Version October 2024
Increased risk for developing serious infections and malignancies with tacrolimus or other immunosuppressants that may lead to hospitalization or death.
Increased mortality in female transplant patients with Astagraf XL. Astagraf XL is not approved for use in liver transplantation.
Dosage guidance:
Dosage form information: 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) or with each other due to significantly different pharmacokinetic properties.
Clinical considerations: Younger children generally require higher maintenance doses on a mg/kg basis than older children, adolescents, or adults (Ref). Adjust initial dose to achieve desired target tacrolimus concentration; consult institutional-specific protocols.
Graft-versus-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 (Ref).
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 (Ref).
Nephrotic syndrome, steroid-resistant or steroid-dependent: Limited data available: Children and Adolescents: Oral: Immediate release: Initial: 0.1 to 0.2 mg/kg/day in divided doses every 12 hours; maximum initial dose: 4 to 5 mg/dose; adjust dose to target serum concentration (Ref).
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 (Ref); 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 (Ref). 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: Note: Although manufacturer labeling suggests delaying tacrolimus initiation until renal function has recovered, current practice and expert recommendations are to initiate tacrolimus before or at the time of transplant (Ref).
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 (Ref).
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 immediate release to extended release (Astagraf XL): Children ≥5 years and Adolescents: Oral: Initiate extended-release treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate release (Ref). Administer once daily. Note: If converting from IV tacrolimus, administer the first extended-release dose 8 to 12 hours after discontinuation of IV (Ref).
Envarsus XR:
Conversion from immediate release to extended release (Envarsus XR): Very limited data: Adolescents: Oral: Administer 60% to 80% of the total daily dose of immediate-release tacrolimus. Titrate to target trough concentrations (Ref).
IV: Limited data available: Infants, Children, and Adolescents: 0.06 mg/kg/day as a continuous IV infusion (Ref). 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).
Transplant, lung; prevention of rejection:
Infants, Children, and Adolescents:
Oral: Immediate release: Initial: 0.3 mg/kg/day divided every 12 hours; if antibody induction treatment administered, reduce dose to 0.1 mg/kg/day. Patients with lung transplant secondary to cystic fibrosis may require higher doses due to reduced bioavailability.
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 (Ref).
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 (Ref).
Note: Dose adjustment should be guided by therapeutic drug monitoring.
Kidney impairment prior to treatment initiation: IV, Oral: Infants, Children, and Adolescents:
Altered kidney function: Initiate with lower end of dosing range. Kidney impairment does not affect the elimination or serum concentrations of tacrolimus; however, tacrolimus may cause nephrotoxicity requiring dose reduction.
Hemodialysis: Unlikely to be significantly dialyzed; no initial dosage adjustment has been recommended.
Peritoneal dialysis: Based on adult data, tacrolimus is not removed by peritoneal dialysis (Ref).
CRRT: IV, Oral: Significant drug removal is unlikely based on adult studies (Ref).
Nephrotoxicity during treatment: Treatment decisions should be individualized and in consultation with nephrology and/or transplant specialists.
Mild impairment:
Immediate-release tacrolimus: Infants, Children, and Adolescents: IV, Oral: There are no dosage recommendations in the manufacturer's labeling.
Astagraf XL: Children ≥5 years and Adolescents: Oral: No dose adjustment necessary.
Moderate impairment:
Immediate-release tacrolimus: Infants, Children, and Adolescents: IV, Oral: There are no dosage recommendations in the manufacturer's labeling.
Astagraf XL: Children ≥5 years and Adolescents: Oral: Monitor levels closely.
Severe impairment:
Immediate-release tacrolimus: Infants, Children, and Adolescents: IV, Oral: There are no dosage recommendations provided in the manufacturer's labeling; however, clearance is decreased in severe impairment; close monitoring is recommended.
Astagraf XL: Children ≥5 years and Adolescents: Oral: Lower initial dose recommended due to decreased clearance.
Liver transplant: Use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing kidney insufficiency related to high whole blood levels of tacrolimus; monitor closely and adjust dosing as needed.
(For additional information see "Tacrolimus (systemic): Drug information")
Dosage guidance:
Dosage form information: 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. Patients should be transitioned from IV to oral tacrolimus as soon as able to tolerate oral administration.
