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Introduction

Calcineurin inhibitor; immunosuppressive agent.

Uses for Tacrolimus (Systemic)

Renal Transplantation

Used in combination with other immunosuppressants for prevention of renal allograft rejection.

Immediate-release oral preparations and the IV formulation are indicated for prophylaxis of organ rejection in adult and pediatric kidney transplant patients. Tacrolimus extended-release capsules (Astagraf XL) are indicated for prophylaxis of organ rejection in adult and pediatric kidney transplant patients who are able to swallow capsules intact. Tacrolimus extended-release tablets (Envarsus XL) are indicated for prophylaxis of organ rejection in de novo adult kidney transplant patients or patients who are converting from tacrolimus immediate-release formulations.

Studies have shown that tacrolimus is superior to cyclosporine for preventing acute rejection and improving allograft survival after kidney transplantation, but increases rates of post-transplant diabetes and of neurological and GI adverse effects.

Efficacy and safety of extended-release formulations comparable to immediate-release capsules for prevention of transplant rejection in de novo kidney transplant patients.

Liver Transplantation

Immediate-release and IV preparations used in combination with other immunosuppressants for prevention of hepatic allograft rejection in adults and pediatric patients.

Use of sirolimus with tacrolimus in de novo liver transplant patients associated with an excess mortality, graft loss, and hepatic artery thrombosis, and is not recommended.

Cardiac Transplantation

Immediate-release and IV preparations used in combination with other immunosuppressants for prevention of cardiac allograft rejection in adults and pediatric patients.

Lung Transplantation

Immediate-release and IV preparations used in combination with other immunosuppressants for prevention of lung allograft rejection in adults and pediatric patients.

Crohn’s Disease

Has been used in the management of fistulizing Crohn’s disease^{† [off-label]}.

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. 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.

Pancreas Transplantation

Prevention of rejection of pancreas allografts^{† [off-label]} (often performed simultaneously with a kidney transplant).

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.

The recommendations also note that tacrolimus is associated with improved allograft survival compared to cyclosporine in pancreas transplant.

Intestinal Transplantation

Prevention of rejection of intestinal allografts^{† [off-label]}.

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.

Other Uses

Prevention of rejection of vascular composite allografts^{† [off-label]}.

Transplantation - Clinical Perspective

KDIGO clinical practice guideline states that immunosuppressive medication recommendations are complex as combinations of multiple drug classes are utilized and choices between varying regimens are determined through an evaluation of benefits and harms.

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.

Consensus recommendations from the ACCP, AST, and the ISHLT state there is no standardized approach to maintenance immunosuppression management in solid organ transplantation and a variety of factors may impact the choice of agents including the transplanted organ, center-specific protocols, provider expertise, insurance and cost issues, and patient characteristics and tolerability of therapy.

The consensus recommendations note that tacrolimus is superior to cyclosporine for the prevention of acute rejection in various solid organ transplants.

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.

Tacrolimus may offer an advantage over cyclosporine in lung transplant regarding prevention of bronchiolitis obliterans syndrome.

Tacrolimus (Systemic) Dosage and Administration

General

Pretreatment Screening

• Evaluate immunizations and give complete complement of needed vaccines before transplantation and treatment.

• 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.

Patient Monitoring

• Therapeutic drug monitoring is recommended for all patients. (See Therapeutic Drug Monitoring under Dosage and Administration.)

• Continuously observe patients receiving IV tacrolimus for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, stop the infusion.

• Examine patients for skin changes periodically.

• Monitor patients for signs and symptoms of infection.

• Perform routine laboratory testing (e.g., for assessment of renal and hepatic function, for monitoring of glucose and potassium concentrations).

• Monitor patients for neurologic changes.

• Check blood pressure periodically.

Dispensing and Administration Precautions

• Tacrolimus should only be used under the supervision of a provider with experience managing immunosuppressive therapy. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.

• When IV tacrolimus is administered, emergency drugs and equipment such as epinephrine and oxygen should be available at the bedside.

• Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills.

• Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in tacrolimus capsules and tacrolimus granules, respectively. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. If a spill occurs, wipe the surface with a wet paper towel.

