Transplantation

1 capsule 0.5 mg contains:
tacrolimus monohydrate - 0.51 mg, equivalent to tacrolimus - 0.50 mg.
1 capsule 1 mg contains:
tacrolimus monohydrate - 1.02 mg, equivalent to tacrolimus - 1.00 mg.
1 capsule 5 mg contains:
tacrolimus monohydrate - 5.11 mg, equivalent to tacrolimus - 5.00 mg.

Capsules 0.5 mg; 1.0 mg; 5.0 mg.
10 capsules in a blister or 60 capsules in a bottle or a jar sealed with a cap with a tamper-evident closure or without it.
1 bottle or jar or 1, 3, 5, 6, 8 or 10 blisters with patient leaflets are placed in a carton pack.

Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants
Treatment of allograft rejection resistant to other modes of immunosuppressive therapy.

Tacrolimus therapy should be carefully controlled by physicians properly qualified and having appropriate equipment. Only physicians experienced in immunosuppressive therapy and management of organ transplant should prescribe tacrolimus or modify immunosuppressive therapy.
Uncontrolled switching of one tacrolimus product to another (including switching from ordinary capsules to extended-release capsules) is not safe. This can lead to graft rejection or increased incidence of side effects, including under- or over-immunosuppression, due to clinically relevant differences in 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 supervision of a transplant specialist. Following conversion, tacrolimus blood concentrations must be monitored and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained at an adequate level.
In case of missed dose of tacrolimus capsules, the next dose should be taken in time. A double dose must not be taken.
General Provisions
The initial doses given below should be considered as recommendations only. In the initial post-surgery period, tacrolimus is generally used in combination with other immunosupressants. The dose may vary depending on the regiment of immunosupressive therapy. The dose of Tacrolimus should be titrated based firstly on the clinical assessment of rejection risk and individual tolerability, and also on the data of tacrolimus blood concentrations monitoring (see below Section ‘Recommendations for therapeutic concentration of tacrolimus in the blood’).
If clinical signs of rejection appear, correction of the immunosuppressive therapy regimen should be considered.
Tacrolimus can be used both orally and intravenously. In most cases tacrolimus in capsules is administered orally; where necessary the capsule content can be mixed with water and introduced through a nasogastric tube.
Administration and Doses
The daily dose of Tacrolimus should be administered as 2 divided equal doses (morning and evening). Capsules should be taken immediately after they are removed from the blister.
The capsules should be taken with liquid, preferable with water. To achieve maximum absorption, capsules should be taken on an empty stomach 1 hour before or in
2-3 hours after meal.
Duration of Treatment
For the prophylaxis of organ rejection immunosupression should be maintained constantly, and, therefore, the duration of treatment is not limited.
Liver Transplant
Prophylaxis of allograft rejection - Adult Patients
The initial oral therapy with Tacrolimus should be stated from a dose of
0.10-0.20 mg/kg/day taken as two divided doses (for example, in the morning and in the evening). If the patient can tolerate oral therapy, Tacrolimus capsules should be administered in about 12 hours after transplantation.
For patients unable to take the treatment orally, intravenous therapy should be started from a 0.01-0.05 mg/kg/day dose used as a continuous 24-hour infusion.
Prophylaxis of Allograft Rejection - Pediatric Patients
The initial dose of Tacrolimus of 0.30 mg/kg/day should be taken as two divided doses (for example, in the morning and in the evening).
For patients unable to take the treatment orally, intravenous therapy should be started from a 0.05 mg/kg/day dose used as a continuous 24-hour infusion.
Supportive Therapy - Adults and Children
Tacrolimus doses are usually reduced in the post-transplant period. In some cases the concomitant immunosupressive products can be discontinued leaving tacrolimus as monotherapy. Dose adjustment can be needed due to changes in tacrolimus pharmacokinetics caused by improved condition of the patient after transplantation.
Treatment of Rejection - Adult and Pediatric Patients
For the treatment of rejection episodes, higher doses of tacrolimus capsules combined with additional corticosteroid therapy and short-term courses of mono-/polyclonal antibodies should be used. If signs of toxicity are noted, a dose reduction may be required.