Graft-versus-host disease (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 (Ref).
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 (Ref).
Treatment:
Oral: Immediate release: 0.06 mg/kg twice daily (Ref).
IV: Initial: 0.03 mg/kg/day (based on lean body weight) as continuous infusion (Ref).
Myasthenia gravis, chronic immunosuppressive therapy (alternative agent) (off-label use):
Note: For use as monotherapy or in combination with glucocorticoids in patients with glucocorticoid-resistant or glucocorticoid-dependent disease (Ref).
Immediate release: Oral: Initial: 3 to 5 mg/day or 0.1 mg/kg/day, in 1 or 2 divided doses; titrate to achieve target trough concentrations. Maximum dose is not established. Onset of clinical response to tacrolimus may take up to 6 to 12 months (Ref).
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 based on donor/recipient factors and institutional protocols. Lower oral doses may be sufficient for maintenance therapy. Adjunctive therapy with other immunosuppressants, including but not limited to corticosteroids, is recommended early post-transplant. The 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 (off-label route) may be considered in those unable to take oral.
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) (Ref).
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 10% to 33% of the total oral daily dose as a continuous infusion over 24 hours or divided twice daily as an intermittent infusion over 4 hours (Ref).
Kidney transplant: Use in combination with azathioprine or mycophenolate mofetil. Note: In African American patients, larger doses may be required to attain target trough concentrations.
Oral:
Immediate release (Prograf): Initial: 0.1 mg/kg twice daily every 12 hours in combination with azathioprine or 0.05 mg/kg twice daily every 12 hours in combination with mycophenolate mofetil; titrate to target trough concentrations.
Conversion from immediate release oral to IV: Administer one-third (1/3rd) of the total daily 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 (Ref). 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.
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.
Lung transplant: Use in combination with an antimetabolite agent (eg, azathioprine, mycophenolate mofetil). Adjunct corticosteroid therapy is recommended in the early postoperative period.
Oral: Immediate release: Initial: 0.075 mg/kg/day in 2 divided doses, administered every 12 hours (titrate to target trough concentrations). Note: Patients with cystic fibrosis may require higher oral doses due to lower bioavailability (monitor trough concentrations and adjust dose accordingly).
IV: Initial: 0.01 to 0.03 mg/kg/day as a continuous infusion.
Off-label dosing:
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 (Ref). May also be administered sublingually at ~50% of the oral/NG dose (Ref).
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 ER 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 (Ref). For patients receiving the initial dose of tacrolimus IV, may begin immediately after transplantation, or up to 2 days postoperatively depending on renal function and hemodynamic stability (Ref). When patient is able to take oral medication, may switch to an oral maintenance regimen (typically transitioned after extubation).
Pancreas transplant (off-label use): Oral, nasogastric: Immediate release: 0.1 mg/kg twice daily; titrate to target trough concentrations (Ref). May also be administered sublingually at ~50% of the oral/NG dose (Ref).
Immunosuppression after solid-organ transplant, sublingual administration: Immediate release: Sublingual (off-label route): 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 (Ref). 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 (Ref). Adjust dose based on serum trough concentrations. Lower doses of sublingual tacrolimus may be required during coadministration of drugs that inhibit tacrolimus metabolism (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Dose adjustment should be guided by therapeutic drug monitoring (Ref).
Kidney impairment prior to treatment initiation:
Note: Avoid concurrent nephrotoxins, consider more frequent therapeutic drug monitoring especially in patients receiving drugs that affect tacrolimus metabolism, and consider targeting the lower end of the therapeutic range to minimize the risk of acute and/or chronic nephrotoxicity with tacrolimus therapy (Ref).
Altered kidney function: IV, Oral: No initial dose adjustment necessary for any degree of kidney dysfunction (Ref).
Hemodialysis, intermittent (thrice weekly): IV, Oral: Unlikely to be significantly dialyzed (Ref): No initial dosage adjustment necessary (Ref).
Peritoneal dialysis: IV, Oral: Not removed by peritoneal dialysis (Ref): No initial dosage adjustment necessary (Ref).
CRRT: IV, Oral: No initial dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): IV, Oral: No initial dosage adjustment necessary (Ref).
Nephrotoxicity during treatment: Treatment decisions should be individualized and in consultation with nephrology and/or transplant specialists.