Other General Considerations

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

Administration

Administer orally (as immediate-release capsules, granules for suspension, extended-release capsules, or extended-release tablets) or by IV infusion depending on the specific indication and whether patient is able to tolerate oral formulations.

If therapy is initiated with the IV formulation, substitute oral therapy as soon as tolerated. Initiate oral tacrolimus 8–12 hours after IV infusion is discontinued.

Because of differences in pharmacokinetic properties, extended-release capsule and tablet products are not interchangeable with each other or with tacrolimus immediate-release capsules or granules for suspension. 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.

Oral Administration

Immediate-release Capsules

Administer immediate-release capsules every 12 hours at consistent times of day to minimize variability in systemic exposure. Take with or without food in the same way for each dose. Do not open or crush capsules.

In liver, heart, or lung transplant patients, administer the initial dose of immediate-release capsules no sooner than 6 hours after transplantation. 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.

Granules for Oral Suspension

Use in patients who have difficulty swallowing capsules. Administer the suspension every 12 hours at consistent times of day. Take with or without food the same way for each dose.

Do not sprinkle tacrolimus granules on food for administration. 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. Add 15-30 mL of room temperature drinking water to the glass, and mix; the granules will not dissolve completely. 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. Do not prepare tacrolimus suspension in a plastic (PVC containing) cup or use plastic tubing, syringes, or other equipment during administration; use glass or metal materials when preparing tacrolimus suspension. A non-PVC oral syringe may be used for administration to younger patients. Do not prepare tacrolimus suspension in advance or store after mixing with water. Consult the manufacturer’s labeling and instructions for detailed information on preparing and administering tacrolimus granules for oral suspension.

Extended-release Capsules (Astagraf XL)

Administer 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. Swallow extended-release capsules whole with liquid; do not chew, divide, or crush the capsules.

If a dose of tacrolimus extended-release capsules is missed by <14 hours, administer missed dose as soon as possible. If a dose is missed by ≥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.

Extended-release Tablets (Envarsus XL)

Administer 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. Swallow extended-release tablets whole with liquid (preferably water); do not chew, divide, or crush the tablets.

If a dose of tacrolimus extended-release tablets is missed by <15 hours, administer missed dose as soon as possible. If a dose is missed by ≥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.

Standardize 4 Safety

Standardized concentrations for tacrolimus have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 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].

IV Administration

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

Do not mix or co-infuse with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir) due to the chemical instability of tacrolimus in alkaline media.

Continuously observe patient for ≥30 minutes following initiation of the IV infusion and then at frequent intervals thereafter for possible allergic manifestations.

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.

Rate of Administration

Administer daily dose over 24 hours by continuous IV infusion.

Standardize 4 Safety

Standardized concentrations for tacrolimus have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 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].

Tacrolimus is not included in the adult continuous infusion standards

Dosage

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

Individualize dosage based on clinical assessments of organ rejection and patient tolerability.

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

Pediatric Patients

Children generally require higher dosages than adults on a weight basis to achieve comparable blood concentrations.

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

Kidney Transplantation

Oral

Immediate-release capsules or granules: Initially, 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL at 1–12 months post-transplant.

Extended-release capsules (Astagraf XL) in combination with basiliximab, mycophenolate mofetil, and steroids: Initially, 300 mcg/kg (0.3 mg/kg) once daily within 24 hours of reperfusion. Typical trough whole blood tacrolimus concentrations should be 10–20 ng/mL in the first month and 5–15 ng/mL after the first month.

Liver Transplantation

Oral

Immediate-release capsules or granules: Initially, 150–200 mcg/kg (0.15–0.2 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL when measured at months 1–12 post-transplant.

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily.

Cardiac Transplantation

Oral

Immediate-release capsules or granules: Initially, 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours. If antibody induction treatment is administered, give 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL when measured at months 1–12 post-transplant.

Lung Transplantation

Oral

Immediate-release capsules or granules: Initially, 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours. If antibody induction treatment is administered, give 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours 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.

Adults

Kidney Transplantation

Oral

Immediate-release capsules or granules: Initially, in combination with azathioprine: 200 mcg/kg (0.2 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 7–20 ng/mL and 5–15 ng/mL when measured at months 1–3 and 4–12 post-transplant, respectively.

