Tacrolimus (Systemic)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Prograf: 0.5 mg, 1 mg, 5 mg

Generic: 0.5 mg, 1 mg, 5 mg

Capsule Extended Release 24 Hour, Oral:

Astagraf XL: 0.5 mg, 1 mg, 5 mg

Packet, Oral:

Prograf: 0.2 mg (50 ea); 1 mg (50 ea)

Solution, Intravenous:

Prograf: 5 mg/mL (1 mL) [contains alcohol, usp, cremophor el]

Tablet Extended Release 24 Hour, Oral:

Envarsus XR: 0.75 mg, 1 mg, 4 mg

Pharmacology

Mechanism of Action

Suppresses cellular immunity (inhibits T-lymphocyte activation), by binding to an intracellular protein, FKBP-12 and complexes with calcineurin dependent proteins to inhibit calcineurin phosphatase activity

Pharmacokinetics/Pharmacodynamics

Absorption

Better in resected patients with a closed stoma; unlike cyclosporine, clamping of the T-tube in liver transplant patients does not alter trough concentrations or AUC; Oral: Incomplete and variable (5% to 67%); the rate and extent of absorption is decreased (27%) by food (particularly a high-fat meal). Oral absorption may be variable in stem cell transplant patients with mucositis due to the conditioning regimen. Systemic exposure (AUC) of single dose granules was ~16% higher than single dose capsules.

Distribution

Distributes to erythrocytes, lung, kidneys, pancreas, liver, heart, and spleen; V_d: Mean: Infants and Children: 2.6 L/kg in liver transplant patients; Adults: 0.85 to 1.41 L/kg in liver and renal transplant patients

Metabolism

Extensively hepatic via CYP3A4 to eight possible metabolites (major metabolite, 31-demethyl tacrolimus, shows same activity as tacrolimus in vitro)

Excretion

Feces (~93%); urine (<1% as unchanged drug)

Clearance: 7 to 103 mL/minute/kg (average: 30 mL/minute/kg); clearance higher in children

Time to Peak

Oral: 0.5 to 6 hours

Half-Life Elimination

Children: Kidney transplant: 10.2 ± 5 hours; Infants and Children: Liver transplant: 11.5 ± 3.8 hours

Adults:

Immediate release: Variable, 23 to 46 hours in healthy volunteers; 2.1 to 36 hours in transplant patients; prolonged in patients with severe impairment

Extended release: 38 ± 3 hours; prolonged in patients with severe impairment

Protein Binding

~99% primarily to albumin and alpha₁-acid glycoprotein

Use in Specific Populations

Special Populations: Hepatic Function Impairment

The mean clearance was substantially lower in patients with severe hepatic impairment.

Special Populations: Race

C_max is lower, T_max is prolonged, and bioavailability is increased in kidney transplant patients who are black.

Use: Labeled Indications

Organ rejection prophylaxis:

Advagraf [Canadian product]: Prevention of organ rejection in allogeneic kidney or liver transplant adult patients in combination with other immunosuppressants.

Astagraf XL: Prevention of organ rejection in kidney transplant recipients in combination with other immunosuppressants.

Envarsus PA [Canadian product]: Prevention of organ rejection in allogeneic kidney or liver transplant adult patients in combination with other immunosuppressants.

Envarsus XR: Prevention of organ rejection in kidney transplant recipients in combination with other immunosuppressants.

Prograf: Prevention of organ rejection in heart, kidney, and liver transplant recipients in combination with other immunosuppressants.

Note: ER products (Advagraf [Canadian product], Astagraf XL, Envarsus PA [Canadian product], and Envarsus XR) are not interchangeable or substitutable with immediate release tacrolimus. In addition, the once-daily formulations (Advagraf [Canadian product], Astagraf XL, Envarsus PA [Canadian product], and Envarsus XR) are not interchangeable with each other due to significantly different pharmacokinetic properties.

Use: Off Label

Crohn disease (perianal/fistulizing disease)byes

Data from a small randomized, double-blind, placebo-controlled study suggests tacrolimus may be effective in improving fistulas in patients with fistulizing (perianal and enterocutaneous) Crohn disease that was refractory to prior treatment with at least 1 antibiotic Sandborn 2003. Case reports also suggest a benefit from the use of tacrolimus in the management of fistulas in patients with Crohn disease and refractory fistulas Ierardi 2000.

Based on the American College of Gastroenterology Guideline for the Management of Crohn’s Disease in Adults, while tacrolimus should not generally be used for the treatment of Crohn disease (due to the toxicity potential), tacrolimus may be used as short-term therapy for management of perianal and cutaneous fistulas in patients with fistulizing Crohn disease.

Graft-versus-host disease (prevention/treatment)c

Data from a retrospective study in patients, converted from cyclosporine to tacrolimus for resistant acute graft-versus-host disease (GVHD) suggests that the use of tacrolimus (systemic) may be beneficial for the prevention and treatment of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation Furlong 2000. Clinical experience also suggests the utility of tacrolimus (systemic) in this setting Przepiorka 1999, Uberti 1999. Additional data may be necessary to further define the role of tacrolimus in this condition.

Immunosuppression (maintenance) after lung transplantayes

Data from a number of clinical trials evaluating the use of tacrolimus in lung transplant support the use of tacrolimus in this setting. Results of a meta-analysis of trials comparing tacrolimus to cyclosporine for primary immunosuppression in lung transplant recipients suggest that while there was no difference in survival or rejection, tacrolimus may be superior to cyclosporine with regard to incidence of bronchiolitis obliterans syndrome (BOS), lymphocytic bronchitis, treatment withdrawal, and arterial hypertension; however, tacrolimus may be inferior with regard to the development of diabetes. The International Society for Heart and Lung Transplantation (ISHLT) registry data indicate that tacrolimus is the most frequently used calcineurin inhibitor for maintenance immunosuppression after lung transplant. Based on an ISHLT clinical practice guideline for the diagnosis and management of BOS, switching to tacrolimus is suggested if cyclosporine-treated patients develop BOS as described by multiple case series.

Intestinal transplantc

Based on recommendations from experts and clinical experience in intestinal transplantation, tacrolimus is recommended as the calcineurin inhibitor of choice for prevention of rejection after intestinal transplant Abu-Elmagd 2009a, Abu-Elmagd 2009b, Horslen 2006. Specific dosing recommendations cannot be made due to insufficient evidence. Additional data may be necessary to further define the role of tacrolimus in intestinal transplant.

Myasthenia graviscyes

Data from a randomized, double-blind, placebo-controlled study suggest that tacrolimus may be beneficial as a steroid-sparing agent in clinically stable patients with myasthenia gravis Yoshikawa 2011.

