PROGRAF Concentrate for solution for infusion Ref.[7768] Active ingredients: Tacrolimus

Prograf therapy requires careful monitoring by adequately qualified and equipped personnel. The medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.

General considerations

The recommended initial dosages presented below are intended to act solely as a guideline. Prograf dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below for recommended target whole blood trough concentrations). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

Prograf can be administered intravenously or orally. In general, dosing may commence orally; if necessary, by administering the capsule contents suspended in water, via nasogastric tubing.

Prograf is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The Prograf dose may vary depending upon the immunosuppressive regimen chosen.

Posology

Dosage recommendations – Liver transplantation

Prophylaxis of transplant rejection – adults

Oral Prograf therapy should commence at 0.10-0.20 mg/kg/day administered as two 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 should be initiated as a continuous 24-hour infusion.

Prophylaxis of transplant rejection – children

An initial oral dose of 0.30 mg/kg/day should be administered in two 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 should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and children

Prograf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Prograf monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Rejection therapy – adults and children

Increased Prograf 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 are noted (e.g. pronounced adverse reactions – see section 4.8) the dose of Prograf may need to be reduced.

For conversion to Prograf, treatment should begin with the initial oral dose recommended for primary immunosuppression.

For information on conversion from ciclosporin to Prograf, see below under “Dose adjustments in specific patient populations”.

Dosage recommendations – Kidney transplantation

Prophylaxis of transplant rejection – adults

Oral Prograf therapy should commence at 0.20-0.30 mg/kg/day administered as two 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 should be initiated as a continuous 24-hour infusion.

Prophylaxis of transplant rejection – children

An initial oral dose of 0.30 mg/kg/day should be administered in two 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 should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and children

Prograf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Prograf-based dual-therapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Rejection therapy – adults and children

Increased Prograf 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 are noted (e.g. pronounced adverse reactions – see section 4.8) the dose of Prograf may need to be reduced.

For conversion to Prograf, treatment should begin with the initial oral dose recommended for primary immunosuppression.

For information on conversion from ciclosporin to Prograf, see below under “Dose adjustments in specific patient populations”.

Dosage recommendations – Heart transplantation

Prophylaxis of transplant rejection – adults

Prograf can be used with antibody induction (allowing for delayed start of Prograf therapy) or alternatively in clinically stable patients without antibody induction.

Following antibody induction, oral Prograf therapy should commence at a dose of 0.075 mg/kg/day administered as two 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 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.

Prophylaxis of transplant rejection – children

Prograf has been used with or without antibody induction in paediatric heart transplantation.

In patients without antibody induction, if Prograf therapy is initiated intravenously, the recommended starting dose is 0.03-0.05 mg/kg/day as a continuous 24-hour infusion targeted to achieve tacrolimus whole blood concentrations of 15-25 ng/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 Prograf therapy is initiated orally, the recommended starting dose is 0.10-0.30 mg/kg/day administered as two divided doses (e.g. morning and evening).

Dose adjustment during post-transplant period in adults and children

Prograf 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.

Rejection therapy – adults and children

Increased Prograf doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes.

In adult patients converted to Prograf, an initial oral dose of 0.15 mg/kg/day should be administered in two divided doses (e.g. morning and evening).

In paediatric patients converted to Prograf, an initial oral dose of 0.20-0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening).

For information on conversion from ciclosporin to Prograf, see below under “Dose adjustments in specific patient populations”.

Dosage recommendations – Rejection therapy, other allografts

The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data. In lung-transplanted patients Prograf has been used 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.

Dosage adjustments in specific patient populations

Patients with liver 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.

Patients with kidney impairment

As the pharmacokinetics of tacrolimus are unaffected by renal function, no dose adjustment should be 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).

Paediatric population

In general, paediatric patients require doses 1½-2 times higher than the adult doses to achieve similar blood levels.

Older people

There is no evidence currently available to indicate that dosing should be adjusted in older people.

Conversion from ciclosporin

Care should be taken when converting patients from ciclosporin-based to Prograf-based therapy (see sections 4.4 and 4.5). Prograf 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, Prograf 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.

Target whole blood trough concentration recommendations

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient.

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood including a semi-automated microparticle enzyme immunoassay (MEIA). 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.

Blood trough levels of tacrolimus should be monitored during the post-transplantation period. When dosed orally, blood trough levels should be drawn approximately 12 hours post-dosing, just prior to the next dose. The frequency of blood level monitoring should be based on clinical needs. As Prograf is a medicinal product with low clearance, adjustments to the dosage regimen may take several days before changes in blood levels are apparent. Blood trough levels should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be monitored following dose adjustment, changes in the immunosuppressive regimen, or following co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5).

Clinical study analysis suggests 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. Subsequently, during maintenance therapy, blood concentrations have generally been in the range of 5-15 ng/ml in liver, kidney and heart transplant recipients.

Method of administration

The concentrate should be used for intravenous infusion only after it is diluted with suitable carrier media.

The concentration of a solution for infusion should be within the range 0.004-0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20–500 ml.

The diluted solution should not be given as a bolus (see section 6.6).

Duration of dosing

Patients should be converted from intravenous to oral medication as soon as individual circumstances permit. Intravenous therapy should not be continued for more than 7 days.

Experience with overdosage is limited. Several cases of accidental overdosage have been reported; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy, increased blood urea nitrogen and elevated serum creatinine concentrations, and increase in alanine aminotransferase levels.

No specific antidote to Prograf therapy is available. If overdosage 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.

2 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.

Store ampoule in the original package in order to protect from light.

Do not store above 25°C.

For storage conditions after dilution of the medicinal product, see section 6.3.

1 ml concentrate for solution for infusion in 2 ml, type I Ph. Eur. clear colourless glass ampoules.

Each carton contains 10 ampoules.

Prograf 5 mg/ml concentrate for solution for infusion must not be injected undiluted.

Prograf 5 mg/ml concentrate for solution for infusion should be diluted in 5% w/v glucose solution or physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers (see section 6.2). Only transparent and colourless solutions should be used.

The concentration of a solution for infusion should be within the range 0.004-0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20–500 ml.

The diluted solution should not be given as a bolus.

Any unused concentrate in an opened ampoule or unused reconstituted solution should be disposed of immediately in accordance with local requirements to avoid contamination.