Immediate-release capsules or granules: Initially, in combination with mycophenolate mofetil/interleukin 2 receptor antagonist: 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 4–11 ng/mL when measured at months 1–12 months post-transplant. Alternatively, in a small clinical trial, initially in combination with mycophenolate mofetil/interleukin 2 receptor antagonist: 150–200 mcg/kg (0.15-0.2 mg/kg) daily. Observed tacrolimus concentrations were 6-16 ng/mL and 5–12 ng/mL during months 1–3 and months 4–12, respectively.

Extended-release capsules (Astagraf XL): Initially, in combination with basliximab, mycophenolate mofetil, and steroids: 150-200 mcg/kg (0.15 to 0.2 mg/kg) once daily prior to reperfusion or within 48 hours of completion of transplant. Typical trough whole blood tacrolimus concentrations should be 7-15 ng/mL in the first month, 5-15 ng/mL in months 2–6, and 5-10 ng/mL ≥6 months.

Extended-release capsules (Astagraf XL): In combination with mycophenolate mofetil, and steroids, without basiliximab induction, a first dose (pre-operative) of 100 mcg/kg (0.1 mg/kg), within 12 hours prior to reperfusion. Subsequent doses postoperatively, 200 mcg/kg (0.2 mg/kg) once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion. Typical trough whole blood tacrolimus concentrations should be 10–15 ng/mL, 5–15 ng/mL, and 5–10 ng/mL when measured at month 1, at months 2–6, or ≥6 months post-transplant, respectively.

Extended-release tablets (Envarsus XR): Initially, 140 mcg/kg (0.14 mg/kg) once daily. Typical trough whole blood tacrolimus concentrations should be 6–11 ng/mL in the first month and 4–11 ng/mL after the first month. To convert from a tacrolimus immediate-release product, administer extended-release tablets once daily at a dose that is 80% of the total daily dose of the immediate-release product. Monitor tacrolimus trough whole blood concentrations and titrate extended-release tablet dosage to achieve trough whole blood concentrations of 4 to 11 ng/mL.

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft. Adults should receive a dosage at the lower end of this range.

Liver Transplantation

Oral

Immediate-release capsules or granules in combination with corticosteroids only: Initially, 100–150 mcg/kg (0.1–0.15 mg/kg) daily, administered in 2 divided doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL when measured at months 1–12 post-transplant.

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft. Adults should receive a dosage at the lower end of this range.

Cardiac Transplantation

Oral

Immediate-release capsules or granules: Initially, in combination with azathioprine or mycophenolate mofetil: 75 mcg/kg (0.075 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 10–20 ng/mL and 5–15 ng/mL when measured in months 1–3 and ≥4 months post-transplant, respectively.

IV

Initially, 10 mcg/kg (0.01 mg/kg) daily in heart transplant patients, administered as a continuous infusion.

Lung Transplantation

Oral

Immediate-release capsules or granules in combination with azathioprine or mycophenolate mofetil: Initially, 75 mcg/kg (0.075 mg/kg) daily, administered in 2 divided doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 10-15 ng/mL and 8-12 ng/mL at months 1-3 and from 4-12 months post-transplant, respectively.

IV

Initially, 10–30 mcg/kg (0.01–0.03 mg/kg) daily commencing after revascularization of the graft. Adults should receive a dosage at the lower end of this range.

Therapeutic Drug Monitoring

Monitoring whole blood tacrolimus concentrations may be useful in assessing organ rejection and toxicity, adjusting dosage, and determining compliance. Factors influencing frequency of monitoring include hepatic or renal dysfunction, addition or discontinuance of potentially interacting drugs, dosage form, and time since transplant.

Therapeutic drug monitoring is not a replacement for renal and hepatic function monitoring and tissue biopsies.

Relative risk of drug toxicity appears to be increased with higher trough concentrations; monitoring of trough whole blood concentrations is recommended.

Methods commonly used for assaying tacrolimus concentrations include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays.

Consult specialized sources for further discussion of the clinical utility of tacrolimus concentration monitoring.

Pharmacogenomic Considerations in Dosing

Pharmacogenetic variations in tacrolimus metabolism may affect dosage requirements. Blood concentrations of tacrolimus are strongly influenced by CYP3A5 genotype.

