Tacrolimus Indications and Dosage
- atopic dermatitis
- eczema
- graft-versus-host disease (GVHD) †
- graft-versus-host disease (GVHD) prophylaxis †
- heart transplant rejection †
- heart transplant rejection prophylaxis
- kidney transplant rejection †
- kidney transplant rejection prophylaxis
- liver transplant rejection †
- liver transplant rejection prophylaxis
- lung transplant rejection †
- lung transplant rejection prophylaxis †
- nephrotic syndrome †
- pancreas transplant rejection prophylaxis †
- psoriasis †
- small bowel transplant rejection prophylaxis †
- uveitis †
† non-FDA-approved indication
Tacrolimus Indications and Dosage
For the treatment of acute liver transplant rejection † :
Intravenous and Oral dosage:
Adults: Tacrolimus has been widely studied for rescue therapy in patients who do not tolerate cyclosporine, have cyclosporine-refractory rejection or chronic rejection. Doses studied include 0.075 - 0.15 mg/kg /day continuous IV infusion, then 0.3 mg/kg/day PO in divided doses. In one study, patients with uncontrolled rejection or complications related to cyclosporine were given tacrolimus 0.15 mg/kg/day IV as a continuous infusion over 24 hours, followed by 0.3 mg/kg/day PO in 2 divided doses every 12 hours. Of the 39 patients meeting criteria for tacrolimus rescue therapy, all but 12 responded to therapy as demonstrated by histopathologic findings and liver function. In a follow-up report, patients receiving cyclosporine were changed to tacrolimus because of failure of the conventional immunosuppressive therapy. The tacrolimus dosage was 0.075 - 0.15 mg/kg IV given over 4 hours, followed by 0.3 mg/kg/day PO in divided doses.
Children: Dosages studied include tacrolimus 0.15 mg/kg/day continuous IV infusion, then 0.15 - 0.33 mg/kg/day PO in divided doses. In children whose immunosuppressive therapy was changed to tacrolimus therapy after early or late graft rejection on conventional immunosuppression, the tacrolimus dosage was 0.15 mg/kg/day IV as a slow infusion, followed by 0.15 mg/kg PO every 12 hours. After a mean follow-up of 150 days, 3 patients had died and 7 patients had retransplantations. In another study, patients were changed from cyclosporine to tacrolimus because of uncontrollable acute rejection, chronic rejection, or nonspecific hepatitis. Patients received a dosage of 0.15 mg/kg IV as a continuous infusion for 4 - 19 days, then 0.2 - 0.33 mg/kg/day PO in divided doses or oral therapy starting on day 4. Of the 18 patients with acute rejection, 11 had a complete response and 7 did not respond. Five patients developed a lymphoproliferative syndrome.
For liver transplant rejection prophylaxis:
Oral dosage:
Adults: 0.10 - 0.15 mg/kg/day PO in 2 divided doses. Adjust dose, as needed, based on tacrolimus trough whole blood concentrations. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation.
Children: 0.15 - 0.2 mg/kg/day PO in 2 divided doses. Adjust dose, as needed, based on tacrolimus trough whole blood concentrations. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation.
Intravenous dosage:
Adults and children: 0.03 - 0.05 mg/kg/day continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adult patients should receive doses at the lower end of the dosing range. Children may require higher doses than adults to achieve the same tacrolimus concentrations. The dose should be adjusted based on tacrolimus trough whole blood concentrations.
For the treatment of acute kidney transplant rejection † :
Intravenous and Oral dosage:
Adults: Tacrolimus has been widely studied for rescue therapy in patients who do not tolerate cyclosporine, have cyclosporine-refractory rejection, or chronic rejection. Tacrolimus dosages studied include 0.02 - 0.1 mg/kg/day IV, followed by 0.3 mg/kg/day PO in 2 divided doses to maintain tacrolimus 12-hour whole blood trough levels of 1 - 2 ng/ml. In one study, 57 of 77 patients (74%) were successfully rescued with tacrolimus therapy and still had functioning allografts with a mean follow-up of 14 months.