Severe impairment (Child-Pugh class C ): Lower initial doses may be required (due to reduced clearance and increased half-life); closely monitor tacrolimus blood concentrations.
Liver transplant recipients: 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. Monitor closely and consider dosage adjustment; some evidence suggests utilizing lower initial doses.
In general, there is an increased risk for the development of diabetes mellitus following transplantation (also known as post-transplant diabetes mellitus [PTDM]) (Ref). The cause of PTDM is multifactorial, of which one modifiable risk factor is the use of calcineurin inhibitors (CNI) (eg, cyclosporine, tacrolimus) (Ref). When compared to cyclosporine, tacrolimus may have a higher incidence of new-onset diabetes and/or impaired fasting glucose (Ref); however dosing strategies employed in early trials comparing the two CNIs may not reflect contemporary practice (ie, CNI-minimization or avoidance strategies) (Ref). While the impact of CNIs on pancreatic beta cells may be reversible (Ref), the risk of graft rejection must be considered when adjusting immunosuppressants in transplant recipients (Ref). Clinicians should note that PTDM is different than the hyperglycemia that is often seen in first few weeks following transplant.
Mechanism: Time-related; exact mechanism has not been fully elucidated. Potential mechanisms include beta cell dysfunction and increased insulin resistance (Ref). Clinicians should note that the cause of PTDM is multifactorial; the use of a CNI is one factor.
Onset: Varied; PTDM may develop early (ie, ≤3 months) or years after transplantation (Ref).
Risk factors:
• Presence of other risk factors for type 2 diabetes
• High trough tacrolimus concentrations (eg, >15 ng/mL during the first month after transplantation) (Ref)
• Black or Hispanic kidney transplant recipients
• Hepatitis C virus infection (Ref)
Tacrolimus use for solid organ and hematopoietic stem cell transplantation may cause drug-induced thrombotic microangiopathy (DITMA) which can result in microangiopathic hemolytic anemia with thrombocytopenia (MAHA), microvascular thrombosis with vessel wall abnormalities (Ref). Patients generally present with kidney impairment and hypertension (Ref); however, other organ systems may also be impacted by tacrolimus-related DITMA (eg, pulmonary, dermatologic, musculoskeletal, hepatic, gastrointestinal) (Ref). Cases of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported. Graft failure may or may not occur (Ref). Resolution may occur with early detection of the syndrome, discontinuation or dose reduction, and initiation of syndrome-specific supportive treatment; however, kidney impairment may persist (Ref).
Mechanism: Dose- and time-dependent; secondary to endothelial dysfunction and increased platelet aggregation (Ref).
Onset: Varied; characterized by a gradual onset of kidney failure that occurs over weeks or months (Ref).
Risk factors:
• In general, risk factors for thrombotic microangiopathy include (Ref):
- Ischemia-reperfusion endothelial injury
- Severe infections
- Kidney infections
- Vascular rejection or graft-versus-host disease
- Human leukocyte antigen mismatch
- Anticardiolipin antibodies
- Malignancies
- Concurrent drugs known to cause DITMA (eg, mTOR inhibitors, antiviral agents)
Mild to severe hyperkalemia may occur in patients who receive a calcineurin inhibitor (CNI), including tacrolimus; one retrospective trial described more severe as well as a longer duration of hyperkalemia in patients treated with tacrolimus as compared to patients who received cyclosporin (Ref). CNI-induced hyperkalemia is commonly associated with hypertension, hyperchloremia, metabolic acidosis, and hypercalciuria (Ref).
Mechanism: Dose-related; CNIs may cause a hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis) which is a result of tubular insensitivity to aldosterone and a subsequent decrease in the activity of the renin-angiotensin-aldosterone system (Ref). In addition, CNIs directly impact the ability to excrete potassium, in part via inhibition of the renal outer medullary potassium (ROMK) channel and Na+/K+-ATPase and activation of the chloride shunt mechanism (Ref). Consideration should also be made for the impact of kidney transplantation (eg, delayed graft function) and concomitant drugs (eg, trimethoprim) on potassium balance (Ref).