Based on the Myasthenia Gravis Foundation of America consensus-based guidance for the management of myasthenia gravis, tacrolimus may be used as an immunosuppressive agent in patients with myasthenia gravis who have not met treatment goals after an adequate trial of pyridostigmine, despite limited positive results in clinical trials. Tacrolimus may be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine Sanders 2016, Yoshikawa 2011.

Rheumatoid arthritis (refractory)b

Data from a randomized, double-blind, multicenter study in patients with disease-modifying antirheumatic drug (DMARD) refractory rheumatoid arthritis supports the use of tacrolimus monotherapy in the treatment of this condition Yocum 2003. The use of tacrolimus using a lower dose in addition to methotrexate in patients who do not respond adequately to methotrexate has also been evaluated Lee 2016.

Contraindications

Hypersensitivity to tacrolimus, polyoxyl 60 hydrogenated castor oil (HCO-60), or any other component of the formulation.

Dosage and Administration

Dosing: Adult

Note: ER products (Advagraf [Canadian product], Astagraf XL, Envarsus PA [Canadian product], and Envarsus XR) are not interchangeable or substitutable with IR tacrolimus. In addition, the once-daily formulations (Advagraf [Canadian product], Astagraf XL, Envarsus PA [Canadian product], and Envarsus XR) are not interchangeable with each other due to significantly different pharmacokinetic properties.

Immunosuppression after solid-organ transplant, sublingual administration: Sublingual (off-label route): Immediate release: Optimal dosing has not been determined. In dosing regimens using sublingual administration of the contents of IR tacrolimus capsules, the sublingual to oral dosing ratio has ranged from 1:3 to 1:1 (Collin 2010; Nasiri-Toosi 2012). However, most studies suggest a dosing ratio of 1:2 (or 50% of the oral dose given sublingually), and most centers use this approach in practice (Doligalski 2014; Watkins 2012). Adjust dose based on serum trough concentrations. Lower doses of sublingual tacrolimus may be required during coadministration of drugs that inhibit tacrolimus metabolism (Collin 2010; Reams 2002).

Prevention of organ rejection in transplant recipients: Note: While recommendations for initial doses exist, drug interactions should be considered. After initial dose, titrate to achieve target trough concentrations. Adjunctive therapy with other immunosuppressants, including but not limited to corticosteroids, is recommended early post-transplant. IV route should only be used in patients not able to take oral medications and continued only until oral medication can be tolerated; anaphylaxis has been reported with IV administration. If switching from IV to oral, the oral dose should be started 8 to 12 hours after stopping the infusion. Sublingual administration may be considered in those unable to take oral.

Liver transplant:

Oral:

Immediate release: Initial: 0.1 to 0.15 mg/kg/day in 2 divided doses, given every 12 hours in combination with corticosteroids (titrate to target trough concentrations); consider lower dose in liver transplant recipients with graft dysfunction.

Extended release:

Advagraf [Canadian product]: 0.1 to 0.2 mg/kg once daily in combination with corticosteroids; initiate within 12 to 18 hours of transplantation; titrate to target trough concentrations. Note: In the US, Astagraf XL is not approved for use in liver transplantation due to an increase in mortality in female liver transplant recipients receiving Astagraf XL.

Conversion from immediate release to extended release (Advagraf [Canadian product]): Patients stable on IR tacrolimus may be converted to extended release by initiating ER treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of IR product. Administer once daily.

Envarsus PA [Canadian product]: Initial: 0.11 to 0.13 mg/kg once daily concomitantly used with corticosteroids and/or mycophenolic acids or azathioprine; initiate within 24 hours of transplantation; titrate to target trough concentrations.

Conversion from immediate release to extended release (Envarsus PA [Canadian product]): Patients stable on IR tacrolimus may be converted to extended release by initiating ER treatment in a 1:0.7 ratio (1 mg IR:0.7 mg ER) (or a 1:0.85 ratio for African American patients) using previously established total daily dose of IR product. Administer once daily.

IV: Initial: 0.03 to 0.05 mg/kg/day as a continuous infusion.

Heart transplant: Use in combination with an antimetabolite agent (eg, azathioprine, mycophenolate mofetil). Instead of an antimetabolite, may also use in combination with an mTOR kinase inhibitor (eg, everolimus, sirolimus) (Fuchs 2014; Guethoff 2015).

Oral: Immediate release: Initial: 0.075 mg/kg/day in 2 divided doses, given every 12 hours (titrate to target trough concentrations).

IV: Initial: 0.01 mg/kg/day as a continuous infusion.

Conversion from oral to continuous IV infusion: According to the ISHLT guidelines for the care of heart transplant recipients, convert from oral to IV by administering one-fifth (1/5th) of the oral daily dose as a continuous infusion over 24 hours (ISHLT [Costanzo 2010]).

Kidney transplant: Use in combination with azathioprine or mycophenolate mofetil. Note: African American patients may require larger doses to attain trough concentration.

Oral:

Immediate release (Prograf): Initial: 0.2 mg/kg/day in combination with azathioprine or 0.1 mg/kg/day in combination with mycophenolate mofetil; titrate to target trough concentrations. Administer in 2 divided doses, given every 12 hours.

Conversion from immediate release oral to IV: Administer one-third (1/3rd) of the oral dose as a continuous infusion over 24 hours.

Extended release (Advagraf [Canadian product], Astagraf XL):

With basiliximab induction (prior to reperfusion or within 48 hours of transplant completion): 0.15 to 0.2 mg/kg once daily (in combination with corticosteroids and mycophenolate); titrate to target trough concentrations.

Without basiliximab induction:

Preoperative dose (administer within 12 hours prior to reperfusion): 0.1 mg/kg (in combination with corticosteroids and mycophenolate).

Postoperative dose (administer at least 4 hours after preoperative dose and within 12 hours of reperfusion): 0.2 mg/kg once daily (in combination with corticosteroids and mycophenolate); titrate to target trough concentrations.

Conversion from IV to extended release (Astagraf XL): Administer the first oral ER dose 8 to 12 hours after discontinuation of IV tacrolimus.

Conversion from immediate release to extended release (Advagraf [Canadian product], Astagraf XL): Initiate ER treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate release (Advagraf Canadian product labeling 2015; Van Hooff 2012). Administer once daily.

Extended release:

Envarsus XR: 0.14 mg/kg/day; titrate to target trough concentrations.

Conversion from IV to extended release (Envarsus XR): Administer the first oral ER dose 8 to 12 hours after discontinuation of IV tacrolimus.

