AHFS Class:

• Calcineurin Inhibitors, Miscellaneous 90:28.28.92

Generic Name(s):

• Tacrolimus

Tacrolimus, a calcineurin inhibitor,1,2,3,4,7,10,11 is a potent immunosuppressive agent.1,2,3,4,7,11,12

Tacrolimus immediate-release oral preparations (conventional capsules, granules for oral suspension) are used in combination with other immunosuppressants for the prevention of organ rejection in adult and pediatric patients receiving kidney, liver, heart, or lung allografts.1 A parenteral preparation of tacrolimus is available for IV use in patients who cannot tolerate oral formulations; patients should be converted from IV to oral therapy as soon as oral therapy is tolerated.1 Tacrolimus also is available as extended-release capsule and tablet formulations for the prevention of rejection of kidney allografts.79,80

Because of differences in pharmacokinetic properties, extended-release capsule and tablet formulations are not interchangeable with each other or with tacrolimus immediate-release formulations.1,79,80 Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products have been reported outside the US.1

Renal Transplantation

Tacrolimus is used in combination with other immunosuppressants for the prevention of rejection of renal allografts.1,37,38,39,42,45,46,47,48,49,52,54 Immediate-release oral preparations of tacrolimus and the IV formulation are indicated for the prophylaxis of organ rejection in adult and pediatric kidney transplant patients.1 Tacrolimus extended-release capsules (Astagraf XL^®) are indicated for the prophylaxis of organ rejection in adult and pediatric kidney transplant patients who are able to swallow capsules intact.79 Tacrolimus extended-release tablets (Envarsus XR^®) are indicated for the prophylaxis of organ rejection in de novo adult kidney transplant patients or patients who are converting from tacrolimus immediate-release formulations.80

Efficacy and safety of tacrolimus in renal allograft transplantation were evaluated in a randomized, multicenter, non-blinded, prospective study that compared tacrolimus-based immunosuppression with a cyclosporine-based regimen in 412 patients ≥6 years of age.1,39 Treatment with study medication was initiated when post-transplant renal function was stable (i.e., serum creatinine ≤4 mg/dL), which was a median of 4 days after transplant (range: 1-14 days).1 All patients received combination immunosuppressive induction therapy with steroids, azathioprine, and an antilymphocyte antibody.1,39 One-year patient survival rates were 95.6% in the tacrolimus group and 96.6% in the cyclosporine group, and one-year graft survival rates were 91.2% and 87.9% in the respective treatment groups.39

Efficacy and safety of tacrolimus in conjunction with mycophenolate mofetil (MMF), corticosteroids, and induction therapy were evaluated in a randomized, open-label, multicenter trial (ELITE-Symphony) in 1589 adult kidney transplant patients.1,87 Patients received standard-dose cyclosporine, MMF, and corticosteroids, or daclizumab induction, MMF, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus.1,87 The initial dosage of tacrolimus used in the study was 0.1 mg/kg per day divided into 2 daily doses; the dosage was then adjusted to achieve a target trough level of 3-7 ng/mL.87 At 12 months, the overall survival rate was similar between all groups and was more than 96%.1,87 Patients who received tacrolimus had improved kidney function (as evidenced by higher estimated creatinine clearance rates), lower rates of biopsy-proven acute rejection, and higher allograft survival than those in the other treatment groups, but were more likely to develop diarrhea and diabetes after transplantation.1,87

In another randomized, open-label, multicenter trial, 424 kidney transplant patients received tacrolimus or cyclosporine in combination with MMF (1 g twice daily), basiliximab induction, and corticosteroids.1 In this trial, the rate for the combined endpoint of biopsy-proven acute rejection, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group.1 Mortality at 12 months in patients receiving tacrolimus in combination with MMF was 4% compared to 2% in those receiving cyclosporine in combination with MMF, including cases attributed to over-immunosuppression.1

Other studies evaluating tacrolimus in kidney transplant recipients have reported one-year graft and patient survival rates of 82-99% and 93-100%, respectively.37,38,39,42,45,46,47,48,49,50,51,52,54,88,500 Numerous randomized controlled studies and meta analyses have shown that tacrolimus is superior to cyclosporine for preventing acute rejection and improving allograft survival after kidney transplantation, but increases post-transplant diabetes, neurological, and GI adverse effects.88,500

Efficacy and safety of tacrolimus extended-release capsules (Astagraf XL^®) for the prevention of rejection of renal allografts in kidney transplant patients were evaluated in 2 multicenter randomized studies (an open-label study that included induction therapy with basiliximab, and a double-blind study without induction) of 12 months' duration that compared extended-release tacrolimus with immediate-release tacrolimus in combination with MMF and corticosteroids.79,83,85 In both studies, the overall rate of treatment failure (i.e., biopsy-proven acute rejection, graft loss, death, or loss to follow-up) at 12 months was not substantially different between the groups and mean estimated glomerular filtration rates were similar at the end of the study.79,83,85 Follow-up of the open-label study that included induction therapy with basiliximab continued to have similar safety and efficacy results through 4 years.84

Efficacy and safety of tacrolimus extended-release tablets (Envarsus XR^®) for prevention of transplant rejection in de novo kidney transplant patients were evaluated in a 12-month randomized, double-blind study and an open-label phase 2 study; both studies compared tacrolimus extended-release tablets once daily to tacrolimus immediate-release capsules twice daily.80,86 All patients received only IL-2 receptor antagonist induction therapy and concomitant treatment with MMF and corticosteroids.80,86 At 12 months, the overall rate of treatment failure (i.e., biopsy-proven acute rejection, graft loss, death, or loss to follow-up) was not substantially different between patients who received tacrolimus extended-release tablets versus those who received the immediate-release capsules.80 There were no deaths or graft failures in the open-label study.80 Follow-up of this study at 24 months continued to report comparable safety and efficacy results between immediate-release and extended-release tacrolimus.86

An additional randomized, open-label multinational study evaluated the use of tacrolimus extended-release tablets administered once daily as a replacement for tacrolimus immediate-release capsules administered twice daily as maintenance immunosuppression to prevent acute allograft rejection in stable adult kidney transplant patients.80 Patients received a kidney transplant 3 months to 5 years before study entry; mycophenolate mofetil or mycophenolate sodium, azathioprine, and/or corticosteroids were allowed as concomitant immunosuppressants during the study period.80 At 12 months, the overall rate of treatment failure (i.e., biopsy-proven acute rejection, graft loss, death, or loss to follow-up) was not substantially different between patients who received tacrolimus extended-release tablets versus those who received the immediate-release capsules.80 Additionally, kidney function (as assessed by mean estimated glomerular filtration rates) was similar in the two treatment groups.80

Liver Transplantation

Tacrolimus (as immediate-release and IV preparations) is used in combination with other immunosuppressants for the prevention of organ rejection in adults and pediatric patients receiving liver transplant.1,2,4,9,13

Efficacy of tacrolimus immediate-release formulations in hepatic allograft transplantation is based on data from 2 prospective, randomized, open-label multicenter studies.1,5,13 One of the studies was conducted in the US; this study excluded patients with renal dysfunction, fulminant hepatic failure with stage IV encephalopathy, and cancers but included pediatric patients aged ≤12 years.1 The other study was conducted in Europe and excluded pediatric patients but did allow enrollment of patient groups excluded from the first study (other than patients who had primary hepatic cancers with metastases).1 Patients in both studies received an immunosuppressive regimen that included corticosteroids and either tacrolimus or cyclosporine; the majority of patients treated with cyclosporine also received azathioprine.1,3,5,13 Tacrolimus and cyclosporine were comparably effective in these patients in terms of patient survival and graft survival 1 year after transplantation.1,3,4,5,13 In the US study, patient and graft survival rates for both groups combined were 88 and 81%, respectively.1 In the European study, patient and graft survival rates for both groups combined were 78 and 73%, respectively.1

