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 Envarsus dose regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.
Envarsus doses are usually reduced in the post-transplant period. Post-transplant changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
A forgotten dose should be taken as soon as possible on the same day. A double dose should not be taken on the next day.
Prophylaxis of kidney transplant rejection
Envarsus therapy should commence at a dose of 0.17 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
Prophylaxis of liver transplant rejection
Envarsus therapy should commence at a dose of 0.11 – 0.13 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
Conversion of Prograf- or Advagraf-treated patients to Envarsus - allograft transplant patients
Allograft transplant patients maintained on twice daily Prograf (immediate-release) or Advagraf (once daily) dosing requiring conversion to once daily Envarsus should be converted on a 1:0.7 (mg:mg) total daily dose basis and the Envarsus maintenance dose should, therefore, be 30% less than the Prograf or Advagraf dose. Envarsus should be administered in the morning.
In stable patients converted from tacrolimus immediate-release products (twice daily) to Envarsus (once daily) on a 1:0.7 (mg:mg) total daily dose basis, the mean systemic exposure to tacrolimus (AUC0-24) was similar to that of immediate-release tacrolimus. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) for Envarsus is similar to that of immediate-release tacrolimus. No studies have been conducted with conversion of patients from Advagraf to Envarsus; however, data from healthy volunteers would suggest that the same conversion rate is applicable as with the conversion from Prograf to Envarsus.
When converting from tacrolimus immediate-release products (e.g. Prograf capsules) or from Advagraf prolonged-release capsules to Envarsus, trough levels should be measured prior to conversion and within two weeks after conversion. Dose adjustments should be made to ensure that similar systemic exposure is maintained after the switch. It should be noted that black patients may require a higher dose to achieve the targeted trough levels.
Conversion from ciclosporin to tacrolimus
Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not recommended. Envarsus 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 fol
