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Tacrolimus (Systemic)

Pronunciation

Pronunciation

(ta KROE li mus)

Index Terms

  • FK506

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Hecoria: 0.5 mg [DSC], 1 mg [DSC], 5 mg [DSC]

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

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

Brand Names: U.S.

  • Astagraf XL
  • Envarsus XR
  • Hecoria [DSC]
  • Prograf

Pharmacologic Category

  • Calcineurin Inhibitor
  • Immunosuppressant Agent

Pharmacology

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

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.

Distribution

Distributes to erythrocytes, lung, kidneys, pancreas, liver, heart, and spleen; Vd: Children: 2.6 L/kg (mean) ; Adults: 0.85 to 1.41 L/kg (mean) 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: 7.7 to 15.3 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

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

Protein Binding

~99% primarily to albumin and alpha1-acid glycoprotein

Special Populations: Hepatic Function Impairment

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

Special Populations: Race

Cmax is lower, Tmax is prolonged, and bioavailability is increased in kidney transplant patients who are black.

Use: Labeled Indications

Organ rejection prophylaxis:

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

Envarsus XR: Prevention of organ rejection in kidney transplant recipients converted from tacrolimus immediate-release formulation, in combination with other immunosuppressants.

Hecoria and Prograf: Prevention of organ rejection in heart, kidney, and liver transplant recipients

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

Off Label Uses

Graft-versus-host disease (prevention/treatment)

Data from a retrospective study in patients, including pediatric 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]. Additionally, another retrospective study in pediatric allogeneic marrow transplantation demonstrated that tacrolimus was well-tolerated in pediatric patients undergoing allogeneic marrow transplantation. 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 transplant

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 transplant

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.

Rheumatoid arthritis (refractory)

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]. Additional trials may be necessary to further define the role of tacrolimus in the treatment of this condition.

Uveitis

Results from controlled and noncontrolled studies demonstrate that tacrolimus is generally effective in treating uveitis. However, limited prospective studies or controlled clinical trials have been performed. Further data are needed to establish the efficacy, safety, optimal dosage, and length of tacrolimus therapy for the treatment of uveitis in adults. An expert review panel recommends tacrolimus as third-line therapy for the treatment of uveitis in adults.

Contraindications

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

Dosing: Adult

Note: Hecoria has been discontinued in the US for more than 1 year.

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 immediate release 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 should 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 (titrate to target trough concentrations), consider lower dose in liver transplant recipients with graft dysfunction.

Extended release: 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 (Advagraf Canadian product labeling 2015). 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 immediate release tacrolimus may be converted to extended release by initiating extended-release treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate-release 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 or mycophenolate mofetil) is recommended. 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 is recommended. Note: African-American patients may require larger doses to attain trough concentration.

Oral:

Immediate release (Hecoria, 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)

Without basiliximab induction: Postoperative dosing (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, Envarsus XR): Administer the first oral extended release dose 8 to 12 hours after discontinuation of IV tacrolimus

Conversion from immediate release to extended release (Advagraf [Canadian product], Astagraf XL): Initiate extended release 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.

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

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

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

Prevention:

Oral: Convert from IV to immediate release 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 extended-release 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 immediate-release tacrolimus although clinical trial data is 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).

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: Hecoria has been discontinued in the US for more than 1 year.

Liver transplant:

Oral: Immediate release: Initial: 0.15 to 0.20 mg/kg/day in 2 divided doses, given every 12 hours (titrate to target trough concentrations)

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

Note: The initial postoperative dose of tacrolimus should begin no sooner than 6 hours after liver and heart transplant and within 24 hours of kidney transplant (but may be delayed until renal function has recovered). Adjunctive therapy with 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 8-12 hours after stopping the infusion. Patients without pre-existing renal or hepatic dysfunction have required (and tolerated) higher doses than adults to achieve similar blood concentrations. It is recommended that therapy be initiated at the high end of the recommended adult IV and oral dosing ranges; dosage adjustments may be required.

Prevention of graft-vs-host disease (GVHD) (off-label use): Oral, IV: Refer to adult dosing.

Dosing: Renal Impairment

Renal impairment does not affect the elimination or serum concentrations of tacrolimus; however, tacrolimus may cause nephrotoxicity requiring dose reduction. Evidence suggests that lower doses should be used; patients should receive doses at the lowest amount of the recommended IV and oral dosing ranges; further reductions in dose below these ranges may be required.

Hemodialysis: Not removed by hemodialysis; supplemental dose is not necessary.

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.

Dosing: Hepatic Impairment

Use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood levels of tacrolimus. The presence of moderate-to-severe hepatic dysfunction (serum bilirubin >2 mg/dL; Child-Pugh score ≥10) appears to affect the metabolism of tacrolimus. The half-life of the drug was prolonged and the clearance reduced after IV administration. The bioavailability of tacrolimus was also increased after oral administration. The higher plasma concentrations as determined by ELISA, in patients with severe hepatic dysfunction are probably due to the accumulation of metabolites of lower activity. These patients should be monitored closely and dosage adjustments should be considered. Some evidence indicates that lower doses could be used in these patients.

