TACROLIMUS–TEVA PROLONGED RELEASE HARD CAPSULE 1MG

TEVA PHARMACEUTICAL INVESTMENTS SINGAPORE PTE. LTD.

TEVA PHARMACEUTICAL INVESTMENTS SINGAPORE PTE. LTD.

Therapeutic

Prescription Only

CAPSULE, EXTENDED RELEASE

**Posology and Method of Administration** Tacrolimus prolonged release (PR) capsule is a once-a-day oral formulation. Tacrolimus PR capsule therapy requires careful monitoring by adequately qualified and equipped personnel. 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. 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 side effects, including under- or over-immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see Special warnings and precautions for use and Undesirable effects – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). 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. Posology The recommended initial doses presented below are intended to act solely as a guideline. Tacrolimus PR capsule 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. Tacrolimus PR capsule 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. In _de novo_ kidney and liver transplant patients AUC0–24 of tacrolimus for Tacrolimus PR capsule on Day 1 was 30% and 50% lower respectively, when compared with that for Tacrolimus immediate release (IR) capsule at equivalent doses. By Day 4, systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in the first two weeks post-transplant with Tacrolimus PR capsule to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Tacrolimus PR capsule 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. _Prophylaxis of kidney transplant rejection_ Tacrolimus PR capsule therapy should commence at a dose of 0.20 – 0.30 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery. Tacrolimus PR capsule doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Tacrolimus PR capsule monotherapy. Post-transplant changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments. _Prophylaxis of liver transplant rejection_ Tacrolimus PR capsule therapy should commence at a dose of 0.10 – 0.20 mg/kg/day administered once daily in the morning. Administration should commence approximately 12–18 hours after the completion of surgery. Tacrolimus PR capsule doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Tacrolimus PR capsule monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments. _Conversion of Tacrolimus IR-treated patients to Tacrolimus PR capsule_ Allograft transplant patients maintained on twice daily Tacrolimus IR capsules dosing requiring conversion to once daily Tacrolimus PR capsule should be converted on a 1:1 (mg:mg) total daily dose basis. Tacrolimus PR capsule should be administered in the morning. In stable patients converted from Tacrolimus IR capsules (twice daily) to Tacrolimus PR capsule (once daily) on a 1:1 (mg : mg) total daily dose basis, the systemic exposure to tacrolimus (AUC0–24) for Tacrolimus PR capsule was approximately 10% lower than that for Tacrolimus IR capsule. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0–24) for Tacrolimus PR capsule is similar to that of Tacrolimus IR. When converting from Tacrolimus IR capsules to Tacrolimus PR capsule, trough levels should be measured prior to conversion and within two weeks after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary dose adjustments made to maintain similar systemic exposure. Dose adjustments should be made to ensure that similar systemic exposure is maintained. _Conversion from ciclosporin to tacrolimus_ Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see Special warnings and precautions for use and Interaction with other medicinal products and other forms of interaction – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). The combined administration of ciclosporin and tacrolimus is not recommended. Tacrolimus PR capsule therapy should be initiated after considering ciclosporin blood concentration 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. _Treatment of allograft rejection_ Increased doses of tacrolimus, 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 Undesirable effects – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_), the dose of Tacrolimus PR capsule may need to be reduced. _Treatment of allograft rejection after kidney or liver transplantation_ For conversion from other immunosuppressants to once daily Tacrolimus PR capsule, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection. Therapeutic drug monitoring 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 optimize 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 (C24) and systemic exposure (AUC0–24) is similar between the two formulations: Tacrolimus PR capsule and Tacrolimus IR capsule. Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus blood trough levels should be determined approximately 24 hours post-dosing of Tacrolimus PR capsule, just prior to the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored following conversion from Tacrolimus IR to Tacrolimus PR capsule, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see Interaction with other medicinal products and other forms of interaction – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Tacrolimus PR capsule dose regimen, it may take several days before the targeted steady state is achieved. Data from clinical studies suggest 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. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 – 15 ng/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 tacrolimus blood trough levels within the recommended target range. _Renal impairment:_ As the pharmacokinetics of tacrolimus are unaffected by renal function (see Pharmacokinetic properties – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_), 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 elderly patients. Method of administration Tacrolimus PR capsule is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Tacrolimus PR capsule be administered once daily in the morning. Tacrolimus prolonged-release hard capsules should be taken immediately following removal from the blister. Patients should be advised not to swallow the desiccant. The capsules should be swallowed **whole** with fluid (preferably water). Tacrolimus PR capsule 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 Pharmacokinetic properties – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). A forgotten morning dose should be taken as soon as possible on the same day. A double dose should not be taken on the next morning. In patients unable to take oral medicinal products during the immediate post-transplant period, tacrolimus therapy can be initiated intravenously. Tacrolimus 5 mg/ml concentrate for solution for infusion should be administered at a dose approximately 1/5th of the recommended oral Tacrolimus PR capsule dose for the corresponding indication.