e therapy. Blood trough levels of tacrolimus should also be closely monitored when clinical signs of toxicity or acute rejection are observed, following conversion between Modigraf granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).
Data from clinical studies suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 nanogram/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood trough levels have generally been in the range 5 - 20 nanogram/ml in liver transplant recipients and 10 - 20 nanogram/ml in kidney and heart transplant patients in the early post-transplant period. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 - 15 nanogram/ml in liver, kidney and heart transplant recipients.
Special populations
Hepatic impairment
Dose reduction may be necessary in patients with severe liver impairment in order to maintain the blood trough levels within the recommended target range.
Renal impirment
As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), no dose adjustment is required. However, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is recommended (including serial serum creatinine concentrations, calculation of creatinine clearance and monitoring of urine output).
Race
In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.
Gender
There is no evidence that male and female patients require different doses to achieve similar trough levels.
Elderly patients
There is no evidence currently available to indicate that dosing should be adjusted in older people.
Paediatric 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 Modigraf granules suspended in water, via nasogastric tubing.
It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).
Modigraf granules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption (see section 5.2).
The required dose is calculated from the weight of the patient, using the minimum number of sachets possible. 2 ml of water (at room temperature) should be used per 1 mg tacrolimus to produce a suspension (up to a maximum of 50 ml, depending on body weight) in a cup. Materials containing polyvinyl chloride (PVC) should not be used (see section 6.2). Granules are added to the water and stirred. It is not advised to use any liquids or utensils to empty the sachets. The suspension can be drawn up via a syringe or swallowed directly by the patient. Thereafter the cup is rinsed once with the same quanti |