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

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).

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):781-4.16518428Esquivel C, So S, McDiarmid S, Andrews W, and Colombani PM, “Suggested Guidelines for the Use of Tacrolimus in Pediatric Liver Transplant Patients,” Transplantation, 1996, 61(5):847-8. 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 suggests that the larger dose should be given in the evening since tacrolimus exposure may be reduced in the evening (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.

Extended release: For all US preparations, 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 immediate release 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 immediate release capsules is not equivalent to dosing of Envarsus XR. When switching from Envarsus XR to immediate release capsules for nasogastric administration, consider administering a 20% to 30% higher total daily dose of immediate release tacrolimus.

Sublingual: If unable to swallow capsules, tacrolimus may be administered sublingually (at a reduced dose) by opening the immediate-release 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

Capsule: 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.

Compatibility

See Trissel’s IV Compatibility Database

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 since the polyoxyl 60 hydrogenated castor oil injectable vehicle may leach phthalates from polyvinyl chloride containers.

Capsule, tablet:

Astagraf XL, Envarsus XR, Prograf: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Hecoria: Store at 20°C to 25°C (68°F to 77°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

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

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

Boceprevir: May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus doses will need to be substantially reduced, and the tacrolimus dosing interval will likely need to be prolonged with concurrent boceprevir. Follow tacrolimus concentrations closely and monitor patients for evidence of tacrolimus toxicity. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. 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

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

Chloramphenicol: 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

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. 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. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

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. Monitor therapy

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

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. Avoid combination

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

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. 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

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

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

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

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. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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. 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. 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

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). Avoid combination

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

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

Telaprevir: May increase the serum concentration of Tacrolimus (Systemic). Management: Significant tacrolimus dose reductions are likely to be required if used with telaprevir. Concurrent use should be performed with great caution and close monitoring of both tacrolimus concentrations and clinical response. Consider therapy modification

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. 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. Avoid combination

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

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

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. 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

>10%:

Cardiovascular: Angina pectoris, atrial fibrillation, atrial flutter, bradycardia, cardiac arrhythmia, cardiac failure, cerebral infarction, cerebral ischemia, chest pain, deep vein thrombophlebitis, deep vein thrombosis, ECG abnormality (QRS or ST segment or T wave), edema, flushing, hemorrhagic stroke, hypertension, hypertrophic cardiomyopathy, hypotension, ischemic heart disease, localized phlebitis, myocardial infarction, orthostatic hypotension, pericardial effusion, peripheral edema, peripheral vascular disease, phlebitis, syncope, tachycardia, thrombosis, vasodilatation, ventricular premature contractions

Central nervous system: Abnormal dreams, abnormality in thinking, agitation, amnesia, anxiety, aphasia, ataxia, brain disease, carpal tunnel syndrome, chills, confusion, depression, dizziness, drowsiness, emotional lability, excessive crying, falling, fatigue, flaccid paralysis, hallucination, headache, hypertonia, hypoesthesia, insomnia, mental status changes, mood elevation, myasthenia, myoclonus, nervousness, neuropathy (including compression), neurotoxicity, nightmares, pain, paresis, paresthesia, peripheral neuropathy, psychosis, seizure, vertigo, voice disorder, writing difficulty

Dermatologic: Acne vulgaris, alopecia, cellulitis, condyloma acuminatum, dermal ulcer, dermatitis (including fungal), dermatological reaction, diaphoresis, exfoliative dermatitis, pruritus, skin discoloration, skin photosensitivity, skin rash, tinea versicolor

Endocrine & metabolic: Acidosis, albuminuria, alkalosis, anasarca, Cushing's syndrome, decreased serum bicarbonate, decreased serum iron, dehydration, diabetes mellitus, gout, hirsutism, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperphosphatemia, hypertriglyceridemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased gamma-glutamyl transferase, increased lactate dehydrogenase, weight changes

Gastrointestinal: Abdominal pain, anorexia, dyspepsia, aphthous stomatitis, cholangitis, colitis, constipation, delayed gastric emptying, diarrhea, duodenitis, dysphagia, enlargement of abdomen, esophagitis (including ulcerative), flatulence, gastric ulcer, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal perforation, hernia, hiccups, increased appetite, intestinal obstruction, nausea, oral candidiasis, pancreatic disease (pseudocyst), pancreatitis (including hemorrhagic and necrotizing), peritonitis, rectal disease, stomach cramps, stomatitis, vomiting

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

Hematologic & oncologic: Anemia, blood coagulation disorder, bruise, decreased prothrombin time, hemolytic anemia, hemorrhage, hypochromic anemia, hypoproteinemia, increased hematocrit, increased INR, Kaposi’s sarcoma, leukocytosis, leukopenia, malignant neoplasm of bladder, malignant neoplasm of thyroid (papillary), neutropenia, pancytopenia, polycythemia, skin neoplasm, thrombocytopenia