For kidney transplant rejection prophylaxis:
Oral dosage:
Adults: 0.2 mg/kg/day PO in 2 divided doses, every 12 hours. The initial dose may be administered within 24 hours of transplantation, but should be delayed until renal function as recovered (e.g., serum creatinine <= 4 mg/dl). Black patients may require higher doses to achieve comparable whole blood levels.
Intravenous dosage † :
Adults: 0.03 - 0.05 mg/kg/day continuous IV infusion. Patients should be started at the lower end of the dosage range. The initial dose may be administered within 24 hours of transplantation, but should be delayed until renal function as recovered (e.g., serum creatinine <= 4 mg/dl).
Intravenous and Oral dosage:
Adolescents and children † : There is no established regimen for tacrolimus in pediatric renal transplantation. In general, initial tacrolimus doses of 0.03 - 0.05 mg/kg/day continuous IV infusion or 0.15 - 0.2 mg/kg/day PO in 2 divided doses have been used. Children may require higher doses than adults to achieve the same tacrolimus concentrations. The dose should be adjusted based on tacrolimus trough whole blood concentrations. In a prospective study comparing tacrolimus and cyclosporine, pediatric patients received tacrolimus 0.1 mg/kg/day as an IV infusion over 24 hours, then 0.3 mg/kg/day PO in divided doses. At 1 year, patient and graft survival rates were 100% and 96%, respectively.
For pancreas transplant rejection prophylaxis † :
- for the management of pancreas/kidney or solitary pancreas transplant rejection prophylaxis † and refractory kidney and/or pancreas transplant rejection † :
Intravenous and Oral dosage:
Adults: Numerous trials have studied the use of tacrolimus in patients receiving pancreas transplant alone, simultaneous pancreas/kidney transplant, and pancreas transplant after kidney transplant. These studies have shown that tacrolimus is effective both as part of primary immunosuppressive therapy and in patients who do not tolerate cyclosporine or develop refractory rejection. For rejection prophylaxis dosages of 4 - 10 mg/day PO in divided doses have been used to maintain tacrolimus whole blood concentrations at an average of 12 ng/ml. In patients who switched to tacrolimus for rejection or rescue therapy the median dose was 10 mg/day PO in divided doses with a median whole blood concentration of 11 ng/ml.
- for islet transplantation rejection prophylaxis † :
Intravenous and Oral dosage:
Adults: In seven patients, immunosuppression with daclizumab, sirolimus, and low-dose tacrolimus 1 mg PO twice daily was begun immediately prior to islet transplantation. The tacrolimus dose was adjusted to maintain a whole blood trough concentration at 12 hours of 3 - 6 ng/ml. No corticosteroids were used as immunosuppression. All patients remain free of the need for exogenous insulin and no episodes of acute rejection have been observed with median follow-up of 11.9 months.
For the management of acute and chronic heart transplant rejection † :
Intravenous and Oral dosage:
Adults, adolescents, and children: Tacrolimus has been studied as rescue therapy in patients with intolerance to cyclosporine, acute rejection during cyclosporine therapy, or chronic rejection following heart transplantation. Tacrolimus 0.05 mg/kg/day IV or 0.2 - 0.3 mg/kg/day PO in 2 divided doses has been given as initial therapy. Tacrolimus doses are adjusted to maintain whole blood concentrations of 7 - 15 ng/ml.
For the management of heart transplant rejection prophylaxis:
NOTE: Tacrolimus is recommended to be used in conjunction with azathioprine or mycophenolate mofetil. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.
Intravenous and Oral dosage:
Adults: 0.075 mg/kg/day PO in 2 divided doses. Adjust dose, as needed, based on tacrolimus trough whole blood concentrations. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. If IV therapy is initially needed, administer 0.0187 - 0.025 mg/kg/day by a continuous IV infusion (personal communication, Astellas Pharma, Inc.). Conversion to PO administration is once oral therapy is tolerated; give the first oral dose 8 - 12 hours after the IV infusion is stopped.
