orin-based to tacrolimus-based therapy (see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not recommended. Tacrolimus therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.
Treatment of allograft rejection
Increased tacrolimus doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity such as severe adverse reactions are noted (see section 4.8), the dose of Modigraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation – adults and paediatric patients
For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with the initial oral dose recommended for primary immunosuppression.
Treatment of allograft rejection after heart transplantation therapy – adults and paediatric patients
In adult patients converted to Modigraf, an initial oral dose of 0.15 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening).
In paediatric patients converted to tacrolimus, an initial oral dose of 0.20 - 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening).
Treatment of allograft rejection after transplantation of other allografts
The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data with the Prograf formulation. Prograf has been used in lung-transplanted patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.
Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship between tacrolimus trough levels (C12) and systemic exposure (AUC0-12) is similar between the 2 formulations Modigraf granules and Prograf capsules.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus blood trough levels should be determined approximately 12 hours post-dosing of Modigraf granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels should be monitored at least twice weekly during the early post-transplant period and then periodically during maintenanc