Conversion from immediate release to extended release (Envarsus XR): Initiate ER treatment with a once-daily dose that is 70% to 80% of the total daily dose of the IR tacrolimus.

Envarsus PA [Canadian product]:0.17 mg/kg/day concomitantly used with corticosteroids and/or mycophenolic acids or azathioprine; initiate within 24 hours of transplantation; titrate to target trough concentrations.

Conversion from immediate release to extended release (Envarsus PA [Canadian product]): Patients stable on IR tacrolimus may be converted to extended release by initiating ER treatment in a 1:0.7 ratio (1 mg IR:0.7 mg ER) (or a 1:0.85 ratio for African American patients) using previously established total daily dose of IR product. Administer once daily.

IV: Initial: 0.03 to 0.05 mg/kg/day as a continuous infusion.

Crohn disease (perianal/fistulizing disease) (off-label use): Oral: Immediate release: Initial: 0.1 mg/kg twice daily; titrate to target concentrations (Sandborn 2003). Note: Due to the toxicity potential, tacrolimus therapy should be limited to short-term use only (ACG [Lichtenstein 2018]).

Graft-versus-host disease (off-label use):

Prevention:

Oral: Convert from IV to IR oral dose (1:4 ratio): Multiply total daily IV dose times 4 and administer in 2 divided oral doses per day, every 12 hours (Uberti 1999; Yanik 2000).

IV: Initial: 0.03 mg/kg/day (based on lean body weight) as continuous infusion. Treatment should begin at least 24 hours prior to stem cell infusion and continued only until oral medication can be tolerated (Przepiorka 1999; Yanik 2000).

Treatment:

Oral: Immediate release: 0.06 mg/kg twice daily (Furlong 2000; Przepiorka 1999).

IV: Initial: 0.03 mg/kg/day (based on lean body weight) as continuous infusion (Furlong 2000; Przepiorka 1999).

Lung transplant (off-label use): Usually used in a combination regimen that contains a corticosteroid and either azathioprine or mycophenolate (Snell 2013).

Oral, nasogastric: Immediate release: 0.05 to 0.3 mg/kg/day in 2 divided doses, given every 12 hours (usual dose: 0.05 mg/kg every 12 hours); titrate to target trough concentrations (Treede 2001; Treede 2012; Zuckermann 2003). May also be administered sublingually at ~50% of the oral/NG dose (Doligalski 2014; Watkins 2012).

Note: May convert from twice-daily dosing to once-daily dosing (on a mg per mg basis) using the ER formulation (Astagraf XL [US] or Advagraf [Canada]) in stable lung transplant recipients (Mendez 2014). May convert to extended-release Envarsus with a once-daily dose that is 70% to 80% of the total daily dose of IR tacrolimus although clinical trial data are lacking.

IV: 0.01 to 0.05 mg/kg over 24 hours as a continuous IV infusion; titrate to target trough concentrations (Treede 2001; Treede 2012; Zuckermann 2003). For patients receiving the initial dose of tacrolimus intravenously, may begin immediately after transplantation, or up to 2 days postoperatively depending on renal function and hemodynamic stability (Treede 2001; Treede 2012; Witt 2013; Zuckermann 2003). When patient is able to take oral medication, may switch to an oral maintenance regimen (typically transitioned after extubation).

Myasthenia gravis (off-label use): Patients who remain significantly symptomatic on pyridostigmine: Oral: Immediate release: Initial: 3 to 5 mg/day or 0.1 mg/kg/day, in one or two divided doses. After initial dose, titrate to achieve target trough concentrations (Ponsetti 2008; Sanders 2016; Yoshikawa 2011). May be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine (Sanders 2016; Yoshikawa 2011). Onset of clinical response to tacrolimus may take up to 6 to 12 months (Cruz 2015).

Rheumatoid arthritis (refractory) (off-label use): Oral: Immediate release: 2 to 3 mg once daily in combination with NSAID and/or oral corticosteroid therapy; 3 mg once daily resulted in better ACR response rates (Yocum 2003). In patients not responsive to methotrexate alone, may add tacrolimus at a lower dose (ie, 1.5 mg once daily) in combination with methotrexate (Lee 2016). Carefully monitor serum creatinine during therapy.

Dosing: Geriatric

Refer to adult dosing. Use with caution; begin at the low end of dosing range.

Dosing: Pediatric

Note: Tacrolimus granules may have higher AUC compared to capsule formulation; if changing between products, monitor tacrolimus concentrations. Extended-release products (Astagraf XL and Envarsus XR) are not interchangeable or substitutable with immediate-release tacrolimus (Prograf capsules and granules). In addition, the once-daily formulations (Astagraf XL and Envarsus XR) are not interchangeable with each other due to significantly different pharmacokinetic properties. Younger children generally require higher maintenance doses on a mg/kg basis than older children, adolescents, or adults (Kim 2005; Montini 2006). Adjust initial dose to achieve desired target tacrolimus concentration; specific institutional protocols should be consulted.

Graft-vs-host disease (GVHD); prevention: Limited data available; dosing regimens variable:

Continuous infusion: Infants, Children, and Adolescents: IV: Initial: 0.03 mg/kg/day (based on lean body weight) as continuous IV infusion; begin prior to pretransplant (specific day varies with protocol); monitor serum drug concentrations and adjust dose accordingly; convert to oral formulation when tolerated (Offer 2015; Yanik 2000).

Intermittent infusion: Children and Adolescents: IV: 0.015 mg/kg/dose every 12 hours as a 2-hour infusion. Treatment was initiated on day −2 or day −3 prior to transplant and continued until oral medication tolerated; dosing based on a descriptive study in 33 patients (median age: 10 years; range: 1.2 to 17 years); during the trial, no infusion related reactions were reported and no higher incidence of toxicity or adverse effects reported (Skeens 2012).

Nephrotic syndrome, steroid-resistant or steroid-dependent: Limited data available: Children and Adolescents: Oral: Immediate release: Initial: 0.1 mg/kg/day divided every 12 hours; adjust to target serum concentration; the reported dose range (regardless of target serum concentration) is 0.06 to 0.19 mg/kg/day in divided doses every 12 hours (Bock 2013; Gulati 2012; Jahan 2015; KDIGO 2012). Goal tacrolimus concentration varies dependent upon type of nephrotic syndrome and patient characteristics; most frequently reported goal is 5 to 10 ng/mL (KDIGO 2012), largely based on experience from transplant data; however, some studies suggest targeting lower trough concentrations of 3 to 5 ng/mL (Bock 2013; Jahan 2015).