Efficacy of tacrolimus immediate-release granules for oral suspension in pediatric liver transplant patients is based on data from a prospective, randomized, open-label multicenter study involving de novo hepatic allograft recipients ≤16 years of age.1,81 In this study, 181 patients received an immunosuppressive regimen containing corticosteroids and either tacrolimus granules for suspension or cyclosporine with azathioprine, starting 6 hours after conclusion of allotransplantation surgery.1,81 Tacrolimus dosing was adjusted throughout the study to maintain whole blood trough levels in the range of 5-20 ng/mL.1,81 The overall failure rate (i.e., biopsy-proven acute rejection, graft loss, death, or loss to follow-up) was comparable for tacrolimus-based and cyclosporine-based immunosuppression regimens (52.7 versus 61.1%, respectively).1,81

The use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is therefore not recommended.1

Cardiac Transplantation

Tacrolimus (as immediate-release and IV preparations) is used in combination with other immunosuppressants for the prevention of organ rejection in adults and pediatric patients receiving cardiac transplant.1,69,70

Efficacy of tacrolimus immediate-release formulations in cardiac allograft transplantation is based on data from 2 open-label, randomized, multicenter studies comparing the safety and efficacy of tacrolimus-based immunosuppression and cyclosporine-based immunosuppression in primary orthotopic heart transplantation.1,69,70

In the first study, which was conducted in Europe, 314 adults received a regimen of antibody induction therapy, corticosteroids, and azathioprine in combination with either tacrolimus or modified cyclosporine for 18 months.1,70 The incidence of biopsy-proven acute rejection at 6 months was substantially lower in the tacrolimus-based group of patients than in those receiving the cyclosporine-based regimen (ISHLT grade 1B acute rejection or greater: 54 versus 66%, respectively; grade 3A or greater: 28 versus 42%, respectively). 70 Tacrolimus and cyclosporine were comparably effective in the treatment groups in terms of patient survival and graft survival 18 months after transplantation (92 and 90%, respectively).1,70

In the second study, which was conducted in the US and consisted of 3 treatment arms, 331 adults undergoing de novo cardiac transplantation received an immunosuppressive regimen containing corticosteroids and either tacrolimus with sirolimus, tacrolimus with mycophenolate mofetil, or modified cyclosporine with mycophenolate mofetil for 1 year; antibody induction therapy also was allowed.1,69 The incidence of biopsy-proven acute rejection (ISHLT grade 3A or greater) or hemodynamic compromise requiring treatment was lower in the tacrolimus-treated patients at 6 months (22-24 versus 32%, respectively) and was significantly lower at 1 year in patients treated with tacrolimus and mycophenolate mofetil compared with patients treated with cyclosporine and mycophenolate mofetil (23 versus 37%, respectively).69 Similar patient and graft survival rates 1 year after transplantation were evident in the 2 mycophenolate mofetil-treated groups with approximately 93% survival reported in the tacrolimus plus mycophenolate mofetil group and 86% survival in the modified cyclosporine plus mycophenolate mofetil group.1,69 However, patients in the tacrolimus and sirolimus group exhibited an increased risk of wound healing complications, renal impairment, and insulin-dependent posttransplant diabetes mellitus; the manufacturer states that this combination is therefore not recommended.1,69

Lung Transplantation

Tacrolimus (as immediate-release and IV preparations) is used in combination with other immunosuppressants for the prevention of organ rejection in adults and pediatric patients receiving lung transplantation.1

Efficacy of tacrolimus immediate-release formulations in lung transplantation is based on observational data from the U.S. Scientific Registry of Transplant Recipients (SRTR).1 Outcomes were evaluated for 19,741 adult and 522 pediatric lung transplant patients receiving tacrolimus in combination with either mycophenolate mofetil or azathioprine at the time of hospital discharge.1 The 1-year graft survival estimates were similar for adults receiving tacrolimus plus mycophenolate mofetil or tacrolimus plus azathioprine (90.9 and 90.8%, respectively).1 In pediatric patients, the 1-year graft survival rates were 91.7 and 84.7% for tacrolimus plus mycophenolate mofetil and tacrolimus plus azathioprine, respectively.1

Transplantation - Clinical Perspective

The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients states that immunosuppressive medication recommendations in this setting are complex as combinations of multiple drug classes are utilized and choices between varying regimens are determined through an evaluation of benefits (e.g., reduced risk of rejection) and harms (e.g., increased risk of infection and malignancy).505 For initial maintenance immunosuppression, KDIGO recommends a combination of immunosuppressive medications including a calcineurin inhibitor (tacrolimus - first line) and an antiproliferative agent (mycophenolate - first line), with or without corticosteroids.505 KDIGO states that there is no reason to delay initiation of calcineurin inhibitor therapy and no evidence that delaying such therapy prevents or ameliorates delayed graft function.505 Additionally, the guideline notes that tacrolimus reduces the risk of acute rejection and improves graft survival as compared to cyclosporine during the first year of transplantation, that low-dose tacrolimus therapy reduces the risk of new onset diabetes after transplant as compared to higher doses, and that the earlier that therapeutic calcineurin inhibitor blood levels can be attained, the more effective the medication will be in preventing acute rejection.505

In 2022, consensus recommendations for the use of maintenance immunosuppression in solid organ transplantation were developed and endorsed by the American College of Clinical Pharmacy (ACCP), American Society of Transplantation (AST), and the International Society for Heart and Lung Transplantation (ISHLT).506 These recommendations state there is no standardized approach to maintenance immunosuppression management in solid organ transplantation.506 A variety of factors may impact choice of agents including the transplanted organ, center-specific protocols, provider expertise, insurance and cost issues, and patient characteristics and tolerability of therapy.506 The consensus recommendations note that tacrolimus is superior to cyclosporine for the prevention of acute rejection in various solid organ transplants.506 Tacrolimus is also superior to cyclosporine with regard to reducing the severity of rejection in kidney and pancreas transplants and is associated with improved allograft survival in kidney, pancreas, and liver transplantation.506 Tacrolimus may offer an advantage over cyclosporine in lung transplant regarding prevention of bronchiolitis obliterans syndrome. 506

Crohn's Disease

Tacrolimus has been used in the management of fistulizing Crohn's disease†.60,61,62,63,64,65 Administration of oral tacrolimus has been effective for fistula improvement, but not for fistula remission in patients with perianal Crohn's disease.61 Efficacy of tacrolimus in the management of fistulizing Crohn's disease has been evaluated in a randomized, double-blind, placebo-controlled study involving 48 patients (≥12 years of age) with one or more open draining enterocutaneous fistulas that had not closed with administration of at least one anti-infective agent.61 Patients were randomized to receive placebo (26 patients) or oral tacrolimus (22 patients) 200 mcg/kg daily for 10 weeks.61,65 Those who were receiving stable dosages of corticosteroids, oral or rectal 5-aminosalicylic acid derivatives, oral anti-infective agents, azathioprine, mercaptopurine, methotrexate, or mycophenolate mofetil continued to receive these drugs during the study.61 The primary outcome was fistula improvement (defined as closure of 50% or more of particular fistulas that were open and draining at baseline and maintenance of such closures for at least 4 weeks), while secondary outcome was fistula remission (defined as closure of all fistulas and maintenance of such closures for at least 4 weeks).61 Fistula improvement was attained in 43% of patients receiving tacrolimus versus 8% of those receiving placebo, while fistula remission was attained in 10 or 8% of patients receiving tacrolimus or placebo, respectively; the difference in fistula remission was not considered statistically significant. 61 Some clinicians state that because of the potential for tacrolimus-associated nephrotoxicity (especially at high doses) and because complete fistula remission has not been achieved with the drug, tacrolimus should be reserved for patients who do not respond to or are intolerant of all other therapies used for the management of fistulizing Crohn's disease (e.g., ciprofloxacin and/or metronidazole, azathioprine or mercaptopurine, infliximab).61

For topical uses of tacrolimus, see 84:06.28.