CPIC guidelines recommend that individuals who express CYP3A5 (extensive or intermediate metabolizers) should increase the recommended starting dose by 1.5–2 times (not to exceed 0.3 mg/kg daily). Those who do not express CYP3A5 (poor metabolizers) should initiate therapy with the standard recommended dose. Therapeutic drug monitoring should be used to guide dose adjustments.

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

Prescribing Limits

Special Populations

Hepatic Impairment

Initiate therapy with the lowest dosage in the recommended range.

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

Use in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency. Monitor these patients closely; consider dosage adjustments.

Renal Impairment

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

In kidney transplant patients with post-operative oliguria, administer initial dose no sooner than 6 hours and within 24 hours of transplantation; the initial dose may be delayed until renal fucntion shows evidence of recovery.

Race or Ethnicity

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

Contraindications

• Known hypersensitivity to tacrolimus or any ingredient in the formulation (e.g., polyoxyl 60 hydrogenated castor oil [HCO-60] in the IV formulation).

Warnings/Precautions

Warnings

Lymphomas and Other Malignancies

Possible increased development of lymphoma or other malignancies, particularly of the skin. Risk may be related to the intensity and duration of immunosupression. (See Boxed Warning.)

Post-transplant lymphoproliferative disorder (PTLD) that appears to be associated with Epstein-Barr virus (EBV) infection reported in immunosuppressed organ transplant patients. Risk of this disorder appears greatest in 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. Monitor EBV serology during treatment.

Serious Infections

Possible increased susceptibility to infection, viral, fungal and protozoal infection, including opportunistic infections, that may be serious or fatal(See Boxed Warning).

Serious viral infections reported include polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection or reactivation of latent viral infections. Principally observed in renal transplant patients (usually within the first year post-transplantation); may result in severe allograft dysfunction and/or graft loss. Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant. Monitor closely for signs of PVAN (e.g., deterioration of renal function); if PVAN develops, institute early treatment, and consider reducing immunosuppressive therapy.

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

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 tacrolimus treatment. Monitor for development of infection and consider changing immunosuppressant dosage to balance the risk of infection with the organ rejection risk.

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

Increased mortality reported in female liver transplant patients who received tacrolimus extended-release capsules (Astragraf XL; See Boxed Warning). This preparation is not labeled for use in liver transplantation.

Sensitivity Reactions

Anaphylaxis

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

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

General Precautions

Interchangeability of Extended-release Products

Medication errors reported, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products. Errors led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus.

Substitute extended-release and immediate-release preparations only under physician supervision.

Instruct patients and caregivers to recognize the appearance of their prescribed dosage form and to contact their healthcare provider if a different product is dispensed or if dosing instructions have changed.

New Onset Diabetes

Increased risk of hyperglycemia or new-onset, insulin-dependent, post-transplant diabetes mellitus reported with tacrolimus use in clinical studies for heart, lung, kidney, and liver transplantation. Black and Hispanic renal transplant patients are most at risk for development of post-transplant diabetes mellitus.

Monitor fasting blood glucose concentrations regularly.

Nephrotoxicity

Potential for nephrotoxicity, especially at high doses.

Monitor S_cr regularly and adjust dosage or discontinue tacrolimus, as needed.

Neurotoxicity

Risk of neurotoxicity (e.g., tremor, headache, other changes in motor function, mental status, or sensory function), especially at high doses.

Closely monitor neurologic function and status.

Consider dosage reduction or discontinue treatment if neurotoxicity occurs.

Hyperkalemia

Possible hyperkalemia (sometimes severe).

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

If hyperkalemia occurs, institute appropriate management (e.g., restriction of potassium intake, administration of potassium-binding resin or mineralocorticoid).

Hypertension

Development of hypertension reported commonly; generally is mild to moderate; may require antihypertensive therapy. Carefully consider use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers).

QT prolongation

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

Reduce tacrolimus dose when co-administering with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. Monitor tacrolimus whole blood concentrations and for QT prolongation.

Myocardial Hypertrophy

Risk of myocardial hypertrophy reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations; generally reversible following dosage reduction or drug discontinuance.

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

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

Immunizations

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

Pure Red Cell Aplasia

Pure red cell aplasia (PRCA) reported. All patients who developed PRCA had risk factors such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA.