Transplant, heart; prevention of rejection: Infants, Children, and Adolescents: Dose should be individualized and titrated to target trough concentration:

Oral: Immediate release: Initial: 0.1 to 0.3 mg/kg/day divided every 12 hours (Pollock-Barziv 2005; Singh 2016; Swenson 1995); Note: Lower initial dose can be used in patients who receive cell-depleting induction treatment.

IV: Limited data available: 0.01 to 0.03 mg/kg/day as a continuous IV infusion (Groetzner 2005). Note: Limit parenteral use to patients unable to take enteral formulations; patients should be switched to an enteral dosage form as soon as possible.

Transplant, kidney; prevention of rejection:

Oral: Dose should be individualized and titrated to target trough concentrations:

Immediate release: Children and Adolescents: Initial: 0.2 to 0.3 mg/kg/day divided every 12 hours (Filler 2005; KDIGO 2009; Kim 2005; Montini 2006)

Extended release: Astagraf XL: Used in combination with corticosteroids and mycophenolate:

With basiliximab induction:

Children ≥4 years and Adolescents <16 years: Initial: 0.3 mg/kg once daily; administer first dose within 24 hours of reperfusion, titrate to target trough concentrations.

Adolescents ≥16 years: Initial: 0.15 to 0.2 mg/kg once daily; administer first dose prior to reperfusion or within 48 hours of transplant. Titrate to target trough concentrations.

Without basiliximab induction: Adolescents ≥16 years:

Preoperative dose: 0.1 mg/kg once; administer within 12 hours prior to reperfusion

Postoperative dose: 0.2 mg/kg once daily; administer first postoperative dose at least 4 hours after preoperative dose and within 12 hours of reperfusion. Titrate to target trough concentrations.

Conversion from IV to extended release (Astagraf XL): Administer the first oral extended-release dose 8 to 12 hours after discontinuation of IV tacrolimus

Conversion from immediate release to extended release (Astagraf XL): Limited data available: Initiate extended-release treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate release; based on experience in adult patients (Van Hooff 2012). Administer once daily.

IV: Limited data available: Infants, Children, and Adolescents: 0.06 mg/kg/day as a continuous IV infusion (Trompeter 2002). Note: Limit parenteral use to patients unable to take enteral formulations; patients should be switched to an enteral dosage form as soon as possible.

Transplant, liver; prevention of rejection: Infants, Children, and Adolescents:

Oral: Immediate release: Initial: 0.15 to 0.2 mg/kg/day divided every 12 hours

IV: 0.03 to 0.05 mg/kg/day as a continuous IV infusion. Note: Limit parenteral use to patients unable to take enteral formulations; patients should be switched to an enteral dosage form as soon as possible (initiate 8 to 12 hours after infusion is stopped).

Dose conversion of different routes of administration:

Conversion of IV continuous infusion to immediate-release oral: GVHD prophylaxis: Limited data available: To convert from IV to oral dose (1:4 ratio): Multiply total daily IV dose by 4 and administer in 2 divided oral doses per day, every 12 hours; titrate to goal trough concentration (Yanik 2000).

Conversion of immediate-release oral to sublingual (using immediate-release capsule): Very limited data available: To convert from oral to sublingual dose (2:1 ratio): Divide oral dose by 2 for sublingual administration. Dosing based on experience in adult solid organ transplant recipients unable to tolerate enteral administration (Doligalski 2014; Tsapepas 2013).

Reconstitution

Injection: Dilute with 5% dextrose injection or 0.9% sodium chloride injection to a final concentration between 0.004 mg/mL and 0.02 mg/mL.

Extemporaneously Prepared

1 mg/mL Oral Suspension (ASHP Standard Concentration) (ASHP 2017)

A 1 mg/mL tacrolimus oral suspension may be made with immediate release capsules, sterile water, Ora-Plus, and Ora-Sweet. Pour the contents of six 5 mg capsules into a plastic amber prescription bottle. Add ~5 mL of sterile water and agitate bottle until drug disperses into a slurry. Add equal parts Ora-Plus and Ora-Sweet in sufficient quantity to make 30 mL. Store in plastic amber prescription bottles; label "shake well." Stable for 4 months at room temperature (Elefante 2006).

Elefante A, Muindi J, West K, et al, “Long-Term Stability of a Patient-Convenient 1 mg/mL Suspension of Tacrolimus for Accurate Maintenance of Stable Therapeutic Levels,” Bone Marrow Transplant. 2006, 37(8):781-784.16518428

0.5 mg/mL Oral Suspension

A 0.5 mg/mL tacrolimus oral suspension may be made with immediate release capsules and a 1:1 mixture of Ora-Plus and Simple Syrup, N.F. Mix the contents of six 5 mg tacrolimus capsules with quantity of vehicle sufficient to make 60 mL. Store in glass or plastic amber prescription bottles; label "shake well." Stable for 56 days at room temperature (Esquivel 1996; Foster 1996).

Esquivel C, So S, McDiarmid S, Andrews W, et al. Suggested Guidelines for the Use of Tacrolimus in Pediatric Liver Transplant Patients. Transplantation. 1996;61(5):847-848.8607198Foster JA, Jacobson PA, Johnson CE, et al, “Stability of Tacrolimus in an Extemporaneously Compounded Oral Liquid (Abstract of Meeting Presentation),” American Society of Health-System Pharmacists Annual Meeting, 1996, 53:P-52(E).9117806

Administration

IV: If IV administration is necessary, administer by continuous infusion (generally, over 24 hours). Do not use PVC tubing when administering diluted solutions. Do not mix with solutions with a pH ≥9 (eg, acyclovir or ganciclovir) due to chemical degradation of tacrolimus (use different ports in multilumen lines). Do not alter dose with concurrent T-tube clamping. Adsorption of the drug to PVC tubing may become clinically significant with low concentrations.

Oral:

Immediate release: Administer with or without food; be consistent with timing and composition of meals if GI intolerance occurs and administration with food becomes necessary (per manufacturer). If dosed once daily, administer in the morning. If dosed twice daily, doses should be 12 hours apart. If the morning and evening doses differ, the larger dose (differences are never >0.5 to 1 mg) should be given in the morning. Some data suggest that the larger dose should be given in the evening because tacrolimus exposure may be reduced in the evening due to diurnal variation (Iwahori 2005; Min 1997; Park 2007). If dosed 3 times daily, separate doses by 8 hours.

Combination therapy with everolimus for liver transplantation: Administer tacrolimus at the same time as everolimus.

Granules for oral suspension: Calculate dose based on patient weight; use the minimum whole number of packets for the required morning or evening dose. If the morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose. Do not use PVC-containing tubing, syringes, or cups to prepare or administer tacrolimus products; a non-PVC oral syringe (dispensed with prescription) may be used in younger patients. Do not sprinkle granules on food.