Clinical Perspective

The American College of Gastroenterology guideline on the management of Crohn's disease in adults strongly recommends that tacrolimus should not be used for moderate-to-severe/moderate-to-high-risk Crohn's disease.507 However, for perianal and cutaneous fistulizing disease, tacrolimus can be administered short-term; significant toxicity precludes the use of tacrolimus on a long-term basis.507

Pancreas Transplantation

Some studies have evaluated the role of tacrolimus in the setting of prevention of rejection of pancreas allografts† (often performed simultaneously with a kidney transplant).508,509 The 2022 ACCP, AST, and ISHLT consensus recommendations for use of maintenance immunosuppression in solid organ transplantation state that tacrolimus is superior to cyclosporine for the prevention of allograft rejection and is also superior for reducing the severity of rejection in pancreas transplantation.506 The recommendations also note that tacrolimus is associated with improved allograft survival compared to cyclosporine in pancreas transplant.506

Intestinal Transplantation

Several studies have evaluated the role of tacrolimus in the prevention of rejection of intestinal allografts†.510,511,512,513 The 2022 ACCP, AST, and ISHLT consensus recommendations for use of maintenance immunosuppression in solid organ transplantation state that tacrolimus is superior to cyclosporine for the prevention of allograft rejection in intestinal transplantation.506

Other Uses

Tacrolimus has also been used to prevent rejection of vascular composite allografts†.514,515,516,517

General

Pretreatment Screening

• Evaluate immunizations and give complete complement of needed vaccines before transplantation and treatment.1,79,80
• Assess patients for a history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, or hypomagnesemia that could increase the risk of torsades de pointes and/or sudden death with tacrolimus use.1,79,80

Patient Monitoring

• Therapeutic drug monitoring is recommended for all patients.1,79,80
• Continuously observe patients receiving IV tacrolimus for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter.1 If signs or symptoms of anaphylaxis occur, stop the infusion.1
• Examine patients for skin changes periodically.1,79,80
• Monitor patients for signs and symptoms of infection.1,79,80
• Perform routine laboratory testing (e.g., for assessment of renal and hepatic function, for monitoring of glucose and potassium concentrations).1,79,80
• Monitor patients for neurologic changes.1,79,80
• Check blood pressure periodically.1,79,80

Dispensing and Administration Precautions

• Tacrolimus should only be used under the supervision of a provider with experience managing immunosuppressive therapy.1,79,80 Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.1
• When IV tacrolimus is administered, emergency drugs and equipment such as epinephrine and oxygen should be available at the bedside.1
• Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills.1
• Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in tacrolimus capsules and tacrolimus granules, respectively.1 If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water.1 If a spill occurs, wipe the surface with a wet paper towel.1

Other General Considerations

• Do not use simultaneously with cyclosporine.1 Tacrolimus or cyclosporine should be discontinued at least 24 hours before initiating the other drug.1 In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.1

Administration

Tacrolimus is administered orally as immediate-release capsules, granules for oral suspension, or extended-release capsules and tablets; tacrolimus also may be administered by IV infusion.1,79,80 Because of the risk of anaphylaxis, IV administration of the drug should be reserved for patients who cannot tolerate oral administration.1 If therapy is initiated with the IV formulation, substitute oral therapy as soon as tolerated.1,4,13 Extended-release formulations of the drug are indicated only in kidney transplant patients.79,80

Because of differences in pharmacokinetic properties, extended-release preparations are not interchangeable with each other or with tacrolimus immediate-release capsules or granules for suspension.1,79,80 When converting between immediate-release capsules and granules for suspension, the total daily dosage should remain the same; therapeutic drug monitoring is recommended when switching between tacrolimus formulations.1

Store tacrolimus capsules and granules for oral suspension at 20 to 25ºC and extended-release capsules and extended-release tablets at 25°C; with excursions permitted between 15 to 30°C.1,79,80 Store tacrolimus injection between 5 to 25°C.1

Oral Administration

Immediate-release Capsules

Tacrolimus immediate-release capsules should be administered every 12 hours at consistent times of day to minimize variability in systemic exposure.1 Tacrolimus immediate-release capsules can be taken with or without food, but because food affects absorption of tacrolimus from the gastrointestinal tract, it should be taken in the same way for each dose.1 Do not open or crush capsules.1

In liver, heart, or lung transplant patients, administer the initial dose of immediate-release capsules no sooner than 6 hours after transplantation.1 In kidney transplant patients, the initial dose of immediate-release capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.1

Granules for Oral Suspension

Tacrolimus granules for oral suspension may be used in patients who have difficulty swallowing capsules.1 To minimize variability in systemic exposure to tacrolimus, the suspension should be administered every 12 hours at consistent times of day.1 Tacrolimus suspension can be taken with or without food, but because food affects absorption of tacrolimus from the gastrointestinal tract, it should be taken in the same way for each dose.1

Tacrolimus granules for oral suspension must be mixed with water to form a suspension prior to administration.1 Do not sprinkle tacrolimus granules on food for administration.1 To prepare tacrolimus suspension, empty the entire contents of the packet or packets needed for the prescribed dose into an empty glass drinking container; check that no granules remain in the packet or packets.1 Add 15-30 mL of room temperature drinking water to the glass, and mix; the granules will not dissolve completely.1 Administer the suspension immediately, then rinse the glass with an additional 15-30 mL of room temperature water, and administer this additional volume to the patient.1 Do not prepare tacrolimus suspension in a plastic (PVC-containing) cup or use plastic tubing, syringes, or other equipment during administration, as tacrolimus granules will adhere to plastic items; use glass or metal materials when preparing tacrolimus suspension.1 A non-PVC oral syringe may be used for administration to younger patients.1 Do not prepare tacrolimus suspension in advance or store after mixing with water.1 The manufacturer's labeling and instructions for use should be consulted for detailed information on preparing and administering tacrolimus granules for oral suspension.1

Extended-release Capsules (Astagraf XL®)

Tacrolimus extended-release capsules should be administered every morning on an empty stomach, at least 1 hour before a meal, or at least 2 hours after a meal, at a consistent time each day to minimize variability in systemic exposure.79 Swallow extended-release capsules whole with liquid; do not chew, divide, or crush the capsules. 79

If a dose of tacrolimus extended-release capsules is missed by up to 14 hours, administer the missed dose as soon as possible.79 If a dose is missed by longer than 14 hours, the regular schedule should be resumed the following morning; the missed dose should not be administered later in the day and an extra dose should not be administered to make up for the missed dose. 79