If PRCA is diagnosed, consider discontinuation of tacrolimus.

Specific Populations

Pregnancy

May cause fetal harm including prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Females of reproductive potential should use effective birth control prior to initiation and during tacrolimus treatment. Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus.

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].

May increase hyperglycemia in pregnant females with diabetes; monitor blood glucose levels regularly. May also exacerbate hypertension in pregnant females and increase the risk of pre-eclampsia; monitor and control BP.

Lactation

Distributed into human milk; effects on infant or milk production unknown. Consider 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 underlying maternal condition.

Females and Males of Reproductive Potential

Females of reproductive potential should use effective birth control prior to initiation and during tacrolimus treatment. Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus.

Based on findings in animals, male and female fertility may be compromised.

Pediatric Use

Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients.

Pediatric patients generally require higher doses of tacrolimus to maintain blood trough concentrations similar to adult patients.

Geriatric Use

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

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

Hepatic Impairment

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

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.

Renal Impairment

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

Race

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

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

Common Adverse Effects

Kidney transplantation (≥30% of patients receiving immediate-release products): 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. The most common adverse reactions reported in ≥30% of patients receiving tacrolimus extended-release capsules were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The most common adverse reactions reported in ≥30% of patients receiving tacrolimus extended-release tablets were: infection and diarrhea.

Liver transplantation (≥40% of patients receiving immediate-release products): tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia.

Heart transplantation (≥15% of patients receiving immediate-release products): abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipidemia.

Lung transplantation: adverse reactions reported of patients receiving immediate-release products were similar to those in kidney, heart, or liver transplant patients treated with tacrolimus.

General

Pretreatment Screening

• Evaluate immunizations and give complete complement of needed vaccines before transplantation and treatment.

• 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.

Patient Monitoring

• Therapeutic drug monitoring is recommended for all patients. (See Therapeutic Drug Monitoring under Dosage and Administration.)

• Continuously observe patients receiving IV tacrolimus for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, stop the infusion.

• Examine patients for skin changes periodically.

• Monitor patients for signs and symptoms of infection.

• Perform routine laboratory testing (e.g., for assessment of renal and hepatic function, for monitoring of glucose and potassium concentrations).

• Monitor patients for neurologic changes.

• Check blood pressure periodically.

Dispensing and Administration Precautions

• Tacrolimus should only be used under the supervision of a provider with experience managing immunosuppressive therapy. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.

• When IV tacrolimus is administered, emergency drugs and equipment such as epinephrine and oxygen should be available at the bedside.

• Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills.

• Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in tacrolimus capsules and tacrolimus granules, respectively. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. If a spill occurs, wipe the surface with a wet paper towel.

Other General Considerations

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

Administration

Administer orally (as immediate-release capsules, granules for suspension, extended-release capsules, or extended-release tablets) or by IV infusion depending on the specific indication and whether patient is able to tolerate oral formulations.

If therapy is initiated with the IV formulation, substitute oral therapy as soon as tolerated. Initiate oral tacrolimus 8–12 hours after IV infusion is discontinued.

Because of differences in pharmacokinetic properties, extended-release capsule and tablet products are not interchangeable with each other or with tacrolimus immediate-release capsules or granules for suspension. 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.

Oral Administration

Immediate-release Capsules

Administer immediate-release capsules every 12 hours at consistent times of day to minimize variability in systemic exposure. Take with or without food in the same way for each dose. Do not open or crush capsules.

In liver, heart, or lung transplant patients, administer the initial dose of immediate-release capsules no sooner than 6 hours after transplantation. 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.

Granules for Oral Suspension

Use in patients who have difficulty swallowing capsules. Administer the suspension every 12 hours at consistent times of day. Take with or without food the same way for each dose.

Do not sprinkle tacrolimus granules on food for administration. 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. Add 15-30 mL of room temperature drinking water to the glass, and mix; the granules will not dissolve completely. 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. Do not prepare tacrolimus suspension in a plastic (PVC containing) cup or use plastic tubing, syringes, or other equipment during administration; use glass or metal materials when preparing tacrolimus suspension. A non-PVC oral syringe may be used for administration to younger patients. Do not prepare tacrolimus suspension in advance or store after mixing with water. Consult the manufacturer’s labeling and instructions for detailed information on preparing and administering tacrolimus granules for oral suspension.

