Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, Netherlands
Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult and paediatric 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. Modigraf is a granular formulation of tacrolimus, for twice-a-day administration. Modigraf therapy requires careful monitoring by adequately qualified and equipped personnel.
The recommended initial doses presented below are intended to act solely as a guideline. Modigraf 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. Modigraf 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. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before steady state is achieved (see below under “Therapeutic drug monitoring” and section 5.2).
Modigraf 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 (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.
Oral Modigraf 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.
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.
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.
Oral Modigraf 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.
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.
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.
Modigraf 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 Modigraf 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.
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 Modigraf 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).
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.
In healthy subjects the systemic exposure to tacrolimus (AUC) for Modigraf was approximately 18% higher than that for Prograf capsules when administered as single doses. There are no safety data available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in critically ill patients.
Stable allograft recipients maintained on Modigraf 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 Modigraf granules, the total daily Modigraf 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 Modigraf should be rounded down to the nearest total daily dose possible with sachets 0.2 mg and 1 mg.
The total daily dose of Modigraf 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. Modigraf 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 Modigraf 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.
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. 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.
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.
For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with the initial oral dose recommended for primary immunosuppression.
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).
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.
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 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 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.
Dose reduction may be necessary in patients with severe liver impairment in order to maintain the 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 older people.
In general, paediatric patients require doses 1½ - 2 times higher than the adult doses to achieve similar blood levels.
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 quantity of water and the rinsings consumed by the patient. The suspension should be administered immediately after preparation.
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.
3 years.
After preparation, the suspension should be administered immediately.
This medicinal product does not require any special storage conditions.
Sachets consisting of layers of polyethylene terephtalate (PET), aluminium (Al) and polyethylene (PE).
Pack size: carton box containing 50 sachets.
No special requirements.
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