Extended-release Tablets (Envarsus XL®)

Tacrolimus extended-release tablets should be administered every morning on an empty stomach, at least 1 hour before a meal, or at least 2 hours after a meal, at a consistent time each day to minimize variability in systemic exposure.80 Swallow extended-release tablets whole with liquid (preferably water); do not chew, divide, or crush the tablets. 80

If a dose of tacrolimus extended-release tablets is missed by up to 15 hours, administer the missed dose as soon as possible.80 If a dose is missed by longer than 15 hours, the regular schedule should be resumed the following morning; the missed dose should not be administered later in the day and an extra dose should not be administered to make up for the missed dose. 80

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of tacrolimus have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].252

IV Administration

Prepare infusion solutions in glass or polyethylene containers; avoid use of PVC containers.1,8 Use PVC-free tubing for administration of more dilute solutions (e.g., those for pediatric patients).1

Tacrolimus injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir) due to the chemical instability of tacrolimus in alkaline media.1

Continuously observe patient for ≥30 minutes following initiation of the IV infusion and then at frequent intervals thereafter for possible allergic manifestations.1 In addition, appropriate equipment and agents for the management of anaphylactic reactions (e.g., epinephrine, oxygen) should be readily available.1 If anaphylaxis occurs, IV infusion of the drug should be discontinued and appropriate therapy instituted.1 The oral formulation of tacrolimus does not contain polyoxyl 60 hydrogenated castor oil,1 and therefore a history of anaphylaxis with the parenteral formulation does not necessarily preclude oral therapy with the drug.1

Dilution

Must be diluted with 0.9% sodium chloride or 5% dextrose injection to a concentration of 4-20 mcg (0.004-0.02 mg) per mL prior to administration.1

Rate of Administration

Administer daily dose over 24 hours by continuous IV infusion.1,9

Standardize 4 Safety

Standardized concentrations for IV tacrolimus have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].249

Dosage

Available as anhydrous tacrolimus; dosage expressed in terms of anhydrous drug.1

Individualize dosage based on clinical assessments of organ rejection and patient tolerability.1,4,13

Dosage requirements generally decline with continued therapy; long-term administration is necessary to prevent rejection.1,4,13

Adult Oral Dosage

Dosage requirements generally decline with continued therapy, and long-term administration is necessary to prevent rejection.1,4,13

Kidney Transplantation

Immediate-release oral preparations in combination with azathioprine: The usual initial adult oral tacrolimus dosage is 200 mcg/kg (0.2 mg/kg) daily, administered in 2 divided daily doses every 12 hours.1 Patients receiving this tacrolimus dosage should have typical trough whole blood tacrolimus concentrations of 7-20 ng/mL and 5-15 ng/mL when measured at months 1-3 and 4-12 post-transplant, respectively.1

Immediate-release oral preparations in combination with mycophenolate mofetil/interleukin 2 receptor antagonist: The usual initial adult oral tacrolimus dosage is 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours.1 Patients receiving this tacrolimus dosage should have typical trough whole blood tacrolimus concentrations of 4-11 ng/mL when measured at months 1-12 post-transplant.1 Alternatively, in a small clinical trial, the initial dose of tacrolimus in combination with mycophenolate mofetil/interleukin 2 receptor antagonist was 150-200 mcg/kg (0.15-0.2 mg/kg) daily and observed tacrolimus concentrations were 6-16 ng/mL and 5-12 ng/mL during months 1-3 and months 4-12, respectively.1

Extended-release capsules (Astagraf XL^®) in combination with basiliximab, mycophenolate mofetil, and steroids: The usual initial dosage is 150-200 mcg/kg (0.15 to 0.2 mg/kg) once daily prior to reperfusion or within 48 hours of completion of transplant.79 Patients receiving this tacrolimus dosage should have typical whole blood tacrolimus concentrations of 7-15 ng/mL, 5-15 ng/mL, and 5-10 ng/mL when measured at month 1, months 2-6, or ≥6 months post-transplant, respectively.79

Extended-release capsules (Astagraf XL^®) in combination with mycophenolate mofetil and steroids (without basiliximab induction): The usual initial dosage is a first dose (pre-operative) of 100 mcg/kg (0.1 mg/kg), within 12 hours prior to reperfusion.79 Subsequent doses postoperatively are 200 mcg/kg (0.2 mg/kg) once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion.79 Patients receiving this tacrolimus dosage regimen should have typical trough whole blood tacrolimus concentrations of 10-15 ng/mL, 5-15 ng/mL, and 5-10 ng/mL when measured at month 1, months 2-6, or ≥6 months post-transplant, respectively.79

Extended-release tablets (Envarsus XR^®): The usual initial dosage of tacrolimus extended-release tablets is 140 mcg/kg (0.14 mg/kg) once daily.80 Patients receiving this tacrolimus dosage should have typical trough whole blood tacrolimus concentrations of 6-11 ng/mL in the first month and 4-11 ng/mL when measured after the first month.80 To convert from a tacrolimus immediate-release product to tacrolimus extended-release tablets, administer tacrolimus extended-release tablets once daily at a dose that is 80% of the total daily dose of the tacrolimus immediate-release product.80 Monitor tacrolimus trough whole blood concentrations and titrate tacrolimus extended-release tablet dosage to achieve trough whole blood concentrations of 4 to 11 ng/mL.80

Liver Transplantation

Immediate-release oral preparations: The usual initial oral tacrolimus dosage in combination with corticosteroids only in hepatic transplant patients is 100-150 mcg/kg (0.1-0.15 mg/kg) daily, administered in 2 divided daily doses every 12 hours.1 In hepatic transplant patients, the typical trough whole blood tacrolimus concentrations should be 5-20 ng/mL when measured at months 1-12 post-transplant.1

Cardiac Transplantation

Immediate-release oral preparations: The usual initial oral tacrolimus dosage in combination with azathioprine or mycophenolate mofetil in cardiac transplant patients is 75 mcg/kg (0.075 mg/kg) daily, administered in 2 divided daily doses every 12 hours.1 Patients receiving this tacrolimus dosage should have typical trough whole blood tacrolimus concentrations of 10-20 ng/mL and 5-15 ng/mL when measured at months 1-3 and from ≥4 months post-transplant, respectively.1

Lung Transplantation

Immediate-release oral preparations: The usual initial oral tacrolimus dosage in combination with azathioprine or mycophenolate mofetil in lung transplant patients is 75 mcg/kg (0.075 mg/kg) daily, administered in 2 divided daily doses every 12 hours.1 Patients receiving this tacrolimus dosage should have typical trough whole blood tacrolimus concentrations of 10-15 ng/mL and 8-12 ng/mL when measured at months 1-3 and from 4-12 months post-transplant, respectively.1 Cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses in lung transplantation to achieve target tacrolimus trough concentrations.1 Monitor tacrolimus trough concentrations and adjust the dose accordingly.1

Crohn's Disease

If tacrolimus is used for the management of fistulizing Crohn's disease†, an oral dosage of 200 mcg/kg daily administered in 2 divided daily doses for 10 weeks was used in one study in patients ≥12 years of age.61,65

Adult IV Dosage

If an adult patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection as a continuous IV infusion only .

