsus were achieved within 3 days in the majority of patients.

In healthy subjects, Tracsus 0.5 mg, Tracsus 1 mg and Tracsus 5 mg Capsules, hard have been shown to be bioequivalent, when administered as equivalent dose.

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 Tracsus was reduced when it was administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and C_max (50%), and an increase in t_max (173%) in whole blood were evident.

In a study of stable renal transplant patients who were administered Tracsus immediately after a standard continental breakfast the effect on oral bioavailability was less pronounced. Decreases in AUC (2 to 12%) and C_max (15 to 38%), and an increase in t_max (38 to 80%) in whole blood were evident.

Bile flow does not influence the absorption of Tracsus.

A strong correlation exists between AUC and whole blood trough levels at steady-state. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.

Distribution and elimination

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.

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance (TBC) estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Paediatric liver transplant recipients have a TBC approximately twice that of adult liver transplant patients. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism are considered to be responsible for the higher clearance rates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours. In adult and paediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased clearance rates contribute to the shorter half-life observed in transplant recipients.

Metabolism and biotransformation

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to pharmacological activity of tacrolimus.

Excretion

Following intravenous and oral administration of ¹⁴C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.

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.

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 Tracsus 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.

Metabolism

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

Elimination

When administered intravenously, tacrolimus has been shown to have a low clearance rate. The average total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically available tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-treated with drugs that are potent inhibitors of CYP3A4.

Following repeated topical application of the ointment the average half-life of tacrolimus was estimated to be 75 hours for adults and 65 hours for children.

Paediatric population

The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, with minimal systemic exposure and no evidence of accumulation (see above).

Absorption

In man, tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed.

Tracsus granules are an immediate-release formulation of tacrolimus for twice daily dosing. Following oral administration of Tracsus granules peak concentrations (C_max) 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 Tracsus 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 Tracsus 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 C_max (50%), and an increase in t_max (173%) in whole blood were evident.

In a study of stable renal transplant patients who were administered tacrolimus immediately after a standard continental breakfast the effect on oral bioavailability was less pronounced. Decreases in AUC (2 to 12%) and C_max (15 to 38%), and an increase in t_max (38 to 80%) in whole blood were evident.

A strong correlation exists between AUC and whole blood trough levels at steady-state for Tracsus. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.

Distribution

In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.

In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.

Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on whole blood averaged 47.6 l.

Metabolism

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to pharmacological activity of tacrolimus.

Excretion

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood was approximately 43 hours. In adult and paediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased clearance rates contribute to the shorter half-life observed in transplant recipients.

Following intravenous and oral administration of ¹⁴C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.

Paediatric data

In paediatric liver transplant patients the mean oral bioavailability of tacrolimus (investigated with the Tracsus granules) is 26%± 23% (individual range in paediatric liver transplant patients 4 - 80%). Data on oral bioavailability of Tracsus in other indications is not available.

After oral administration (0.30 mg/kg/day) to paediatric liver transplant patients, steady-state concentrations of tacrolimus were achieved within 3 days in the majority of patients.

In paediatric liver and kidney transplant patients, values for total body clearance of 2.3 ± 1.2 ml/min/kg and 2.1 ± 0.6 ml/min/kg, respectively, have been observed. Highly variable age dependent total body clearance and half life were observed in limited paediatric clinical investigations, especially in early childhood.

The half-life in paediatric transplant patients averages approximately 12 hours.

Absorption

In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed. Tracsus is a prolonged-release formulation of tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood concentration (C_max) of approximately 2 hours (t_max).

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 Tracsus was reduced when it was administered after a meal. Both the rate and extent of absorption of Tracsus were reduced when administered with food.

Bile flow does not influence the absorption of tacrolimus and therefore treatment with Tracsus may commence orally.

A strong correlation exists between AUC and whole blood trough levels at steady-state for Tracsus. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.

Distribution

In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.

In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.

Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on whole blood averaged 47.6 l.

Metabolism

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to the pharmacological activity of tacrolimus.

Excretion

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.

Following intravenous and oral administration of ¹⁴C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.

Absorption

The oral bioavailability of Tracsus was decreased when the 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, Tracsus 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. Tracsus is a prolonged-release formulation of tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood concentration (C_max) of approximately 6 hours (t_max) 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 Tracsus as compared to the same dose of tacrolimus immediate-release formulation (Prograf) in kidney transplant patients.

Higher C_avg (~50%), reduced peak trough fluctuation (C_max/C_min) and a longer T_max were seen for Tracsus when compared with both, tacrolimus immediate-release formulation (Prograf) and a tacrolimus once daily formulation (Advagraf). Mean values for C_max, percentage degree of fluctuation and percentage degree of swing were significantly lower with administration of Tracsus tablets.

A strong correlation exists between AUC and whole blood trough levels at steady-state for Tracsus. 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.

In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (>98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.

Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1,300 L (healthy subjects). Corresponding data based on whole blood averaged 47.6 L.

Biotransformation

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to the pharmacological activity of tacrolimus.

Elimination

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 L/h. In adult liver, kidney, and heart transplant patients, values of 4.1 L/h, 6.7 L/h, and 3.9 L/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 30 hours.

Following intravenous and oral administration of ¹⁴C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.

Table 7 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of Tracsus in healthy subjects and in kidney transplant patients. Whole blood tacrolimus concentrations in these pharmacokinetic studies were measured using validated HPLC/MS/MS assays.

Table 7: Pharmacokinetic Parameters of Tracsus (Given Once Daily) in Healthy Subjects and in Kidney Transplant Patients (Under Fasted Conditions)

In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC24, for Tracsus 0.2 mg/kg once daily on Day 1 post-transplant was 18% (Ratio [SD]: 0.822 [1.647]) lower when compared with PROGRAF® (tacrolimus immediate-release) 0.2 mg/kg/day given twice daily. By Day 3 post-transplant, the AUC24 was similar between the two formulations. On Day 14 (steady state), the AUC24 for Tracsus was 21% (Ratio [SD]: 1.207 [1.326]) higher than that of PROGRAF (tacrolimus immediate-release), at comparable trough concentrations (C24).