Onset: Varied; may occur soon after transplant or later during the course of therapy (Ref)
Risk factors:
• Concurrent use of other drugs that may cause hyperkalemia (eg, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, trimethoprim/sulfamethoxazole)
Immediate hypersensitivity reactions, including anaphylaxis, have been reported (Ref). Delayed hypersensitivity reactions, including generalized pruritus, eczematous drug eruption, symmetric drug-related intertriginous and flexural exanthema, and contact urticaria following topical application have also been reported (Ref). In addition, use of systemic tacrolimus in post-transplant recipients has been associated with a greater occurrence of IgE-mediated sensitization and possible increased risk of allergic disease, including food allergies (Ref).
Mechanism:
Immediate hypersensitivity reactions: Non–dose-related; likely related to polyoxyl 60 hydrogenated castor oil, a solubilizer contained in IV tacrolimus (Ref).
Delayed hypersensitivity reactions: Non–dose-related; immunologic (ie, involving a T-cell mediated drug-specific immune response) (Ref).
Onset:
Immediate hypersensitivity reactions: Rapid; generally occur within 1 hour of administration (Ref).
Delayed hypersensitivity reactions: Varied; contact urticaria has occurred after 2 days of topical tacrolimus application (Ref), and generalized rashes have been documented up to 30 months after initiation of treatment (Ref). New food allergies in post-transplant recipients who are treated with tacrolimus may occur after many months of therapy (Ref).
Risk factors:
• Greater IgE-mediated sensitization in patients treated with tacrolimus compared to cyclosporine (Ref)
• Macrolide cross-sensitivity: Although tacrolimus is a macrolide drug, cross-reactivity is unlikely to occur (Ref), albeit one case of possible cross-reactivity has been reported (Ref).
In general, there is an increased risk for the development of hypertension following kidney transplantation (Ref). The cause of post-transplant hypertension is multifactorial, of which one modifiable risk factor is the use of calcineurin inhibitors (CNI) (eg, cyclosporine, tacrolimus) (Ref). Tacrolimus-based regimens may be associated with a lower incidence of hypertension as compared to cyclosporine-based regimens (Ref); however, the risk of graft rejection must be considered when adjusting immunosuppressants in transplant recipients (Ref). Hypertension may lead to adverse short-term and long-term allograft outcomes as well as increased cardiovascular morbidity and mortality (Ref).
Mechanism: Exact mechanism is unknown. Multiple mechanisms may contribute including tubular salt reabsorption, peripheral vasoconstriction, and the sympathetic nervous system (Ref). Vasoconstriction is caused by an increase of vasoconstrictor mediators (eg, sympathetic tone, renin-angiotensin system, endothelin-1) and a decrease of vasodilator mediators (eg, prostaglandins, nitric oxide) (Ref). Tacrolimus may activate the sodium chloride cotransporter in the kidney; this effect appears to be mediated, in part, by the kinases WNK4 and SPAK (Ref). Clinicians should note that the cause of post-transplant hypertension is multifactorial; the use of a CNI is one factor.
Onset: Varied; may occur soon after transplant or later during the course of therapy (Ref).
Risk factors:
In general, demographic and transplant-specific risk factors for post-transplant hypertension include (Ref):
• Preexisting hypertension
• Elevated body mass index
• Males
• Black patients
• Older donor age
• Delayed graft function
• Glucocorticoid use
• Recurrent disease
• Acute rejection
• Post-transplant proteinuria
Tacrolimus is an immunosuppressant; therefore, use may result in bacterial, viral, fungal, and protozoal infections, including opportunistic infections. Infections may be severe and potentially fatal.
Viral infections reported with use of tacrolimus include polyomavirus infection (which may result in polyomavirus associated nephropathy [PVAN]), JC virus-associated progressive multifocal leukoencephalopathy, cytomegalovirus disease, and reactivation of hepatitis B or hepatitis C (Ref). PVAN, primarily from activation of BK virus, may lead to the deterioration of kidney function and/or kidney graft loss, especially in kidney transplant recipients (Ref). Risk of infectious complications in transplant recipients may be higher with calcineurin inhibitors (CNIs), including tacrolimus, as compared to mTOR inhibitors (eg, sirolimus, everolimus)(Ref); however, tacrolimus may be associated with a lower risk of infections as compared to glucocorticoids or other immunosuppressants (eg, cyclophosphamide) when used for the treatment of lupus nephritis or idiopathic membranous nephropathy (Ref).