Hepatic: Abnormal hepatic function tests, ascites, cholestatic jaundice, hepatic injury, hepatitis (including acute, chronic, and granulomatous), hyperbilirubinemia, increased serum alkaline phosphatase, jaundice

Hypersensitivity: Hypersensitivity reaction

Immunologic: Graft complications

Infection: Abscess, infection, sepsis

Neuromuscular & skeletal: Arthralgia, arthropathy, back pain, leg cramps, muscle spasm, muscle weakness of the extremities, myalgia, osteoporosis, tremor, weakness

Ophthalmic: Amblyopia, blurred vision, conjunctivitis, visual disturbance

Otic: Hearing loss, otalgia, otitis externa, otitis media, tinnitus

Renal: Acute renal failure, hydronephrosis, increased blood urea nitrogen, increased serum creatinine, renal disease (BK nephropathy), renal function abnormality, renal tubular necrosis

Respiratory: Allergic rhinitis, asthma, atelectasis, cough, flu-like symptoms, pleural effusion, pneumothorax, pulmonary edema, respiratory tract infection

Miscellaneous: Fever, postoperative pain, postoperative wound complication, wound healing impairment

1% to 10%: Gastrointestinal: Gastroenteritis (2% to 7%)

<1% (Limited to important or life-threatening): Adult respiratory distress syndrome, agranulocytosis, anaphylactoid reaction, anaphylaxis, angioedema, basal cell carcinoma, biliary tract disease (stenosis), blindness, cerebrovascular accident, coma, deafness, decreased serum fibrinogen, delirium, disseminated intravascular coagulation, dysarthria, graft versus host disease (acute and chronic), hemiparesis, hemolytic-uremic syndrome, hemorrhagic cystitis, hepatic cirrhosis, hepatic failure, hepatic necrosis, hepatic veno-occlusive disease, hepatosplenic T-cell lymphomas, hepatotoxicity, hyperpigmentation, immune thrombocytopenia, interstitial pulmonary disease, leukemia, leukoencephalopathy, liver steatosis, lymphoproliferative disorder (post-transplant or related to Epstein-Barr virus), malignant lymphoma, malignant melanoma, multi-organ failure, mutism, optic atrophy, osteomyelitis, photophobia, polyarthritis, progressive multifocal leukoencephalopathy (PML), prolonged partial thromboplastin time, prolonged Q-T interval on ECG, pulmonary hypertension, pure red cell aplasia, quadriplegia, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, septicemia, squamous cell carcinoma, status epilepticus, Stevens-Johnson syndrome, supraventricular extrasystole, supraventricular tachycardia, thrombotic thrombocytopenic purpura, torsades de pointes, toxic epidermal necrolysis, urticaria, venous thrombosis, ventricular fibrillation

ALERT: U.S. Boxed Warning

Malignancies and serious infection:

Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression and may lead to hospitalization or death.

Experienced physician:

Only health care providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Mortality in liver transplantation (Astagraf XL):

Increased mortality in female transplant patients with Astagraf XL. Astagraf XL is not approved for use in liver transplantation.

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; the risk of developing bacterial, viral (including CMV), fungal, and protozoal infections, including opportunistic infections, is increased. Infections may result in serious and fatal outcomes. 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 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 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; begin therapy no sooner than 6 hours and within 24 hours post-transplant, but may be delayed until renal function has recovered.

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.

Other warnings/precautions:

• 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: [US Boxed Warning]: 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).

• Lactose intolerance: Oral formulations contain lactose; the Canadian labeling does not recommend use of these products in patients who may be lactose intolerant (eg, Lapp lactase deficiency, glucose-galactose malabsorption, galactose intolerance).

• 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 Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. 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). Transient neonatal hyperkalemia and renal dysfunction have been reported.

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 women 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).

In general, women who have had a kidney transplant should be instructed that fertility will be restored following the transplant but that pregnancy should be avoided for ~2 years. Tacrolimus may be used as an immunosuppressant during pregnancy. The risk of infection, hypertension, and pre-eclampsia may be increased in pregnant women who have had a kidney transplant (EPBG 2002).

The National Transplantation Pregnancy Registry (NTPR) is a registry which follows pregnancies which occur in maternal transplant recipients or those fathered by male transplant recipients. The NTPR encourages reporting of pregnancies following solid organ transplant by contacting them at 877-955-6877 or NTPR@giftoflifeinstitute.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinitis, pharyngitis, nausea, vomiting, diarrhea, constipation, heartburn, lack of appetite, insomnia, back pain, or joint pain. Have patient report immediately to prescriber signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of infection, signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling), abnormal heartbeat, angina, 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, weight gain, weight loss, pale skin, severe loss of strength and energy, severe abdominal pain, or signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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