Adults should generally receive initial dosages at the lower end of the following ranges.1

Kidney Transplantation

The usual initial starting dose of tacrolimus injection is 30-50 mcg/kg (0.03-0.05 mg/kg) daily in renal transplant patients, administered as a continuous infusion.1

Liver Transplantation

The usual initial starting dose of tacrolimus injection is 30-50 mcg/kg (0.03-0.05 mg/kg) daily in hepatic transplant patients, administered as a continuous infusion.1

Cardiac Transplantation

The usual initial starting dose of tacrolimus injection is 10 mcg/kg (0.01 mg/kg) daily in heart transplant patients, administered as a continuous infusion.1

Lung Transplantation

The usual initial starting dose of tacrolimus injection is 10-30 mcg/kg (0.01-0.03 mg/kg) daily in lung transplant patients, administered as a continuous infusion.1

Pediatric Oral Dosage

Generally, children require and tolerate higher tacrolimus maintenance dosages than adults.1,4

To convert pediatric patients from tacrolimus granules to tacrolimus capsules or from tacrolimus capsules to tacrolimus granules, the total daily dose should remain the same.1 Perform therapeutic drug monitoring after conversion of one tacrolimus formulation to another.1

Kidney Transplantation

The usual initial oral immediate-release tacrolimus dosage in pediatric kidney transplant patients is 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours.1 In pediatric kidney transplant patients, the typical trough whole blood tacrolimus concentrations should be 5-20 ng/mL when measured at months 1-12 post-transplant.1

The usual initial oral tacrolimus dosage for tacrolimus extended-release capsules in combination with basiliximab, mycophenolate mofetil, and steroids is 300 mcg/kg (0.3 mg/kg) once daily within 24 hours of reperfusion.79 Patients receiving this tacrolimus dosage should have typical whole blood tacrolimus concentrations of 10-20 ng/mL in the first month and 5-15 ng/mL when measured after the first month.79

Liver Transplantation

The usual initial oral tacrolimus dosage in pediatric liver transplant patients is 150-200 mcg/kg (0.15-0.2 mg/kg) daily, administered in 2 divided daily doses every 12 hours as an immediate-release formulation.1 In pediatric liver transplant patients, the typical trough whole blood tacrolimus concentrations should be 5-20 ng/mL when measured at months 1-12 post-transplant.1

Cardiac Transplantation

The usual initial oral tacrolimus dosage in pediatric heart transplant patients is 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours as an immediate-release formulation.1 If antibody induction treatment is administered, a dose of 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours should be given.1 In pediatric heart transplant patients, the typical trough whole blood tacrolimus concentrations should be 5-20 ng/mL when measured at months 1-12 post-transplant.1

Lung Transplantation

The usual initial oral tacrolimus dosage in pediatric lung transplant patients is 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours as an immediate-release preparation.1 If antibody induction treatment is administered, a dose of 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours should be given.1 In pediatric lung transplant patients, the typical trough whole blood tacrolimus concentrations should be 10-20 ng/mL at weeks 1-2 and 10-15 ng/mL for week 2 to month 12 post-transplant.1

Cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses in lung transplantation to achieve target tacrolimus trough concentrations.1 Monitor tacrolimus trough concentrations and adjust the dose accordingly.1

Pediatric IV Dosage

If a pediatric patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection as a continuous intravenous infusion only .1 Discontinue the infusion as soon as the patient can tolerate oral administration with the first dose of oral tacrolimus given 8-12 hours after discontinuing the intravenous infusion.1

Liver Transplantation

The usual intravenous dose is 0.03-0.05 mg/kg/day.1

Therapeutic Drug Monitoring

Monitoring blood tacrolimus concentrations is essential for assessing organ rejection and toxicity, adjusting dosage, and determining compliance.1,2,3,4,6,13 Factors influencing frequency of monitoring include, but are not limited to, hepatic or renal dysfunction, the addition or discontinuance of potentially interacting drugs, and the time since transplant.1 The manufacturer states that therapeutic drug monitoring is not a replacement for renal and hepatic function monitoring and tissue biopsies.1 The relative risk of drug toxicity (e.g., nephrotoxicity, post-transplant diabetes mellitus) appears to be increased with higher trough concentrations.1 Therefore, the monitoring of trough whole blood concentrations is recommended to assist in the clinical evaluation of toxicity.1 Methods commonly used for assaying tacrolimus concentrations include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays.1 Specialized sources should be consulted for further discussion of the clinical utility of therapeutic monitoring of tacrolimus.1

Pharmacogenomic Considerations in Dosing

Enzymes in the cytochrome P450 (CYP) 3A family are responsible for the oxidative metabolism of tacrolimus.82 Variations in these genes responsible for tacrolimus metabolism may affect tacrolimus dosage requirements.82 Blood concentrations of tacrolimus are strongly influenced by CYP3A5 genotype.82 In kidney, heart, and lung transplant patients, over 50 clinical studies have found that individuals with the CYP3A5*1/*1 or CYP3A5*1/*3 genotype have significantly lower dose-adjusted trough concentrations of tacrolimus as compared to those with the CYP3A5*3/*3 genotype, with *1 carriers requiring 1.5-2 times the dose to achieve similar blood concentrations.82 CPIC guidelines recommend that individuals that are extensive or intermediate metabolizers (CYP3A5 expressers) should increase the recommended starting dose of tacrolimus by 1.5<2 times (total dose not to exceed 0.3 mg/kg daily).82 Poor metabolizers (CYP3A5 nonexpressers) should initiate therapy with the standard recommended dose.82 Therapeutic drug monitoring should be used to guide dosage adjustments.82

If genotype information is known at the initiation of therapy, it may be used to individualize initial tacrolimus dosing and more rapidly achieve therapeutic drug concentrations.82 However, initiation of tacrolimus therapy should not be delayed to await genotyping test results.82

Special Populations

Hepatic Impairment

Initiate therapy with the lowest dosage in the recommended range.1,79,80

Further dosage reduction may be required (e.g., in patients with severe hepatic impairment [Child-Pugh score ≥10]).1

The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus.1 These patients should be monitored closely, and dosage adjustments should be considered.1

Renal Impairment

Initiate therapy with the lowest dosage in the recommended range.1 Further dosage reduction may be required.1

In patients who develop postoperative oliguria, the initial dose of tacrolimus should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.1

Race or Ethnicity

Black patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to white patients.1

Contraindications

• Known hypersensitivity to tacrolimus or any ingredient in the formulation (e.g., polyoxyl 60 hydrogenated castor oil [HCO-60] in the IV formulation).1,79,80 Dyspnea, rash, pruritus, and acute respiratory distress syndrome have been reported.1

Warnings/Precautions

Warnings

Lymphomas and Other Malignancies

Possible increased development of lymphoma or other malignancies, particularly of the skin, has been reported in patients receiving immunosuppressive therapies, such as tacrolimus.1,4,7,21 79,80 This risk may be related to the intensity and duration of immunosuppression.1,79,80 A boxed warning about the risk for developing serious malignancies has been included in the prescribing information.1,79,80

Post-transplant lymphoproliferative disorder (PTLD), which appears to be associated with Epstein-Barr virus (EBV) infection, has been reported in immunosuppressed organ transplant patients.1,2,4,7,24,27,79,80 Risk of this disorder appears greatest in patients who are seronegative, including many young children who are at risk for primary EBV infections while immunosuppressed or whose immunosuppressive regimen is changed to tacrolimus following long-term immunosuppressive therapy.1,22,24,27 Monitoring of EBV serology during treatment is recommended.1,79,80