Mechanism: Exact mechanism unknown; related to pharmacologic action. Tacrolimus inhibits T-lymphocyte activation by interacting with an intracellular protein, FKBP-12 and calcineurin dependent proteins to inhibit calcineurin phosphatase activity.
Onset: Varied; in general, the onset of infections following solid organ transplant varies greatly; most clinically important infections occur within the first 180 days (Ref).
Risk factors:
• Concurrent use of other immunosuppressive agents or preexisting immune function impairment
• Increased tacrolimus exposure
• CMV infection: Transplant recipients that are CMV seronegative at the time of transplant who receive a graft from a CMV seropositive donor
In general, use of immunosuppressive agents may result in an increased risk of lymphoproliferative disorders and/or neoplasms (including skin carcinoma) (Ref). The risk of malignant lymphoma may be higher in transplant recipients who receive tacrolimus as compared to cyclosporine (Ref); however, not all studies have observed this pattern (Ref).
Mechanism: Dose- and time-related; related to the pharmacologic action. Tacrolimus inhibits T-lymphocyte activation by interacting with an intracellular protein, FKBP-12 and calcineurin dependent proteins to inhibit calcineurin phosphatase activity.
Onset: Delayed. Post-transplant lymphoproliferative disorders (PTLD) and non-skin, non-lymphoma malignancies generally occur during the first year after transplant when immunosuppressive therapy is most aggressive; however, the incidence of skin malignancies increase more linearly with time (Ref).
Risk factors:
• Intensity of immunosuppression (Ref)
• Concurrent use of other immunosuppressive agents or preexisting immune function impairment
• Epstein-Barr virus (EBV) seronegative transplant recipients (Ref)
- In general, pediatric transplant recipients are at a higher risk of PTLD as these patients are more likely to be EBV seronegative at transplantation (Ref)
- Clinicians may also consider the role that EBV acute infection and/or reactivation may play in the risk of EBV-associated lymphoma in patients receiving immunosuppressive therapies; risk not well defined (Ref)
• Pretransplant malignancy (Ref)
• Fewer HLA matches (Ref)
• History of at least 1 prior rejection episode (Ref)
• Age <25 years or >60 years (Ref)
• Skin carcinoma: Exposure to sunlight/UV light
Use of calcineurin inhibitors (CNIs), including tacrolimus, may result in acute or chronic nephrotoxicity. Tacrolimus is thought to have a lower nephrotoxicity potential as compared to cyclosporine; however, not all studies have observed this benefit (Ref).
Acute CNI nephrotoxicity: Considered acute, functional, dose-dependent, and generally reversible after dose reduction or discontinuation; characterized by increased serum creatinine concentrations, hyperkalemia, and/or hyperuricemia unexplained by other causes for acute kidney injury (AKI) with a concurrent increase in tacrolimus trough concentration to >20 ng/mL (Ref). Kidney biopsy may or may not reveal an acute arteriolopathy and/or tubular vacuolization (Ref). Acute microvascular toxicity may also occur and is differentiated by the presence of glomerular capillary thrombosis as well as thrombi in the arterioles; presentation may range from asymptomatic to hemolytic uremic syndrome (Ref).
Chronic tacrolimus nephrotoxicity (CTN): Considered chronic, structural, progressive, and irreversible; all three compartments of the kidney (vessels, tubulo-interstitium, glomeruli) may be involved (Ref). Nodular hyaline deposits in the media of afferent arterioles are considered a hallmark; kidney biopsy may reveal arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (“striped fibrosis”), glomerular capsular fibrosis, global and focal segmental glomerulosclerosis, juxtaglomerular apparatus hyperplasia, and/or tubular microcalcifications (Ref). Additional extra-renal symptoms may be present due to tubular functional alterations and ion homeostasis (eg, hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, hyperuricemia); hypertension may also occur (Ref).
Mechanism: Not clearly established; however, the main mechanisms are changes in glomerular and tubular function and the main targets are tubular epithelial cells, vascular endothelial cells, arteriolar myocytes, and interstitial fibroblasts (Ref).