Empty the entire contents of each packet into a glass cup. Add 15 to 30 mL of room temperature drinking water; mix and administer the entire contents of the cup (granules will not completely dissolve). Administer immediately after preparation. For younger patients, the suspension can be drawn up via a non-PVC oral syringe (dispensed with prescription). Add additional 15 to 30 mL of water to rinse the cup or syringe to ensure all of the medication is taken.

Extended release: For all US preparations and Envarsus PA [Canadian product], administer on an empty stomach at least 1 hour before or 2 hours after a meal. Advagraf [Canadian product] labeling suggests that the capsule may be taken with food if necessary but should be administered consistently with or without food. Swallow whole, do not chew, crush, or divide. Take once daily in the morning at a consistent time each day. Missed doses may be taken up to 14 hours (15 hours for Envarsus XR) after scheduled time; if >14 hours (>15 hours for Envarsus XR), resume at next regularly scheduled time; do not double a dose to make up for a missed dose.

Nasogastric tube: If unable to swallow capsules, contents of IR capsule(s) may be mixed with water and flushed through a nasogastric tube; clamp nasogastric tube for 30 to 60 minutes after administration (Taylor 2001). Note: Dosing for IR capsules is not equivalent to dosing of Envarsus XR. When switching from Envarsus XR to IR capsules for nasogastric administration, consider administering a 20% to 30% higher total daily dose of IR tacrolimus.

Sublingual: If unable to swallow capsules, tacrolimus may be administered sublingually (at a reduced dose) by opening the IR capsules and placing the contents of the capsule(s) under the tongue, allowing contents to completely dissolve. The patient should avoid swallowing for 5 to 15 minutes and avoid oral intake for 15 to 30 minutes; also avoid mechanical suctioning for at least 30 minutes after administration (Doligalski 2014; Pennington 2015; Watkins 2012). Note: Absorption of a single dose of tacrolimus suspension given by the sublingual route was inadequate (Snell 2013b).

Dietary Considerations

Administer immediate release with or without food; be consistent with timing and composition of meals, food decreases bioavailability. Administer extended release on an empty stomach 1 hour before or 2 hours after a meal. Avoid grapefruit and grapefruit juice. Avoid alcohol.

Storage

Injection: Prior to dilution, store at 5°C to 25°C (41°F to 77°F). Following dilution, stable for 24 hours in D₅W or NS in glass or polyethylene containers. Do not store in polyvinyl chloride containers because the polyoxyl 60 hydrogenated castor oil injectable vehicle may leach phthalates from polyvinyl chloride containers.

Capsule, tablet: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Granules for oral suspension: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Afatinib: Tacrolimus (Systemic) may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10 mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer tacrolimus simultaneously with or after the dose of afatinib. Consider therapy modification

Alcohol (Ethyl): May increase the absorption of Tacrolimus (Systemic). More specifically, the initial absorption rate may be increased, as alcohol may speed the release of tacrolimus from extended-release tablets. Management: Advise patients receiving extended-release tacrolimus (Astagraf XL or Envarsus XR brands) not to take the medication with alcoholic beverages. Consider therapy modification

Amiodarone: Tacrolimus (Systemic) may enhance the QTc-prolonging effect of Amiodarone. Amiodarone may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of Tacrolimus (Systemic). Specifically, this increase in tacrolimus concentrations may occur during the first week of combined therapy. Asunaprevir may decrease the serum concentration of Tacrolimus (Systemic). Specifically, this decrease in tacrolimus concentrations may occur with continued prolonged combination therapy. Monitor therapy

Azithromycin (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of Tacrolimus (Systemic). Exceptions: Clevidipine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Tacrolimus (Systemic). Exceptions: Bepridil. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Chloramphenicol (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose reductions will likely be required with initiation of concurrent chloramphenicol. Monitor tacrolimus concentrations and response closely following initiation and/or discontinuation of chloramphenicol. Consider therapy modification

Cinacalcet: May decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Clotrimazole (Oral): May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Clotrimazole (Topical): May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Colchicine: Tacrolimus (Systemic) may increase the serum concentration of Colchicine. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Corticosteroids (Systemic): May decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase. Monitor therapy

Crizotinib: May increase the serum concentration of Tacrolimus (Systemic). Avoid combination

CycloSPORINE (Systemic): May enhance the nephrotoxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Tacrolimus (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor clinical tacrolimus response closely and frequently monitor tacrolimus serum concentrations with concurrent use of any strong CYP3A4 inhibitor. Tacrolimus dose reductions and/or prolongation of the dosing interval will likely be required. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: May decrease the serum concentration of Tacrolimus (Systemic). Specifically, this decrease in tacrolimus concentrations may occur with continued prolonged combination therapy. Daclatasvir may increase the serum concentration of Tacrolimus (Systemic). Specifically, this increase in tacrolimus concentrations may occur during the first week of combined therapy. Monitor therapy

Danazol: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Dronedarone: Tacrolimus (Systemic) may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase the serum concentration of Tacrolimus (Systemic). Management: Monitor for increased serum tacrolimus concentrations, tacrolimus toxicity, and QTc interval prolongation if combined with dronedarone. Tacrolimus dose adjustments may be needed. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Efavirenz: May decrease the serum concentration of Tacrolimus (Systemic). Management: Closely monitor tacrolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of tacrolimus may be required. Consider therapy modification

Efonidipine: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Enzalutamide: May decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Eplerenone: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Ertapenem: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Erythromycin (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Fenofibrate and Derivatives: Tacrolimus (Systemic) may enhance the nephrotoxic effect of Fenofibrate and Derivatives. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluconazole: May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely and adjust oral tacrolimus dose as necessary when concomitantly administered with fluconazole. Reduced doses of tacrolimus will likely be required. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Avoid combination

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin: May decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Fosphenytoin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Glecaprevir and Pibrentasvir: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Grapefruit Juice: May decrease the metabolism of Tacrolimus (Systemic). Avoid combination

Grazoprevir: May decrease the serum concentration of Tacrolimus (Systemic). Grazoprevir may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Isavuconazonium Sulfate: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Itraconazole: May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely and adjust dose as necessary when concomitantly administered with itraconazole. Tacrolimus dose reductions will likely be required. The magnitude of this interaction may be greater in older patients. Consider therapy modification

Ivacaftor: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required when taken with ketoconazole due to elevated plasma concentrations of tacrolimus. Monitor tacrolimus concentrations and clinical response closely. Consider therapy modification