Serious Infections

Patients receiving immunosuppressant therapy, including tacrolimus, have an increased risk of susceptibility to viral, fungal and protozoal infection, including opportunistic infections, that may be serious or fatal.1,2,4 20,21,22,23,24,28,29,30,32,79,80 A boxed warning about the risk for developing serious infections has been included in the prescribing information for tacrolimus.1

Serious viral infections reported with use of tacrolimus include polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection1,79,80 or reactivation of latent viral infections.484,485,486,487,488,489,490,491,492 These infections are principally observed in renal transplant patients (usually within the first year post-transplantation) and may result in severe allograft dysfunction and/or graft loss.484,485,486,487,488,489,490,491,492 Risk appears to correlate with the degree of overall immunosuppression rather than the use of a specific immunosuppressant. Monitor closely for signs of PVAN (e.g., deterioration of renal function);484,485,486,488 if PVAN develops, institute early treatment, and consider reducing immunosuppressive therapy.484,485,486,487,488,490,492

Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus has also been reported with tacrolimus use.1,79,80,493,494,495,496,497 Use of multiple immunosuppressive agents may contribute to risk of PML.495,496,497 Consider possible diagnosis of PML in any immunocompromised patient who develops progressive neurologic deficits.495,496 If PML develops, consider decreasing total immunosuppression.493,494,495,496

Cytomegalovirus (CMV)-seronegative transplant patients who receive an organ from a CMV-seropositive donor are at higher risk of developing CMV infection and CMV disease during treatment with tacrolimus.1,79,80 Monitor for development of infection and consider changing immunosuppressant dosage to balance the risk of infection with the organ rejection risk.79,80

Increased Mortality in Female Liver Transplant Patients (Extended-release Capsules [Astagraf XL®])

Increased mortality has been reported in female patients who received tacrolimus extended-release capsules (Astagraf XL^®) for the prevention of liver allotransplantation rejection.79 A boxed warning about this risk has been included in the prescribing information for the extended-release capsules.79 Mortality occurred in 18 and 8% of female liver transplant patients who received tacrolimus extended-release capsules (Astagraf XL^®) and tacrolimus immediate-release product (Prograf^®), respectively.79 Tacrolimus extended-release capsules (Astagraf XL^®) are not labeled for use in prophylaxis of organ rejection in liver transplantation.79

Other Warnings and Precautions

Anaphylaxis

Risk of anaphylaxis associated with IV tacrolimus therapy; reserve for patients who cannot accommodate oral administration.1

Have appropriate equipment and agents for the treatment of anaphylactic reactions readily available whenever tacrolimus is administered IV and monitor patients during administration of the infusion.1 If anaphylaxis occurs, immediately discontinue the IV infusion and institute appropriate therapy (e.g., epinephrine, oxygen).1

Interchangeability of Extended-release Products

Outside the U.S., medication errors were reported, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products; these errors led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus.1,79,80 Interchange or substitution between tacrolimus extended-release products and tacrolimus immediate-release products must occur only under physician supervision.1,79,80 Instruct patients and caregivers to recognize the appearance of their prescribed dosage form and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.1,79,80

New-onset Diabetes

Increased risk of hyperglycemia1,2,4,7,9,13,16,21,24,29,30,31,32 or new-onset, insulin-dependent, post-transplant diabetes mellitus was reported with tacrolimus use in clinical studies for heart, lung, kidney, and liver transplantation.1,4,7,9,13,22,29,79,80 Black and Hispanic renal transplant patients are most at risk for development of post-transplant diabetes mellitus.1,79,80

Development of insulin-dependent diabetes mellitus reported in 20% of renal transplant patients receiving tacrolimus; insulin resistance was reversible in 15 and 50% of these patients at 1 and 2 years post-transplant, respectively.1

Development of insulin-dependent diabetes mellitus also reported in 11-18% of hepatic transplant patients receiving the drug; insulin resistance was reversible in 31-45% of these patients at 1 year post-transplant.1

Monitor fasting blood glucose concentrations regularly in patients receiving tacrolimus.1,79,80

Nephrotoxicity

Nephrotoxicity1,4,6,7,9,13,21,22,23,24,31,32,79,80 is among the most common adverse effects of tacrolimus in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy, and tubular-interstitial effects.1 Nephrotoxicity occurred in approximately 36<40%, 52%, and 59% of patients receiving the drug following hepatic, renal, and cardiac transplantation, respectively, in clinical trials.1 Increased serum creatinine concentration occurred in 24<45%1 and increased BUN1,13 in 12<30%1 of patients receiving tacrolimus in clinical trials. Nephrotoxicity may be dose related and may respond to dosage reduction or temporary interruption of tacrolimus administration.1,79,80

The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors or drugs associated with nephrotoxicity.1

Monitor S_cr and tacrolimus blood concentrations regularly during tacrolimus treatment and adjust dosage or discontinue tacrolimus, as needed.1,79,80

Neurotoxicity

Risk of neurotoxicity (e.g., tremor, headache, other changes in motor function, mental status, or sensory function) in patients receiving tacrolimus, especially at high doses.1,17,18,19,22,79,80

Closely monitor neurologic function and status. 79,80 Consider dosage reduction or discontinue treatment if neurotoxicity occurs.1,79,80

Hyperkalemia

Possible hyperkalemia (sometimes severe) reported in patients receiving tacrolimus during clinical studies.1,2,4,7,9,21,22,23,24,28,31,79,80

Monitor serum potassium concentrations regularly; carefully consider concomitant use of potassium-sparing diuretics, ACE inhibitors, or angiotensin receptor blockers.1,79,80

If hyperkalemia occurs, institute appropriate management (e.g., restriction of potassium intake, administration of potassium-binding resin or mineralocorticoid).2,4,7,21,22,24

Hypertension

Development of hypertension reported commonly; generally is mild to moderate.1,79,80 Antihypertensive therapy may be required, but should be selected to carefully consider use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers).1,79,80

Concomitant Use with Sirolimus

The use of sirolimus with tacrolimus immediate-release products in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT).1 The use of sirolimus (at a dose of 2 mg per day) with tacrolimus in heart transplant patients in a U.S. clinical trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus.1 The use of sirolimus concomitantly with tacrolimus is not recommended.1 The use of sirolimus with tacrolimus may also increase the risk of thrombotic microangiopathy.1

QT Prolongation

Tacrolimus may prolong the QT interval and increase the risk of causing torsades de pointes.1,79,80 Use of tacrolimus should be avoided in patients with known QT interval prolongation.1,79,80 79,80 Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment for those who have congestive heart failure or bradyarrhythmias; those who are receiving drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmic agents); and in those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia.1,79,80 1,79,80 80

When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.1,79,80

Myocardial Hypertrophy

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations; this effect is generally reversible following dosage reduction or drug discontinuance.1,23,25,31

Consider performing echocardiographic evaluation if renal failure or clinical manifestations of ventricular dysfunction occur.1

If myocardial hypertrophy is diagnosed, consider decreasing dosage or discontinuing therapy.1

Immunizations

Tacrolimus may interfere with the safety and effectiveness of vaccines.1,79,80 Avoid use of live vaccines during treatment with tacrolimus.1,79,80 Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.1,79,80 When possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus.1,79,80

Pure Red Cell Aplasia

Pure red cell aplasia (PRCA) has been reported in patients treated with tacrolimus.1 Although a mechanism has not been confirmed, all patients who developed PRCA reported risk factors such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA.1,79 If PRCA is diagnosed, discontinuation of tacrolimus should be considered.1,79,80

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus.1 Risk factors for thrombotic microangiopathy that can occur in transplant patients include severe infections, graft-versus-host disease (GVHD), HLA mismatch, and calcineurin inhibitor and mTOR inhibitor use.1 These risk factors may, either alone or combined, contribute to the risk of thrombotic microangiopathy.1

Cannabidiol Drug Interactions

Patients should be closely monitored for an increase in tacrolimus levels and adverse reactions suggestive of toxicity when tacrolimus is administered with cannabidiol.1 Dosage reduction of tacrolimus should be considered as needed.1

Specific Populations

Pregnancy

Tacrolimus may cause fetal harm if administered to pregnant females.1 Data from postmarketing surveillance and The Transplantation Pregnancy Registry International (TPRI) suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress.1 Females of reproductive potential should use effective birth control prior to intitation and during tacrolimus treatment.1 Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus.1

TPRI is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus; clinicians are encouraged to advise their patients to register by contacting the TPRI at 1-877-955-6877 or their website [Web].