When the patient is transferred to tacrolimus capsule therapy, the recommended initial doses are the same as in initial immunosuppression. Information on patient crossover from cyclosporine to tacrolimus is given in the end of section “Dosage adjustments in specific populations”.
Kidney Transplant
Prophylaxis of Allograft Rejection - Adult Patients
The initial oral dosage of Tacrolimus should be 0,20-0,30 mg/kg/day taken as two doses (for example, in the morning and in the evening). The therapy should be started within 24 hours after transplantation.
For patients unable to take the treatment orally, intravenous therapy should be started from a 0.05-0.10 mg/kg/day dose used as a continuous 24-hour infusion.
Prophylaxis of Allograft Rejection - Pediatric Patients
The initial dose of Tacrolimus capsules of 0.30 mg/kg/day should be taken as two divided doses (for example, in the morning and in the evening).
For patients unable to take the treatment orally, intravenous therapy should be started from a 0.075-0.100 mg/kg/day dose used as a continuous 24-hour infusion.
Supportive Therapy - Adults and Children
In the course of supportive therapy the doses of tacrolimus are generally lower. In some cases, concomitant immunosuppressive therapy can be cancelled leaving tacrolimus as the basic component of double-agent therapy. Dose adjustment can be needed due to changes in tacrolimus pharmacokinetics caused by improved condition of the patient after transplantation.
Treatment of Rejection Reaction- Adult and Pediatric Patients
For the treatment of rejection episodes, higher doses of tacrolimus combined with additional corticosteroid therapy and short-term courses of mono-/polyclonal antibodies should be used. If signs of toxicity are noted, a dose reduction may be required.
When the patient is transferred to tacrolimus capsule therapy, the recommended initial doses are the same as in initial immunosuppression. Information on patient crossover from cyclosporine to tacrolimus is given in the end of section “Dosage adjustments in specific populations”.
Heart Transplant
Prophylaxis of Allograft Rejection - Adult Patients
Tacrolimus can be used concomitantly with the induction antibody therapy (that permits to postpone the start of tacrolimus usage) or without antibodies administration in clinically stable patients. After the antibody induction the oral therapy with tacrolimus capsules should be started from the dose of 0,075 mg/kg/day taken as two doses (for example, in the morning and in the evening) for 5 days after surgery as soon as the clinical condition of the patient is stable. For patients unable to take the treatment orally, intravenous therapy should be started from a 0.01-0.02 mg/kg/day dose used as a continuous 24-hour infusion. There is an alternative approach where oral administration of tacrolimus starts within 12 hours post-transplant. This approach is intended for patients showing no signs of internal organs impairment (for example, of kidney). In this case tacrolimus in the initial dose of 2-4mg/day should be combined with mycophenolate mofetil and corticosteroids or with sirolimus and corticosteroids.
Prophylaxis of Allograft Rejection - Pediatric Patients
In pediatric patients who have received heart transplant the initial immunosuppression with tacrolimus can be either combined with antibody induction or used separately. In those cases when antibody induction is not used, tacrolimus is administered intravenously. The recommended initial dose is 0,03 – 0,05 mg/kg/day as a continuous
24-hour infusion until the concentration of tacrolimus in whole blood reaches
15-25 ng/ml. As soon as clinically possible the patient should be transferred to oral administration of the product. The starting oral dose of
0,30 mg/kg/day should be given in 8-12 hours after discontinuing of intravenous infusion.
After the antibody induction, the oral administration of tacrolimus should be started from
0,10-0,30 mg/kg/day taken as two doses (for example, in the morning and in the evening).
Supportive Therapy - Adults and Children
In the course of supportive therapy the doses of tacrolimus are generally lower. Dose adjustment can be needed due to changes in tacrolimus pharmacokinetics caused by improved condition of the patient after transplantation.
Treatment of Rejection Reaction- Adult and Pediatric Patients
For the treatment of rejection episodes, higher doses of tacrolimus combined with additional corticosteroid therapy and short-term courses of mono-/polyclonal antibodies should be used.