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Ledipasvir: May decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Letermovir: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

LevoFLOXacin (Systemic): May enhance the QTc-prolonging effect of Tacrolimus (Systemic). LevoFLOXacin (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Metoclopramide: May increase the serum concentration of Tacrolimus (Systemic). Specifically, treatment of gastroparesis may increase tacrolimus concentrations. Monitor therapy

Mifamurtide: Tacrolimus (Systemic) may diminish the therapeutic effect of Mifamurtide. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Tacrolimus (Systemic). MiFEPRIStone may increase the serum concentration of Tacrolimus (Systemic). Management: Avoid tacrolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nelfinavir: May increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Monitor therapy

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: May decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Phenytoin. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Posaconazole: May increase the serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to approximately one-third of original dose when starting posaconazole. Tacrolimus blood concentrations should be monitored closely during and at discontinuation of posaconazole. Consider therapy modification

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Protease Inhibitors: May decrease the metabolism of Tacrolimus (Systemic). Consider therapy modification

Proton Pump Inhibitors: May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H2-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk. Exceptions: Pantoprazole. Consider therapy modification

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Ranolazine: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Tacrolimus (Systemic). Management: Consider alternatives when possible. If these combination are used, monitor for reduced tacrolimus concentrations/effects following rifamycin initiation/dose increase, or increased concentrations/effects following rifamycin discontinuation/dose decrease. Consider therapy modification

Ritonavir: May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose reductions may be needed with concurrent ritonavir. Monitor tacrolimus concentrations closely to determine dose; doses of tacrolimus 0.5 mg to 1 mg every week may be adequate. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Saquinavir: May increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Schisandra: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Serotonin Reuptake Inhibitor/Antagonists: May decrease the metabolism of Tacrolimus (Systemic). Exceptions: TraZODone. Consider therapy modification

Sevelamer: May decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Sirolimus: May enhance the adverse/toxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may enhance the adverse/toxic effect of Sirolimus. Sirolimus may decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Sofosbuvir: May decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

St John's Wort: May decrease the serum concentration of Tacrolimus (Systemic). Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Temsirolimus: Tacrolimus (Systemic) may enhance the adverse/toxic effect of Temsirolimus. Temsirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Temsirolimus may decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Tofisopam: May increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Voriconazole: May increase the serum concentration of Tacrolimus (Systemic). Management: When starting voriconazole in patients already receiving tacrolimus, reduce tacrolimus dose to one-third of the original dose. Monitor tacrolimus blood levels closely. Consider therapy modification

Adverse Reactions

Adverse reactions reported with combination therapy.

>10%:

Cardiovascular: Acute cardiorespiratory failure, angina pectoris, atrial fibrillation, atrial flutter, bradycardia, cardiac arrhythmia, cardiac failure, cardiac fibrillation, chest pain, deep vein thrombophlebitis, deep vein thrombosis, ECG abnormality (including abnormal QRS complex), edema, flushing, hemorrhagic stroke, hypertension, hypotension, orthostatic hypotension, peripheral edema, phlebitis, ST segment changes on ECG, syncope, tachycardia, thrombosis, vasodilation

Central nervous system: Abnormal dreams, abnormality in thinking, agitation, amnesia, anxiety, ataxia, chills, confusion, depression, dizziness, drowsiness, emotional lability, encephalopathy, falling, fatigue, flaccid paralysis, hallucination, headache, hypertonia, hypoesthesia, insomnia, intolerance to temperature, mobility disorder, mood elevation, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, neurotoxicity, nightmares, pain, paralysis (monoparesis, quadriparesis, quadriplegia), paresthesia, peripheral neuropathy, psychomotor disturbance, psychosis, seizure, vertigo, voice disorder, writing difficulty

Dermatologic: Acne vulgaris, alopecia, cellulitis, condyloma acuminatum, dermal ulcer, dermatitis, diaphoresis, ecchymoses, exfoliative dermatitis, fungal dermatitis, hyperhidrosis, hypotrichosis, pityriasis versicolor, pruritus, skin discoloration, skin photosensitivity, skin rash

Endocrine & metabolic: Acidosis, albuminuria, alkalosis, anasarca, cushingoid appearance, Cushing syndrome, decreased serum bicarbonate, decreased serum iron, dehydration, diabetes mellitus (including new-onset), gout, hirsutism, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipidemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased gamma-glutamyl transferase, increased lactate dehydrogenase, metabolic acidosis, weight gain

Gastrointestinal: Abdominal distention, abdominal pain, anorexia, aphthous stomatitis, biliary tract disease, cholangitis, cholestasis, constipation, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal disease, gastrointestinal hemorrhage, gastrointestinal perforation, hernia of abdominal cavity, hiccups, increased appetite, intestinal obstruction, nausea, oral candidiasis, pancreatic pseudocyst, peritonitis, stomatitis, ulcerative esophagitis, vomiting

Genitourinary: Anuria, bladder spasm, cystitis, dysuria, hematuria, nephrotoxicity, nocturia, oliguria, proteinuria, pyuria, toxic nephrosis, urinary frequency, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, vaginitis

Hematologic & oncologic: Anemia, benign skin neoplasm, decreased platelet count, decreased white blood cell count, disorder of hemostatic components of blood, hemolytic anemia, hemorrhage, hypochromic anemia, hypoproteinemia, hypoprothrombinemia, increased hematocrit, Kaposi sarcoma, leukocytosis, leukopenia, neutropenia, polycythemia, thrombocytopenia, thrombotic microangiopathy

Hepatic: Abnormal hepatic function tests, ascites, cholestatic jaundice, granulomatous hepatitis, hepatitis (including acute and chronic), hepatotoxicity, hyperbilirubinemia, increased liver enzymes, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, jaundice

Hypersensitivity: Hypersensitivity reaction

Immunologic: CMV viremia, graft complications

Infection: Abscess, bacterial infection (may be serious), BK virus (including nephropathy), candidiasis, cytomegalovirus disease, Epstein-Barr infection, herpes simplex infection, herpes zoster infection, infection, opportunistic infection, polyomavirus infection, sepsis (children & adolescents), serious infection

Neuromuscular & skeletal: Arthralgia, asthenia, back pain, lower limb cramp, muscle cramps, muscle spasm, myalgia, myasthenia, osteoporosis, tremor

Ophthalmic: Amblyopia, blurred vision, conjunctivitis, visual disturbance

Otic: Otalgia, otitis media, tinnitus

Renal: Acute renal failure, hydronephrosis, increased blood urea nitrogen, increased serum creatinine, renal insufficiency, renal failure syndrome, renal tubular necrosis