Tacrolimus may increase hyperglycemia in pregnant females with diabetes; monitor blood glucose levels regularly.1 Tacrolimus also may exacerbate hypertension in pregnant females and increase the risk of pre-eclampsia, therefore blood pressure should be monitored and controlled.1

Lactation

Tacrolimus has been reported to be distributed into human milk; however, the effects on the infant or milk production has not been assessed.1 Consider the benefits of breast-feeding along with the importance of tacrolimus to the mother and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.1

Females and Males of Reproductive Potential

Tacrolimus can cause fetal harm when administered to pregnant females.1 Advise female and male patients of reproductive potential to speak to their healthcare provider to discuss family planning options including appropriate contraception prior to starting treatment with tacrolimus.1 Females of reproductive potential should use effective birth control prior to intitation and during tacrolimus treatment.1 Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus.1

Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus.1

Pediatric Use

Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients in clinical studies.1 Clinical experience in children suggests that the safety and efficacy of tacrolimus are similar to those in adults.23,24,27

A randomized, active-controlled study of tacrolimus in primary liver transplantation of pediatric patients ≤16 years of age included 91 patients who were randomized to tacrolimus-based therapy and 90 patients receiving cyclosporine-based therapy.1 At 12 months, the incidence rate of biopsy-proven acute rejection, graft loss, death, or loss to follow-up was 52.7% in the tacrolimus group and 61.1% in the cyclosporine group.1

Efficacy and safety of tacrolimus immunosuppression in pediatric lung transplation were also established in 450 patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil or 72 patients receiving tacrolimus immediate-release products in combination with azathioprine; one-year graft survival estimates from time of discharge were 91.7% and 84.7%, respectively.1

Pharmacokinetic studies have been conducted in pediatric patients, with dosage adjustments made based on clinical status and whole blood concentrations.1 Pediatric patients generally require higher doses of tacrolimus to maintain trough whole blood concentrations similar to adult patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.1

If evidence of renal impairment exists or develops, adjust dosage.1

Hepatic Impairment

Decreased clearance in patients with severe hepatic impairment; adjust dosage and closely monitor blood concentrations in these patients.1

Hepatic transplant patients experiencing post-transplant hepatic impairment may be at increased risk of renal impairment secondary to high blood tacrolimus concentrations; monitor such patients closely and consider dosage adjustment.1

Renal Impairment

Patients with renal impairment had similar pharmacokinetic profiles of tacrolimus compared to that in healthy volunteers with normal renal function.1 Consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment; further dosage reductions below the targeted range may be required.1

Potential for nephrotoxicity; monitor patient closely. Dosage adjustments recommended.1

Race

Black renal transplant patients may require higher doses than patients of other races to maintain comparable whole blood trough drug concentrations.1

Black and Hispanic patients are at increased risk for new onset diabetes post-transplantion.1 Monitor blood glucose concentrations and treat appropriately.1

Common Adverse Effects

Kidney Transplantation

The most common adverse reactions reported in ≥30% of patients receiving immediate-release products were: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia.1 The most common adverse reactions reported in ≥30% of patients receiving tacrolimus extended-release capsules were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia.79 The most common adverse reactions reported in ≥30% of patients receiving tacrolimus extended-release tablets were: infection and diarrhea.80

Liver Transplantation

The most common adverse reactions reported in ≥40% of patients receiving immediate-release products were: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia.1

Heart Transplantation

The most common adverse reactions reported in ≥15% of patients receiving immediate-release products were: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipidemia.1

Lung Transplantation

Adverse reactions reported in lung tranplant patients receiving immediate-release products were similar to those in kidney, heart, or liver transplant patients treated with tacrolimus.1

Tacrolimus is metabolized by CYP isoenzymes, principally CYP3A.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A Inducers

Concomitant use of tacrolimus and strong CYP3A4 inducers such as antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine, and phenobarbital), and St. John's wort may decrease tacrolimus whole blood trough concentrations and increase the risk of rejection.1,79,80 When these drugs are used together, increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations.79,80

Strong CYP3A Inhibitors

Concomitant use of tacrolimus and strong CYP3A4 inhibitors such as protease inhibitors (e.g, nelfinavir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, cobicistat, letermovir, and Schisandra sphenanthera extracts may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).1,79,80 A rapid, sharp rise in tacrolimus levels may occur early with coadministration, despite an immediate reduction of tacrolimus dose.1 When these drugs are used together, reduce the tacrolimus dose (for voriconazole and posaconazole, give one third of the original dose) and adjust the dose based on tacrolimus whole blood trough concentrations.1,79,80 Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1<3 days and continue monitoring as necessary when these drugs are used concomitantly.79,80

Mild or Moderate CYP3A4 Inhibitors

Concomitant use of tacrolimus and mild to moderate CYP3A4 inhibitors such as clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).1,79,80 Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed when these drugs are used concomitantly.79,80

Mild or Moderate CYP3A4 Inducers

Concomitant use of tacrolimus and mild to moderate CYP3A4 inducers such as methylprednisolone or prednisone may decrease tacrolimus whole blood trough concentrations.1,79,80 Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.1,79,80

Mycophenolic Acid

When tacrolimus is used concomitantly with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not.1,79,80 Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.1,79,80

Antacids

Concomitant use of magnesium and aluminum hydroxide antacids may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).1,79,80 Monitor tacrolimus whole blood trough concentrations throughout therapy and reduce the tacrolimus dose if necessary.1,79,80

Metoclopramide

Concomitant use of metoclopramide may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).1,79,80 Monitor tacrolimus whole blood trough concentrations throughout therapy and reduce the tacrolimus dose if necessary.1,79,80

Immunosuppressants

Because of the risk of oversuppression of the immune system and associated susceptibility to infection and risk of lymphoma, the manufacturer recommends that combination immunosuppressant therapy be used with caution.1,79,80

Concomitant use of tacrolimus and sirolimus in de novo liver transplant recipients has been associated with an increased risk of hepatic artery thrombosis (HAT), graft loss, and death.59 Most cases of HAT occurred within 30 days post-transplantation and led to graft loss or death.59 In one study reporting excess mortality and graft loss in association with combined use of sirolimus and tacrolimus in de novo liver transplant recipients, many of the patients had evidence of infection at or near the time of death.59 In addition, concomitant use of tacrolimus and sirolimus in cardiac transplant recipients in one arm of a US clinical trial was associated with an increased risk of wound healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus.1,69 Therefore, the manufacturer states that concurrent administration of tacrolimus and sirolimus is not recommended.1,69