Extended-release Capsules (Astagraf XL)

Administer 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. Swallow extended-release capsules whole with liquid; do not chew, divide, or crush the capsules.

If a dose of tacrolimus extended-release capsules is missed by <14 hours, administer missed dose as soon as possible. If a dose is missed by ≥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.

Extended-release Tablets (Envarsus XL)

Administer 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. Swallow extended-release tablets whole with liquid (preferably water); do not chew, divide, or crush the tablets.

If a dose of tacrolimus extended-release tablets is missed by <15 hours, administer missed dose as soon as possible. If a dose is missed by ≥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.

Standardize 4 Safety

Standardized concentrations for tacrolimus have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 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].

IV Administration

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

Do not mix or co-infuse with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir) due to the chemical instability of tacrolimus in alkaline media.

Continuously observe patient for ≥30 minutes following initiation of the IV infusion and then at frequent intervals thereafter for possible allergic manifestations.

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.

Rate of Administration

Administer daily dose over 24 hours by continuous IV infusion.

Standardize 4 Safety

Standardized concentrations for tacrolimus have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 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].

Tacrolimus is not included in the adult continuous infusion standards

Dosage

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

Individualize dosage based on clinical assessments of organ rejection and patient tolerability.

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

Pediatric Patients

Children generally require higher dosages than adults on a weight basis to achieve comparable blood concentrations.

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

Kidney Transplantation

Oral

Immediate-release capsules or granules: Initially, 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL at 1–12 months post-transplant.

Extended-release capsules (Astagraf XL) in combination with basiliximab, mycophenolate mofetil, and steroids: Initially, 300 mcg/kg (0.3 mg/kg) once daily within 24 hours of reperfusion. Typical trough whole blood tacrolimus concentrations should be 10–20 ng/mL in the first month and 5–15 ng/mL after the first month.

Liver Transplantation

Oral

Immediate-release capsules or granules: Initially, 150–200 mcg/kg (0.15–0.2 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL when measured at months 1–12 post-transplant.

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily.

Cardiac Transplantation

Oral

Immediate-release capsules or granules: Initially, 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours. If antibody induction treatment is administered, give 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL when measured at months 1–12 post-transplant.

Lung Transplantation

Oral

Immediate-release capsules or granules: Initially, 300 mcg/kg (0.3 mg/kg) daily, administered in 2 divided daily doses every 12 hours. If antibody induction treatment is administered, give 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours 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.

Adults

Kidney Transplantation

Oral

Immediate-release capsules or granules: Initially, in combination with azathioprine: 200 mcg/kg (0.2 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 7–20 ng/mL and 5–15 ng/mL when measured at months 1–3 and 4–12 post-transplant, respectively.

Immediate-release capsules or granules: Initially, in combination with mycophenolate mofetil/interleukin 2 receptor antagonist: 100 mcg/kg (0.1 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 4–11 ng/mL when measured at months 1–12 months post-transplant. Alternatively, in a small clinical trial, initially in combination with mycophenolate mofetil/interleukin 2 receptor antagonist: 150–200 mcg/kg (0.15-0.2 mg/kg) daily. Observed tacrolimus concentrations were 6-16 ng/mL and 5–12 ng/mL during months 1–3 and months 4–12, respectively.

Extended-release capsules (Astagraf XL): Initially, in combination with basliximab, mycophenolate mofetil, and steroids: 150-200 mcg/kg (0.15 to 0.2 mg/kg) once daily prior to reperfusion or within 48 hours of completion of transplant. Typical trough whole blood tacrolimus concentrations should be 7-15 ng/mL in the first month, 5-15 ng/mL in months 2–6, and 5-10 ng/mL ≥6 months.

Extended-release capsules (Astagraf XL): In combination with mycophenolate mofetil, and steroids, without basiliximab induction, a first dose (pre-operative) of 100 mcg/kg (0.1 mg/kg), within 12 hours prior to reperfusion. Subsequent doses postoperatively, 200 mcg/kg (0.2 mg/kg) once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion. Typical trough whole blood tacrolimus concentrations should be 10–15 ng/mL, 5–15 ng/mL, and 5–10 ng/mL when measured at month 1, at months 2–6, or ≥6 months post-transplant, respectively.