Acute CNI nephrotoxicity: Dose-related (Ref); secondary to vasoconstriction of the afferent and efferent glomerular arterioles and reductions in renal blood flow and GFR resulting in hypoperfusion and parenchymal ischemia. Vasoconstriction is caused by an increase of vasoconstrictor mediators (eg, sympathetic tone, renin-angiotensin system, endothelin-1) and a decrease of vasodilator mediators (eg, prostaglandins, nitric oxide) (Ref).
CTN: Dose- and time-related; exact mechanism is unknown; a combination of hemodynamic changes and direct toxic effects on tubular epithelial cells is thought to play a role (Ref). Nodular hyaline deposits may cause narrowing of the vascular lumen which contributes to the development of interstitial fibrosis, tubular atrophy, and glomerular sclerosis. In addition, renal vasoconstriction may result in local hypoxia or ischemia and subsequent cellular injury. Upregulation of transforming growth factor-beta (TGF-β) and activation of the renin-angiotensin system may also contribute to the tubular-interstitial effects seen in patients with CTN. Furthermore, CNIs may be directly toxic to tubular and interstitial cells as well cause a decrease in the excretion of other endogenous toxic substances via inhibition of P-glycoprotein (multidrug resistance protein 1 [MR1] or ATP-binding cassette subfamily B, member 1 [ABCB1]).
Onset: Varied; in one trial, the acute phase of CNI nephrotoxicity occurred with a median onset of 6 months post-transplantation, whereas the chronic phase occurred at a median onset of 3 years (Ref).
Risk factors:
• Systemic overexposure to tacrolimus (Ref)
• Increased local exposure to tacrolimus (eg, due to ABCB1 genotype or expression in renal tubular epithelial cells or drug interactions) (Ref)
• Increased exposure to metabolites of tacrolimus (eg, due to CYP3A4/5 genotype or expression in the renal tubular epithelial cells or drug interactions) (Ref)
• Older kidney age (Ref)
• Concurrently administered with CYP3A inhibitors
• Concurrent nephrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (Ref)
• Genetic polymorphisms of other genes (eg, TGF-β, ACE), including patients with FOXP3 rs3761548 AA and AC genotypes (Ref)
• Patients with high tacrolimus clearance may be at an increased risk of interstitial fibrosis and tubular atrophy; intermittent underexposure may lead to alloimmune activation and subsequent fibrosis (Ref)
Dose-related neurotoxicity may occur with use of calcineurin inhibitors (CNIs), including tacrolimus. Neurotoxicity may be more common with immediate-release tacrolimus as compared to cyclosporine (Ref).
Mild symptoms may include tremor, neuralgia, peripheral neuropathy, headache, mood changes (agitation, anxiety), and insomnia (Ref). Tremor is a common manifestation and generally involves the upper extremities, especially upon extension (Ref); tremor may be more common with immediate-release tacrolimus as compared to extended-release formulations (Ref). Headaches are often described as migrainous, occipital, and frequent (eg, weekly) (Ref).
More severe symptoms of neurotoxicity may occur less frequently and include seizures, visual disturbance (including cortical blindness), dysarthria and akinetic mutism, severe psychomotor disturbance, stupor, coma, delusions, psychosis, hallucinations, cerebellar ataxia, or asthenia (Ref).
Reversible posterior leukoencephalopathy syndrome (RPLS) has been rarely reported (Ref); symptoms (mental status changes, headache, hypertension, seizures, and visual disturbances) are reversible with dose reduction or discontinuation of therapy.
Mechanism: Dose-related; exact mechanism is unknown. Tacrolimus-induced neurotoxicity may be related to the ability of CNIs to increase the permeability of the blood brain barrier (BBB) via multiple mechanisms; once within the CNS, tacrolimus may cause neurotoxicity via calcineurin inhibition (Ref).
Onset: Varied; CNI-induced neurotoxicity may occur within weeks after transplantation (Ref). Onset of RPLS has been described days to years post-transplant; onset may differ depending on the transplanted organ (Ref).