Nephrotoxic Drugs

Because of the potential for additive or synergistic impairment of renal function, tacrolimus should be used with caution in patients receiving other nephrotoxic drugs (e.g., aminoglycoside antibiotics, amphotericin B, cisplatin, ganciclovir, nucleotide reverse transcriptase inhibitors, protease inhibitors).1,79,80 Monitor renal function and consider dosage reduction if nephrotoxicity occurs with concomitant use of these drugs.1,79,80

Cyclosporine

Concomitant administration of tacrolimus and cyclosporine has resulted in additive/synergistic nephrotoxicity.1 To avoid excessive nephrotoxicity, tacrolimus should not be used concomitantly with cyclosporine.1,4 The manufacturer recommends delaying initiation of tacrolimus or cyclosporine therapy for at least 24 hours after discontinuance of the other therapy.1 Initiation of tacrolimus or cyclosporine therapy may be further delayed in the presence of elevated cyclosporine or tacrolimus levels.1

Direct Acting Antiviral (DAA) Therapy

The pharmacokinetics of tacrolimus may be affected by changes in liver function during DAA therapy, related to clearance of HCV virus.79,80 Monitor tacrolimus whole blood trough concentrations throughout therapy and adjust tacrolimus dose if necessary.1,79,80

Alcohol

When taken with tacrolimus extended-release capsules or extended-release tablets, alcohol may modify the rate of release of tacrolimus79,80 and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation ).79,80 Patients should be instructed to avoid alcoholic beverages.79,80

Grapefruit and Grapefruit Juice

Because grapefruit and grapefruit juice affect CYP3A-mediated metabolism of tacrolimus, it may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).1,79,80 Patients should be instructed to avoid grapefruit-containing foods and beverages.1,79,80

Potassium-sparing Diuretics

Concomitant use of tacrolimus and potassium-sparing diuretics ACE inhibitors, or angiotensin receptor blockers may result in potentially severe hyperkalemia and should be carefully considered.1,79,80

ACE inhibitors

Concomitant use of tacrolimus and ACE inhibitors may result in potentially severe hyperkalemia and should be carefully considered.1,79,80

Angiotensin Receptor Blockers

Concomitant use of tacrolimus and angiotensin receptor blockers may result in potentially severe hyperkalemia and should be carefully considered.1,79,80

Calcium Channel Blocking Agents

Concomitant use of tacrolimus and calcium channel blocking agents may increase tacrolimus blood concentrations. Monitor tacrolimus whole blood trough concentrations throughout therapy and reduce tacrolimus dose if necessary.1,79,80

Vaccines

The possibility that the immune response to vaccination may be diminished in patients receiving tacrolimus should be considered.1,79,80 Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.1,79,80 In addition, the manufacturer recommends that live vaccines (e.g., measles, mumps, rubella, oral polio, BCG, yellow fever, TY21a typhoid) be avoided during therapy with the drug.1,79,80 Administer the complete complement of vaccines before transplantation and treatment with tacrolimus when possible.1,79,80

Cannabidiol

Tacrolimus blood levels may increase upon concomitant use with cannabidiol.1 Closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity with concomitant administration.1 A dose reduction of tacrolimus should be considered as needed.1

Description

Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis .1,2,3,4,7,10,11 The drug is a potent immunosuppressive agent 1,2,3,4,7,11,12 that is pharmacologically but not structurally related to cyclosporine2,3,4,7,10,11 and that exhibits only limited antimicrobial activity.7,10 Tacrolimus is approximately 10- to 200-fold more potent than cyclosporine on a weight basis in various in vitro T-cell test systems of immune function.3,4,7,11,12

In animals, tacrolimus inhibits cell-mediated immune responses such as allograft rejection, delayed hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft-vs-host disease while humoral immunity is inhibited to a lesser extent.1,4 Increased survival of the host and of the transplanted graft of liver, kidney, heart, bone marrow, small bowel, pancreas, lung, trachea, skin, cornea, and limb has been shown in animals receiving the drug.1,2,3,4

The exact mechanism(s) of immunosuppressive action of tacrolimus has not been elucidated but appears to involve inhibition of the activation and proliferation of T cells, as well as T helper cell dependent B-cell response.1,2,3,7,10,11,12 Studies suggest that tacrolimus binds to an intracellular protein, FKBP-12.1,2,4,7 Binding of the complex of tacrolimus and FKBP-12 with calcium, calmodulin, and calcineurin inhibits the phosphatase activity of calcineurin, which may prevent the dephosphorylation and translocation of nuclear factor of activated T cells (NF-AT).1,4,7 NF-AT putatively initiates gene transcription for the formation of lymphokines (e.g., interleukin-2, gamma interferon) involved in the activation of T cells.1,4,7

Advice to Patients

• Advise patients and/or caregivers about potential benefits and risks of tacrolimus.1 Advise patients and/or caregivers to read the medication guide.1
• Advise patients to inspect their tacrolimus medicine when they receive a new prescription and before taking it.1,79,80 If the appearance of the product is not the same as usual, or if dosage instructions have changed they should contact their healthcare provider to make sure that they have the right medicine.1,79,80
• Risk of lymphomas and other malignancies, particularly of the skin.1,79,80 Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor.79,80
• Risk of infections, including opportunistic infections; advise patients to inform their clinician if they develop fever, sweats, chills, or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin.1,79,80
• Risk of new onset diabetes mellitus; advise patients to inform their clinician if frequent urination or increased thirst or hunger develops.1,79,80
• Risk of nephrotoxicity; advise patients of the importance of monitoring renal function.1,79,80
• Risk of neurotoxicity; advise patients to contact their physician if vision changes, delirium, or tremors develop.1,79,80
• Risk of hypertension developing or worsening during therapy.1,79,80 Advise patients of the importance of regular monitoring of blood pressure during treatment.1,79,80
• Risk of myocardial hypertrophy; advise patients to inform their clinician if they develop symptoms of tiredness, swelling, and/or shortness of breath.1
• Inform patients that any necessary immunizations should be completed prior to transplantation and initiation of tacrolimus.1,79,80 Avoid administration of live vaccines during treatment and consider decreased immunogenic response of inactivated vaccines.1,79,80
• Risk of thrombotic microangiopathy; advise patients that blood clotting problems may occur with therapy.1 This risk may increase when patients take tacrolimus and sirolimus or everolimus together, or when certain infections develop.1 Advise patients to seek immediate medical care if they develop fever, petequiae or bruises, fatigue, confusion, yellowing of the skin or eyes, or low urine output.1
• Advise patients of the importance of routine laboratory testing (e.g., for assessment of renal and hepatic function, for monitoring of glucose and potassium concentrations).1,79,80
• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements.1,79,80
• Advise patients to avoid grapefruit products during treatment with tacrolimus.1,79,80 Also advise patients to avoid alcohol with use of extended-release products.1,79,80
• Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,79,80 Advise females of childbearing potential and male patients with female partners of childbearing potential of the need for effective contraception during therapy.1,79,80 Advise patients if they become pregnant or father a pregnancy to enroll in the in the voluntary Transplantation Pregnancy Registry International.1 To enroll or register, patients can call the toll free number 1-877-955-6877 or visit [Web].1,79,80
• Advise patients of the potential for tacrolimus use to affect male and female fertility.1,79,80
• Inform patients of other important precautionary information.1 79,80,1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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