Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Teva B.V., Swensweg 5, 2031GA Haarlem, Netherlands
Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.
Tacforius is a once-a-day oral formulation of tacrolimus. Tacforius therapy requires careful monitoring by adequately qualified and equipped personnel. This medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of adverse reactions, including under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.
The recommended initial doses presented below are intended to act solely as a guideline. Tacforius is routinely administered in conjunction with other immunosuppressive agents in the initial postoperative period. The dose may vary depending upon the immunosuppressive regimen chosen. Tacforius dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below under “Therapeutic drug monitoring”). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.
In de novo kidney and liver transplant patients AUC0-24 of tacrolimus for the prolonged-release capsules on Day 1 was 30% and 50% lower respectively, when compared with that for the immediate release capsules at equivalent doses. By Day 4, systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in the first two weeks post-transplant with Tacforius to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Tacforius dose regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.
Tacforius therapy should commence at a dose of 0.20-0.30 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
Tacforius doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Tacforius monotherapy. Post-transplant changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Tacforius therapy should commence at a dose of 0.10-0.20 mg/kg/day administered once daily in the morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Tacforius doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Tacforius monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Allograft transplant patients maintained on twice daily immediate release capsules dosing requiring conversion to once daily Tacforius should be converted on a 1:1 (mg:mg) total daily dose basis. Tacforius should be administered in the morning.
In stable patients converted from tacrolimus immediate release capsules (twice daily) to tacrolimus prolonged-release capsules (once daily) on a 1:1 (mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC0-24) for tacrolimus prolonged-release capsules was approximately 10% lower than that for tacrolimus immediate release capsules. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) for tacrolimus prolonged-release capsules is similar to that of tacrolimus immediate release capsules. When converting from tacrolimus immediate release capsules to Tacforius prolonged-release capsules, trough levels should be measured prior to conversion and within two weeks after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary dose adjustments made to maintain similar systemic exposure. Dose adjustments should be made to ensure that similar systemic exposure is maintained.
Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not recommended. Tacforius therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12-24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.
Increased doses of tacrolimus, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity such as severe adverse reactions are noted (see section 4.8), the dose of Tacforius may need to be reduced.
For conversion from other immunosuppressants to once daily Tacforius, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection.
In adult patients converted to Tacforius, an initial oral dose of 0.15 mg/kg/day should be administered once daily in the morning.
Although there is no clinical experience with tacrolimus prolonged-release capsules in lung-, pancreas- or intestine-transplanted patients, tacrolimus immediate release capsules have been used in lung-transplanted patients at an initial oral dose of 0.10-0.15 mg/kg/day, in pancreas-transplanted 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.
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) is similar between the two formulations of tacrolimus prolonged-release capsules and tacrolimus immediate release capsules.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus blood trough levels should be determined approximately 24 hours post-dosing of Tacforius, just prior to the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored following conversion from tacrolimus immediate release capsules to Tacforius, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Tacforius dose regimen it may take several days before the targeted steady state is achieved.
Data from clinical studies suggest that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood trough levels have generally been in the range 5-20 ng/ml in liver transplant recipients and 10-20 ng/ml in kidney and heart transplant patients in the early post-transplant period. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5-15 ng/ml in liver, kidney and heart transplant recipients.
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.
As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), no dose adjustment is required. However, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is recommended (including serial serum creatinine concentrations, calculation of creatinine clearance and monitoring of urine output).
In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.
There is no evidence that male and female patients require different doses to achieve similar trough levels.
There is no evidence currently available to indicate that dosing should be adjusted in the elderly.
The safety and efficacy of Tacforius in children under 18 years of age have not yet been established. Limited data are available but no recommendation on a posology can be made.
Tacforius is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Tacforius be administered once daily in the morning. Tacforius prolonged-release hard capsules should be taken immediately following removal from the blister. Patients should be advised not to swallow the desiccant. The capsules should be swallowed whole with fluid (preferably water). Tacforius should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption (see section 5.2). A forgotten morning dose should be taken as soon as possible on the same day. A double dose should not be taken on the next morning.
In patients unable to take oral medicinal products during the immediate post-transplant period, tacrolimus therapy can be initiated intravenously (see Summary of Product Characteristics for tacrolimus 5 mg/ml concentrate for solution for infusion) at a dose approximately 1/5th of the recommended oral dose for the corresponding indication.
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.
Tacforius 0.5 mg / 1 mg prolonged-release hard capsules: 2 years.
Tacforius 3 mg / 5 mg prolonged-release hard capsules: 30 months.
After opening the aluminium wrapper: 1 year
Store in the original package in order to protect from light and moisture.
This medicinal product does not require any special temperature storage conditions.
Transparent PVC/PVDC aluminium blister or perforated unit-dose blister wrapped in an aluminium pouch with a desiccant containing 10 capsules per blister.
Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30x1, 50x1 and 100x1 prolonged-release hard capsules in perforated unit-dose blisters.
Pack sizes: 30, 50, 60 and 100 prolonged-release hard capsules in blisters or 30x1, 50x1, 60x1 and 100x1 prolonged-release hard capsules in perforated unit-dose blisters.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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