Respiratory: Acute respiratory distress syndrome, asthma, atelectasis, bronchitis, decreased lung function, dyspnea, flu-like symptoms, increased cough, nasopharyngitis, pharyngitis, pleural effusion, pneumonia, pneumothorax, productive cough, pulmonary edema, pulmonary emphysema, respiratory tract infection, rhinitis, sinusitis

Miscellaneous: Abnormal healing, accidental injury, crying, fever, postoperative pain, postoperative wound complication, ulcer, wound healing impairment

1% to 10%:

Gastrointestinal: Gastrointestinal infection

Infection: Fungal infection

Respiratory: Upper respiratory tract infection

<1%, postmarketing, and/or case reports: Abnormal T waves on ECG, acute myocardial infarction, agranulocytosis, allergic rhinitis, aphasia, biliary obstruction, blindness, carpal tunnel syndrome, cerebral infarction, colitis, coma, cortical blindness, deafness, decreased serum fibrinogen, delayed gastric emptying, disseminated intravascular coagulation, dysarthria, enterocolitis, Epstein-Barr-associated lymphoproliferative disorder, febrile neutropenia, gastric ulcer, glycosuria, graft versus host disease, hearing loss, hemiparesis, hemolytic-uremic syndrome, hemorrhagic cystitis, hemorrhagic pancreatitis, hepatic cirrhosis, hepatic cytolysis, hepatic failure, hepatic necrosis, hepatic sinusoidal obstruction syndrome, hepatosplenic T-cell lymphomas, hot and cold flashes, hot flash, hyperpigmentation, hypertrophic cardiomyopathy, immune thrombocytopenia, increased amylase, increased INR, inflammatory polyarthropathy, interstitial pulmonary disease, ischemic heart disease, jitteriness, leukemia, leukoencephalopathy, limb pain (including calcineurin-inhibitor induced pain syndrome), liver steatosis, lymphoproliferative disorder, malignant lymphoma, malignant melanoma, mental status changes, multi-organ failure, mutism, necrotizing pancreatitis, optic atrophy, optic neuropathy, oral mucosa ulcer, pancreatitis, pancytopenia, pericardial effusion, photophobia, progressive multifocal leukoencephalopathy, prolonged partial thromboplastin time, prolonged QT interval on ECG, pulmonary hypertension, pulmonary infiltrates, pure red cell aplasia, respiratory distress, respiratory failure, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, speech disturbance, status epilepticus, Stevens-Johnson syndrome, supraventricular extrasystole, supraventricular tachycardia, thrombotic thrombocytopenic purpura, torsades de pointes, toxic epidermal necrolysis, urticaria, ventricular fibrillation, ventricular premature contractions, weight loss

Warnings/Precautions

Concerns related to adverse events:

• Anaphylaxis: Injection: Hypersensitivity reactions, including anaphylaxis, have been reported with tacrolimus injection. Tacrolimus injection contains polyoxyl 60 hydrogenated castor oil (HCO-60), a castor oil derivative. HCO-60 is a solubilizer similar to polyoxyethylated castor oil (also known as polyoxyl 35 castor oil or Cremophor EL); polyoxyethylated castor oil is associated with hypersensitivity reactions (Nicolai 2012). Tacrolimus intravenous (IV) use should be limited to patients unable to take oral capsules. Monitor patient for a minimum of 30 minutes after initiation of infusion and then at frequent intervals; discontinue infusion if anaphylaxis occurs. Patients should be transitioned from IV to oral tacrolimus as soon as the patient can tolerate oral administration.
• Cardiovascular: Myocardial hypertrophy has been reported; may be reversible with dose reduction or discontinuation. Prolongation of the QT/QTc and torsade de pointes may occur; avoid use in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia.
• Diabetes mellitus (post-transplant): The risk for new-onset diabetes and insulin-dependent post-transplant diabetes mellitus (PTDM) is increased with tacrolimus use after transplantation, including in patients without pretransplant history of diabetes mellitus. Insulin dependence may be reversible. Monitor blood glucose frequently. Risk is increased in African-American and Hispanic kidney transplant patients.
• Gastrointestinal perforation: Gastrointestinal perforation may occur; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm.
• Hyperkalemia: Mild-to-severe hyperkalemia may occur; monitor serum potassium levels and avoid use of potassium-sparing diuretics.
• Hypertension: Hypertension may commonly occur; antihypertensive treatment may be necessary; avoid use of potassium-sparing diuretics due to risk of hyperkalemia. Concurrent use of calcium channel blockers may require tacrolimus dosage adjustment.
• Infections: [US Boxed Warning]: Immunosuppressant agents, including tacrolimus, increase the risk of infection that may lead to hospitalization or death; the risk of developing bacterial, viral (including CMV), fungal, and protozoal infections, including opportunistic infections, is increased. Latent viral infections may be activated, including BK virus (associated with polyoma virus-associated nephropathy [PVAN]) and JC virus (associated with progressive multifocal leukoencephalopathy [PML]); may result in serious adverse effects. Immunosuppression increases the risk for CMV viremia and/or CMV disease; the risk of CMV disease is increased for patients who are CMV-seronegative prior to transplant and receive a graft from a CMV-seropositive donor. Monitor for development of infection; consider reduction in immunosuppression if PVAN, PML, CMV viremia and/or CMV disease occurs.
• Malignancy: [US Boxed Warning]: Immunosuppressant agents, including tacrolimus, may be associated with the development of malignancies that may lead to hospitalization or death, including lymphoma and other malignancies (predominantly skin malignancies). The risk for malignancies is related to intensity/duration of therapy. Limit or avoid sun and ultraviolet light exposure; use appropriate sun protection. Post-transplant lymphoproliferative disorder related to EBV infection has been reported in immunosuppressed organ transplant patients; risk highest in EBV seronegative patients, which includes many young children; use combination immunosuppressant therapy with caution.
• Nephrotoxicity: Nephrotoxicity (acute or chronic) may occur when used in high doses, in patients with impaired renal function, with other nephrotoxic drugs (eg, sirolimus, cyclosporine), or when administered concomitantly with CYP3A inhibitors (due to increased tacrolimus concentrations). Monitor renal function and consider dosage reduction if nephrotoxicity occurs.
• Neurotoxicity: Neurotoxicity may occur especially when used in high doses; tremor, headache, coma, and delirium have been reported and are associated with serum concentrations. Seizures may also occur. Posterior reversible encephalopathy syndrome (PRES) has been reported; symptoms (altered mental status, headache, hypertension, seizures, and visual disturbances) are reversible with dose reduction or discontinuation of therapy; stabilize blood pressure and reduce dose with suspected or confirmed PRES diagnosis.
• Pure red cell aplasia (PRCA): PRCA has been reported in patients receiving tacrolimus. Use with caution in patients with risk factors for PRCA including parvovirus B19 infection, underlying disease, or use of concomitant medications associated with PRCA (eg, mycophenolate). Discontinuation of therapy should be considered with diagnosis of PRCA.