Extended-release tablets (Envarsus XR): Initially, 140 mcg/kg (0.14 mg/kg) once daily. Typical trough whole blood tacrolimus concentrations should be 6–11 ng/mL in the first month and 4–11 ng/mL after the first month. To convert from a tacrolimus immediate-release product, administer extended-release tablets once daily at a dose that is 80% of the total daily dose of the immediate-release product. Monitor tacrolimus trough whole blood concentrations and titrate extended-release tablet dosage to achieve trough whole blood concentrations of 4 to 11 ng/mL.

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft. Adults should receive a dosage at the lower end of this range.

Liver Transplantation

Oral

Immediate-release capsules or granules in combination with corticosteroids only: Initially, 100–150 mcg/kg (0.1–0.15 mg/kg) daily, administered in 2 divided doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 5–20 ng/mL when measured at months 1–12 post-transplant.

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft. Adults should receive a dosage at the lower end of this range.

Cardiac Transplantation

Oral

Immediate-release capsules or granules: Initially, in combination with azathioprine or mycophenolate mofetil: 75 mcg/kg (0.075 mg/kg) daily, administered in 2 divided daily doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 10–20 ng/mL and 5–15 ng/mL when measured in months 1–3 and ≥4 months post-transplant, respectively.

IV

Initially, 10 mcg/kg (0.01 mg/kg) daily in heart transplant patients, administered as a continuous infusion.

Lung Transplantation

Oral

Immediate-release capsules or granules in combination with azathioprine or mycophenolate mofetil: Initially, 75 mcg/kg (0.075 mg/kg) daily, administered in 2 divided doses every 12 hours. Typical trough whole blood tacrolimus concentrations should be 10-15 ng/mL and 8-12 ng/mL at months 1-3 and from 4-12 months post-transplant, respectively.

IV

Initially, 10–30 mcg/kg (0.01–0.03 mg/kg) daily commencing after revascularization of the graft. Adults should receive a dosage at the lower end of this range.

Therapeutic Drug Monitoring

Monitoring whole blood tacrolimus concentrations may be useful in assessing organ rejection and toxicity, adjusting dosage, and determining compliance. Factors influencing frequency of monitoring include hepatic or renal dysfunction, addition or discontinuance of potentially interacting drugs, dosage form, and time since transplant.

Therapeutic drug monitoring is not a replacement for renal and hepatic function monitoring and tissue biopsies.

Relative risk of drug toxicity appears to be increased with higher trough concentrations; monitoring of trough whole blood concentrations is recommended.

Methods commonly used for assaying tacrolimus concentrations include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays.

Consult specialized sources for further discussion of the clinical utility of tacrolimus concentration monitoring.

Pharmacogenomic Considerations in Dosing

Pharmacogenetic variations in tacrolimus metabolism may affect dosage requirements. Blood concentrations of tacrolimus are strongly influenced by CYP3A5 genotype.

CPIC guidelines recommend that individuals who express CYP3A5 (extensive or intermediate metabolizers) should increase the recommended starting dose by 1.5–2 times (not to exceed 0.3 mg/kg daily). Those who do not express CYP3A5 (poor metabolizers) should initiate therapy with the standard recommended dose. Therapeutic drug monitoring should be used to guide dose adjustments.

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

Prescribing Limits

Special Populations

Hepatic Impairment

Initiate therapy with the lowest dosage in the recommended range.

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

Use in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency. Monitor these patients closely; consider dosage adjustments.

Renal Impairment

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

In kidney transplant patients with post-operative oliguria, administer initial dose no sooner than 6 hours and within 24 hours of transplantation; the initial dose may be delayed until renal fucntion shows evidence of recovery.

Race or Ethnicity

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

Metabolized by CYP isoenzymes, principally CYP3A.

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions are likely with drugs that are potent inhibitors or inducers of CYP3A, possibly resulting in increased or decreased blood concentrations of tacrolimus. If such drugs are used concomitantly, monitor blood tacrolimus concentrations and adjust dosage as needed.

Specific Drugs and Foods