Intravenous dosage:
Infants and children † : The optimal dosing regimen of tacrolimus in pediatric heart transplantation has not been determined. Tacrolimus dosage 0.03 - 0.05 mg/kg/day continuous IV infusion to achieve whole blood levels of 15 - 20 ng/ml has been studied. In a retrospective review, tacrolimus doses < 0.05 mg/kg/day IV may result in a clinically important delay in reaching therapeutic levels. Frequent monitoring of tacrolimus whole blood levels is recommended during the first 48 hours, especially when the initial level is > 10 ng/ml to avoid toxicity.
For the rescue treatment for lung transplant rejection † or the management of lung transplant rejection prophylaxis † :
Intravenous and Oral dosage:
Adults: Tacrolimus has been studied as primary immunosuppression and as rescue therapy in patients undergoing lung transplantation. In a randomized study comparing tacrolimus with cyclosporine, the initial tacrolimus dose was 0.025 mg/kg/day continuous IV infusion, which was increased to 0.075 mg/kg/day IV, and then changed to 0.15 mg/kg/day PO in divided doses to maintain a 12-hour trough whole blood concentration of 1 - 1.5 ng/ml.
Adolescents and children: In a study comparing tacrolimus and cyclosporine, 11 pediatric patients (ages 3 - 18 years) received an initial tacrolimus dose of 0.05 mg/kg/day IV, followed by 0.3 mg/kg/day PO in 2 divided doses to maintain whole blood trough concentrations of 1 - 2 ng/ml.
For the management of small bowel transplant rejection prophylaxis † :
Intravenous and Oral dosage:
Adults and children: In one report, adults and children received tacrolimus 0.1 - 0.15 mg/kg/day IV, followed by 0.3 mg/kg/day PO in divided doses for either small-bowel, small-bowel and liver, or multivisceral transplantation. In a subsequent report of 15 patients who received tacrolimus 0.1 - 0.15 mg/kg/day IV, followed by 0.3 mg/kg/day PO in divided doses for small-bowel, with or without the colon, transplantation, actuarial patient survival rates at 6, 12, and 18 months were 100%, 88%, and 70%, respectively. The overall incidence of rejection was 94%.
For the treatment of graft-versus-host disease (GVHD) † in combination with other immunosuppressants:
NOTE: Tacrolimus has been designated an orphan drug by the FDA for this indication.
Intravenous dosage:
Adults and adolescents: A dosage of 0.1 mg/kg/day IV in 2 divided doses has been studied. The dose should be adjusted based on tacrolimus trough whole blood concentrations. The responsiveness of steroid-refractory graft-versus-host disease to tacrolimus is marginal. Tacrolimus has also been used successfully in the treatment of chronic graft-versus-host disease.
Children: A dosage of 0.1 mg/kg/day continuous IV infusion has been utilized.
Oral dosage:
Adults and adolescents: Doses of 0.3 mg/kg/day PO in 2 divided doses, starting when the patient can tolerate oral medications have been given. The dose should be adjusted based on tacrolimus trough whole blood concentrations.
Children: See dosage for adults and adolescents. Children may require higher doses to maintain therapeutic whole blood trough concentrations of tacrolimus.
For graft-versus-host disease (GVHD) prophylaxis † :
Intravenous dosage:
Adults, adolescents, and children: Doses of 0.03 mg/kg/day continuous IV infusion, starting 1 - 2 days prior to bone marrow transplantation (day -1 or -2) have been recommended. Beginning tacrolimus on day -2 may be of benefit in pediatric patients. The dose should be adjusted based on tacrolimus trough whole blood concentrations. Usually given in combination with methotrexate.
Oral dosage:
Adults, adolescents, and children: Doses of 0.12 mg/kg/day PO in 2 divided doses, starting when the patient is able to tolerate oral medications have been recommended. The dose should be adjusted based on tacrolimus trough whole blood concentrations. Usually given in combination with methotrexate. Children may require higher doses to maintain therapeutic whole blood trough concentrations of tacrolimus.