When the patient is transferred to tacrolimus capsule therapy, the initial doses (for adults – 0,15 mg/kg/day; for children – 0,2-0,3 mg/kg/day) should be taken as two doses (for example, in the morning and in the evening).
Information on patient crossover from cyclosporine to tacrolimus is given in the end of section “Dosage adjustments in specific populations”.
Recommended doses for the treatment of other organs allogeneic transplant rejections
The recommendations for tacrolimus doses for patients who have received allogeneic transplants of lung, pancreas and small intestine are based on the data of selected prospective clinical trials. The starting doses after lung transplantation is 0,10-0,15 mg/kg/day, for allogeneic transplantation of pancreas – 0,2 mg/kg/day. In patients who received allogeneic small intestine transplants the starting dose of tacrolimus is 0,3 mg/kg/day.
Dosage adjustments in specific populations
Patients with Hepatic Impairment
Patients with severe hepatic impairment may require lower doses to maintain the minimum concentration of tacrolimus within recommended values.
Patients with Renal Impairment
No dosage adjustment is needed because the renal function does not affect the pharmacokinetics of tacrolimus. However, due to tacrolimus nephrotoxicity it is recommended that the renal function be carefully monitored (including the concentration of serum creatinine, creatinine clearance, and diuresis level).
Pediatric Patients
For children the doses to reach initial tacrolimus concentrations in the blood are generally 1,5-2 times higher than the adult doses.
Geriatric Patients
At present there are no data to confirm that dose adjustment is required for elderly patients.
Crossover from cyclosporine therapy
Concomitant usage of cyclosporine and tacrolimus may increase the cyclosporine half-life and enhance toxic effects. Therefore, precautions should be taken for patient crossover from cyclosporine to tacrolimus therapy. Treatment with tacrolimus capsules should start only after assessment of blood cyclosporine concentration and patient condition. In case of high cyclosporine concentration in patient blood, the crossover to tacrolimus should be postponed. In practice, tacrolimus is administered in 12-24 hours after termination of cyclosporine therapy Due to possible abnormal clearance of cyclosporine, the monitoring of cyclosporine concentration should be continued after crossover.
Recommendations for therapeutic concentration of tacrolimus in the blood
The dosage of tacrolimus capsules should be selected on the basis of clinical assessment of rejection and drug tolerability for each patient. Immune methods including the semi-automated microparticle enzyme immunoassay (MIFA) are used for whole blood tacrolimus assay aimed at dosage adjustment. Comparison of the concentrations in published literature to individual clinical concentrations using the current assays must be made with precaution and with knowledge and understanding of the assay method.
In the post-transplant period it is important that minimum tacrolimus concentrations in the whole blood should be controlled. Blood samples for assay of minimum tacrolimus concentration in oral administration should be taken in 12 hours after administration immediately before taking the next dose. The frequency of blood tacrolimus assay should be based on clinical needs. Since tacrolimus is a product with low level clearance, the time to reach the minimum steady-state concentration of tacrolimus in the blood after dose adjustment may be up to several days. The minimum tacrolimus concentrations in the blood should be monitored approximately twice a week during the early post-transplant period and then periodically during the supportive therapy. The minimum tacrolimus concentrations in the blood should also be monitored when tacrolimus capsule strength or immunosuppressive regimen is changed or after concomitant usage with medicinal products affecting tacrolimus concentration in the whole blood.
According to clinical trials data, the treatment with tacrolimus capsules is most successful in cases when the minimum tacrolimus concentration in the blood is not greater than 20 ng/mg. Data on tacrolimus concentration in the whole blood should be interpreted with respect to assessment of clinical condition of the patient.
In clinical practice, in the early post-transplant period the minimum tacrolimus concentration in the whole blood generally vary within 5-20 ng/ml after liver transplantation and within 10-20 ng/ml after kidney and heart transplantation. Later, during the supportive therapy after liver, kidney and heart transplantation tacrolimus concentration is maintained from 5 to 15 ng/ml.