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.

Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

In healthy subjects, the administration of escalating Tracsus doses ranging from 1.5 mg to 10 mg resulted in dose-proportional increases in tacrolimus AUC and C24h, and no change in elimination half-life.

Food Effects

The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 24 healthy subjects, administration of Tracsus immediately following a high-fat meal (150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories) reduced the Cmax, AUCt, and AUCinf of tacrolimus by approximately 25% compared with fasting values. Food delayed the median Tmax from 2 hours in the fasted state to 4 hours in the fed state; however, the terminal half-life remained 36 hours regardless of dosing conditions. The time when a meal is consumed also affected tacrolimus bioavailability. In 24 healthy subjects, when Tracsus was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%. Administration of Tracsus 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%. Tracsus capsules should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.

Chronopharmacokinetic Effect

In 23 healthy subjects, a diurnal effect on the absorption of tacrolimus was observed. Evening dosing of Tracsus reduced AUCinf by 35% relative to morning dosing. Tracsus capsules should be taken consistently at the same time every morning.

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as tacrolimus immediate-release, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

In a mass balance study of orally-administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

The elimination half-life of tacrolimus after oral administration of 4 mg Tracsus daily for 10 days was 38 ± 3 hours in 24 healthy subjects.

Table 5 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily Tracsus in healthy subjects and in kidney transplant patients, under fasted conditions. Whole blood tacrolimus concentrations in the pharmacokinetic studies were measured using validated HPLC/MS/MS assays.

Table 5: Pharmacokinetic Parameters of Tracsus by Study Day in Healthy Subjects and Kidney Transplant Patients Under Fasted Conditions

In adult kidney transplant patients ≥ 6 months post-transplant switched to ENVARSUS® XR at 67% to 80% of the daily dose of tacrolimus immediate-release capsules, the steady state tacrolimus exposures (AUC24) and tacrolimus trough concentrations (C24) were comparable to the AUC24 and C24 measured prior to the switch. However, the mean Cmax estimate was 30% lower and the median Tmax was more prolonged (6 hours versus 2 hours) following administration of Tracsus as compared to that of tacrolimus immediate-release capsules.

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. In healthy subjects, the oral bioavailability of Tracsus was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release formulations at steady state. In healthy subjects who received single Tracsus doses ranging from 5 mg to 10 mg, the mean AUC and C24 of tacrolimus increased linearly and the elimination half-life did not change with increasing doses.

Food Effects

The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 26 healthy subjects, administration of Tracsus following a high-fat breakfast reduced the systemic exposure (AUC) to tacrolimus by approximately 55% and the peak plasma concentration of tacrolimus (Cmax) by 22%, with no effect on the time to reach maximum plasma concentration (Tmax), compared to when Tracsus was administered under fasted conditions.

Chronopharmacokinetic Effect

In 26 healthy subjects, administration of Tracsus tablets in the evening resulted in a 15% lower AUC0-inf, and a 20% lower C24, as compared to morning dosing.

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as immediate-release formulation, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system 3A (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

In a mass balance study of orally administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

The elimination half-life of tacrolimus after oral administration of 2 mg Tracsus once-daily for 10 days was 31.0 ± 8.1 hours (mean ± SD) in 25 healthy subjects.

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus. When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with Tracsus in clinical transplantation.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic dosages and the offspring showed reduced birth weights, viability and growth.

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

Repeated dose toxicity and local tolerance

Repeated topical administration of tacrolimus ointment or the ointment vehicle to rats, rabbits and micropigs was associated with slight dermal changes such as erythema, oedema and papules.

Long-term topical treatment of rats with tacrolimus led to systemic toxicity including alterations of kidneys, pancreas, eyes and nervous system. The changes were caused by high systemic exposure of rodents resulting from high transdermal absorption of tacrolimus. Slightly lower body weight gain in females was the only systemic change observed in micropigs at high ointment concentrations (3%).

Rabbits were shown to be especially sensitive to intravenous administration of tacrolimus, reversible cardiotoxic effects being observed.

Mutagenicity

In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus.

Carcinogenicity

Systemic carcinogenicity studies in mice (18 months) and rats (24 months) revealed no carcinogenic potential of tacrolimus.

In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumours were observed. In the same study an increased incidence of lymphoma was detected in association with high systemic exposure.

In a photocarcinogenicity study, albino hairless mice were chronically treated with tacrolimus ointment and UV radiation. Animals treated with tacrolimus ointment showed a statistically significant reduction in time to skin tumour (squamous cell carcinoma) development and an increase in the number of tumours. It is unclear whether the effect of tacrolimus is due to systemic immunosuppression or a local effect. The risk for humans cannot be completely ruled out as the potential for local immunosuppression with the long-term use of tacrolimus ointment is unknown.

Reproduction toxicity

Embryo/foetal toxicity was observed in rats and rabbits, but only at doses that caused significant toxicity in maternal animals. Reduced sperm function was noted in male rats at high subcutaneous doses of tacrolimus.

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.

When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 nanogram/mL which is more than 6-fold higher than mean peak concentrations observed with Tracsus in clinical transplantation.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic doses and the offspring showed reduced birth weights, viability and growth.

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.

When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with Tracsus in clinical transplantation.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic doses and the offspring showed reduced birth weights, viability and growth.

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic doses and the offspring showed reduced birth weights, viability and growth.

A negative effect of tacrolimus on male fertility in the form of reduced sperm count and motility was observed in rats.