For short-term or intermittent long-term treatment of moderate-to-severe atopic dermatitis (i.e., eczema):
NOTE: Topical tacrolimus is a second line agent to treat atopic dermatitis in patients unresponsive to or intolerant of other first line agents; long-term safety has not been established.
NOTE: If no improvement occurs after 6 weeks of treatment or if exacerbation of atopic dermatitis occurs, treatment should be stopped and other therapeutic options considered.
Topical dosage (0.03% and 0.1% ointment):
Adults and adolescents > 15 years: Apply a thin layer to the affected areas twice daily. Rub in gently and completely. Treatment should continue for one week after clearing of signs and symptoms. Do not use under occlusive dressings. A European study revealed that topical tacrolimus (0.03%, 0.1%, and 0.3%) every 12 hours for 3 weeks was an effective treatment for atopic dermatitis and statistically superior to vehicle alone.
Topical dosage (0.03% ointment):
Adolescents and children 2 - 15 years: Apply a thin layer to the affected areas twice daily. Rub in gently and completely. Treatment should continue for one week after clearing of signs and symptoms. Do not use under occlusive dressings.
Children < 2 years † : A retrospective study reported that 12 patients (< 2 years of age) treated with topical tacrolimus 0.1% or 0.03% had significant improvement in their atopic dermatitis without adverse effects. No measurable serum tacrolimus concentrations were reported. Randomized, placebo-controlled studies are needed. A thin layer of ointment should be applied to the affected areas twice daily. Rub in gently and completely. Treatment should continue for one week after clearing of signs and symptoms. Do not use under occlusive dressings.
For the treatment of severe, recalcitrant, plaque-type psoriasis † :
Oral dosage:
Adults: In one study, patients with severe, recalcitrant, plaque-type psoriasis were given tacrolimus initially as 0.05 mg/kg/day PO and was increased to 0.1 mg/kg/day PO at week 3 and to 0.15 mg/kg/day PO at week 6 if necessary. By the end of the study, tacrolimus-treated patients had a significantly greater reduction in the Psoriasis Area and Severity Index than did placebo-treated patients.
For the treatment of severe, refractory uveitis † :
Oral dosage:
Adults: In patients with refractory uveitis, a dose of 0.1 - 0.15 mg/kg/day PO in 2 divided doses given for 12 weeks was effective in 60 - 83% of patients. Higher doses of 0.2 mg/kg/day PO have also been used; however, an increase in adverse effects has been reported with these dosages. A tacrolimus whole blood trough concentration of 15 - 25 ng/ml has been recommended.
For the treatment of steroid- and cyclosporine-resistant nephrotic syndrome † :
Oral dosage:
Adults and children: In a pilot study, 7 patients with steroid-resistant nephrotic syndrome received a dose of 0.1 mg/kg/day PO for at least 3 months. This dose was effective in decreasing proteinuria to 50% to normal protein levels. In the management of cyclosporine- and steroid- resistant nephrotic syndrome after renal transplantation, the use of tacrolimus may only be useful in a small group of patients (i.e., patients with de novo nephrotic syndrome following transplantation). Patients with chronic rejection should not be changed from cyclosporine to tacrolimus to treat post-transplantation nephrotic syndrome.
Therapeutic Drug Monitoring:
The two methods commonly used for the determination of tacrolimus whole blood concentrations are a microparticle enzyme immunoassay (MEIA) and an ELISA. Both methods use the same antibody for tacrolimus. Patients with elevated serum bilirubin levels (> 3 mg/dl) may require close monitoring with more specific assay techniques (e.g., HPLC). In general, it is recommended that trough whole blood tacrolimus concentrations should be below 20 ng/ml to avoid severe toxicity. The lower limit is not well defined. Some patients with tacrolimus whole blood concentrations < 5 ng/ml have adequate immunosuppression. The following reference ranges of tacrolimus whole blood levels have been recommended:
Adult kidney transplant patients <= 3 months post-transplant: 7 - 20 ng/ml
Adult kidney transplant patients 4 - 12 months post-transplant: 5 - 15 ng/ml
Adult and pediatric liver transplant patients up to 12 months post-transplant: 5 - 20 ng/ml
Adult and pediatric patients for prevention of acute graft-versus-host disease: 10 - 20 ng/ml
NOTE: Tacrolimus plasma concentrations have also been used in some studies. The therapeutic range for plasma tacrolimus levels is 1 - 2 ng/ml.