Disease-related concerns:

• Hepatic impairment: Use with caution; utilize lowest recommended IV or oral dose; additional dose reductions may be necessary; severe hepatic impairment (Child-Pugh score ≥10) may require decreased dose.
• Renal impairment: Due to potential for further nephrotoxicity, utilize lowest recommended IV or oral dose; additional dose reductions may be necessary. Delay initiation of therapy in kidney transplant patients if postoperative oliguria occurs.

Concurrent drug therapy:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Concomitant use with strong CYP3A inducers and/or inhibitors may alter tacrolimus whole blood concentrations, potentially leading to rejection and/or increased toxicity, respectively. Monitor tacrolimus whole blood trough concentrations closely.
• Everolimus combination therapy: In liver transplantation, the tacrolimus dose and target range should be reduced to minimize the risk of nephrotoxicity when used in combination with everolimus.
• Sirolimus combination therapy: Extended release tacrolimus in combination with sirolimus is not recommended in renal transplant patients; the safety and efficacy of immediate release tacrolimus in combination with sirolimus has not been established in this patient population. Concomitant use was associated with increased mortality, graft loss, and hepatic artery thrombosis in liver transplant patients, as well as increased risk of renal impairment, wound healing complications, and PTDM in heart transplant recipients.

Dosage form specific issues:

• Extended release: [US Boxed Warning]: Astagraf XL was associated with increased mortality in female liver transplant recipients; the use of extended release tacrolimus is not approved for use in liver transplantation. Mortality at 12 months was 10% higher in females who received extended release tacrolimus compared to females who received regular release tacrolimus.
• Injection: Each mL of injection contains polyoxyl 60 hydrogenated castor oil (HCO-60) (200 mg) and dehydrated alcohol USP 80% v/v. Anaphylaxis has been reported with the injection, use should be reserved for those patients not able to take oral medications.
• Lactose: Oral formulations contain lactose.

Other warnings/precautions:

• Discontinuation of therapy: Myasthenia gravis: Abrupt cessation of this or any immunosuppressant, especially in clinically unstable individuals, may result in rapid deterioration of myasthenic symptoms and possibly myasthenic crisis (Melzer 2016).
• Error prevention: Immediate release and extended release capsules are NOT interchangeable or substitutable. The extended release formulation is a once-daily preparation; and immediate release formulation is intended for twice-daily administration. Serious adverse events, including organ rejection, may occur if inadvertently substituted.
• Experienced physician: Should be administered under the supervision of a physician experienced in immunosuppressive therapy and organ transplantation in a facility appropriate for monitoring and managing therapy.
• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Patients should not be immunized with live vaccines during or shortly after treatment and should avoid close contact with recently vaccinated (live vaccine) individuals. Inactivated vaccines may be administered (response may be diminished).
• Monitoring of concentrations: Closely monitor tacrolimus levels to assist in dose adjustment, monitor compliance, prevent organ rejection, and reduce drug-related toxicity.

Monitoring Parameters

Renal function, hepatic function, serum electrolytes (magnesium, phosphorus, potassium), glucose and blood pressure, measure 3 times/week for first few weeks, then gradually decrease frequency as patient stabilizes. Signs/symptoms of anaphylactic reactions during IV infusion should also be monitored. Patients should be monitored for hypersensitivity during the first 30 minutes of the infusion, and frequently thereafter. Monitor for QT prolongation; consider echocardiographic evaluation in patients who develop renal failure, electrolyte abnormalities, or clinical manifestations of ventricular dysfunction.

Whole blood concentrations should be used for monitoring (trough for oral therapy drawn typically within 30 minutes prior to the next dose); frequency varies depending on transplant type, time since transplantation, and clinical situation. Tacrolimus serum levels may be falsely elevated in infected liver transplant patients due to interference from beta-galactosidase antibodies.

Pregnancy

Pregnancy Considerations

Tacrolimus crosses the human placenta and is measurable in the cord blood, amniotic fluid, and newborn serum. Tacrolimus concentrations in the placenta may be higher than the maternal serum (Jain 1997). Infants with lower birth weights have been found to have higher tacrolimus concentrations (Bramham 2013).

Miscarriage, preterm delivery, low birth weight, birth defects (including cardiac, craniofacial, neurologic, renal/urogenital, and skeletal abnormalities), renal dysfunction, transient neonatal hyperkalemia, and fetal distress have been reported following in utero exposure to tacrolimus in infants of organ transplant recipients. However, mothers were also taking a concomitant medication known to cause adverse pregnancy outcomes.

Tacrolimus pharmacokinetics are altered during pregnancy. Whole blood concentrations decrease as pregnancy progresses; however, unbound concentrations increase. Measuring unbound concentrations may be preferred, especially in females with anemia or hypoalbuminemia. If unbound concentration measurement is not available, interpretation of whole blood concentrations should account for RBC count and serum albumin concentration (Hebert 2013; Zheng 2012).

Tacrolimus may be used as an immunosuppressant during pregnancy. The risk of infection, hypertension, and pre-eclampsia may be increased in pregnant females who have had a kidney transplant (EBPG 2002). Hypertension and diabetes during pregnancy have been reported in both kidney and liver transplant patients receiving tacrolimus.

Family planning and contraceptive options for males and females of reproductive potential should be evaluated prior to starting treatment.

The Transplant Pregnancy Registry International (TPRI) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPRI encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Patient Education

What is this drug used for?

• It is used to keep the body from harming the organ after an organ transplant.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue
• Stuffy nose
• Abdominal pain
• Sore throat
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Heartburn
• Lack of appetite
• Trouble sleeping
• Back pain
• Joint pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
• Infection
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Skin sores
• Abnormal heartbeat
• Chest pain
• Shortness of breath
• Severe dizziness
• Passing out
• Vision changes
• Tremors
• Difficulty moving
• Severe headache
• Bruising
• Bleeding
• Swelling of arms or legs
• Burning or numbness feeling
• Mole changes
• Skin growths
• Skin changes
• Swollen glands
• Night sweats
• Excessive weight gain
• Weight loss
• Pale skin
• Severe loss of strength and energy
• Vomiting blood
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes
• Black, tarry, or bloody stools
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.