Patients with hepatic impairment:
Patients with hepatic impairment should receive doses at the lowest value of the recommended intravenous and oral dosing ranges. Further reductions in dose below these ranges may be required.
Patients with renal impairment:
Patients with renal impairment should receive doses at the lowest value of the recommended intravenous and oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria or significant renal impairment (i.e., as noted by serum creatinine >= 4 mg/dl).
† non-FDA-approved indication
[ Last revised: 4/26/2006 9:12:00 AM ]
References
. Shapiro AM, Lakely JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230 - 8.
. Gruessner RWG, Burke GW, Stratta R, et al. A multicenter analysis of the first experience of FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 1996;61:261 - 73.
. The European FK 506 Multicentre Psoriasis Study Group. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. Arch Dermatol 1996;132:419 - 23.
. Przepiorka D, Devine S, Fay J, et al. Practical considerations in the use of tacrolimus for allogeneic marrow transplantation. Bone Marrow Transplant 1999;24:1053 - 6.
. Fung JJ, Todo S, Jain A et al. Conversion from cyclosporine to FK 506 in liver allograft recipients with cyclosporine-related complications. Transplant Proc 1990;22:6 - 12.
. Fung JJ, Todo S, Tzakis A et al. Conversion of liver allograft recipients from cyclosporine to FK 506 based immunosuppression: benefits and pitfalls. Transplant Proc 1991;23:14 - 21.
. Tzakis AG, Fung JJ, Todo S et al. Use of FK 506 in pediatric patients. Transplant Proc 1991;23:924 - 7.
. Reding R, Wallemacq PE, Lamy ME et al. Conversion from cyclosporine to FK-506 for salvage of immunocompromised pediatric liver allografts. Transplantation 1994;57:93 - 100.
. Scantlebury VP, Shapiro R, Tzakis A et al. Pediatric kidney transplantation at the University of Pittsburgh. Transplant Proc 1994;26:46 - 7.
. Jordan ML, Shapiro R, Vivas CA et al. FK506 “rescue” for resistant rejection of renal allografts under primary cyclosporine immunosuppression. Transplantation 1994;57:860 - 5.
. Robinson BV, Boyle GJ, Miller SA, et al. Optimal dosing of intravenous tacrolimus following pediatric heart transplantation. J Heart Lung Transplant 1999;18:786 - 91.
. Griffith BP, Bando K, Hardesty RL et al. A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation. Transplantation 1994;57:848 - 51.
. Armitage JM, Fricker FJ, Kurland G et al. Pediatric lung transplantation: the years 1985 to 1992 and the clinical trial of FK-506. J Thorac Cardiovasc Surg 1993;105:337 - 46.
. Todo S, Tzakis A, Reyes J et al. Intestinal transplantation in humans under FK-506. Transplant Proc 1993;25:1198 - 9.
. Todo S, Tzakis A, Reyes J et al. Small intestinal transplantation in humans with or without the colon. Transplantation 1994;57:840 - 8.
. Ruzicka T, Bieber T, Schopf E et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337:816 - 21.
. Mochizuki M, Masuda K, Sakane T et al. A clinical trial of FK506 in refractory uveitis. Am J Ophthalmol 1993;115:763 - 9.
. McMauley J, Shapiro R, Ellis D, et al. Pilot trial of FK 506 in the management of steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 1993;8:1286 - 90.
. McCauley J, Shapiro R, Jordan M, et al. FK 506 in the management of nephrotic syndrome after renal transplantation. Tranplant Proc 1993;25:1351 - 4.
. Patel RR, Vander Straten MR, Korman NJ. The safety and efficacy of tacrolimus therapy in patients younger than 2 years with atopic dermatitis. Arch Dermatol 2003;139:1184 - 86.
Related entries
Syndicate
|