Risk factors:
• Increased tacrolimus exposure; specifically dosing strategies that result in high peak concentrations (eg, immediate-release formulations, IV administration) or alterations in clearance or metabolism (eg, advanced liver failure, drug interactions) (Ref)
• Increased donor age (Ref)
• Prior history of hepatic encephalopathy in liver transplant recipients (Ref)
• RPLS: Risk is increased in patients with significant fluid overload, elevated blood pressure, or impaired kidney function (Ref)
Pure red cell aplasia (PRCA), a type of anemia which can range from subclinical to severe, and is a relatively rare disease that has been reported in patients receiving tacrolimus concomitantly with other immunosuppressive agents (eg, corticosteroids, mycophenolate mofetil) (Ref). Symptoms may include fatigue, lethargy, or pallor. Occurrence of PRCA may warrant treatment interruption, dosage adjustment, or discontinuation (Ref); the risk of reduced immunosuppression and graft rejection should be considered in transplant recipients.
Mechanism: Exact mechanism unknown (Ref); the impact of concurrent disease processes (eg, parvovirus B19 infection) should be considered (Ref).
Onset: Delayed (Ref)
Risk factors:
• Concomitant use of other immunosuppressive agents or preexisting immune function impairment
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported with combination therapy.
>10%:
Cardiovascular: Acute cardiorespiratory failure, angina pectoris, atrial fibrillation, atrial flutter, bradycardia, cardiac arrhythmia, cardiac fibrillation, chest pain, deep vein thrombophlebitis, deep vein thrombosis, ECG abnormality (including abnormal QRS complex and ST segment changes on ECG), edema, flushing, heart failure, hypertension (table 1), hypotension, orthostatic hypotension, peripheral edema, phlebitis, syncope, tachycardia, thrombosis, vasodilation
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
39% |
47% |
Children & adolescents |
Granules |
N/A |
Liver transplant |
91 |
90 |
|
32% |
35% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
28% |
30% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
47% |
56% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
62% |
69% |
Adults |
N/A |
N/A |
Heart transplant |
157 |
157 |
|
50% |
52% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
23% |
23% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
Dermatologic: Acne vulgaris, alopecia, benign skin neoplasm, cellulitis, condyloma acuminatum, dermal ulcer, dermatitis, diaphoresis, ecchymoses, exfoliative dermatitis, fungal dermatitis, hyperhidrosis, hypotrichosis, pruritus, skin discoloration, skin photosensitivity, skin rash, tinea versicolor
Endocrine & metabolic: Acidosis, albuminuria, alkalosis, anasarca, Cushing syndrome, cushingoid appearance, decreased serum bicarbonate, decreased serum iron, dehydration, diabetes mellitus (including new-onset) (table 2), hirsutism, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperkalemia (table 3), hyperphosphatemia, hypertriglyceridemia, hyperuricemia (table 4), hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia (table 5), hyponatremia, hypophosphatemia, increased lactate dehydrogenase, metabolic acidosis (table 6), weight gain
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
75% |
61% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
36% |
35% |
Adolescents & adults |
Extended release |
N/A |
Kidney transplant |
162 |
151 |
|
26% |
16% |
Adults |
N/A |
N/A |
Heart transplant |
157 |
157 |
|
24% |
9% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
16% |
14% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
13% |
7% |
N/A |
N/A |
N/A |
Heart transplant |
75 |
83 |
|
20% |
4% |
N/A |
N/A |
N/A |
Kidney transplant |
151 |
151 |
|
18% |
13% |
N/A |
N/A |
N/A |
Liver transplant |
239 |
236 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
12% |
10% |
Children & adolescents |
Granules |
N/A |
Liver transplant |
91 |
90 |
|
26% |
19% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
20% |
23% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
45% |
26% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
31% |
32% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
15% |
11% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
<15% |
N/A |
Adolescents & adults |
Immediate release |
N/A |
Kidney transplant |
N/A |
N/A |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
40% |
29% |
Children & adolescents |
Granules |
N/A |
Liver transplant |
91 |
90 |
|
28% |
22% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
24% |
27% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
48% |
45% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
34% |
17% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
12% |
12% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
26% |
17% |
Children & adolescents |
Granules |
N/A |
Liver transplant |
91 |
90 |
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 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, nocturia, oliguria, proteinuria, pyuria, toxic nephrosis, urinary frequency, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, vaginitis
Hematologic & oncologic: Anemia, 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 gamma-glutamyl transferase, increased liver enzymes, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, jaundice
Hypersensitivity: Hypersensitivity reaction
Immunologic: Graft complications
Infection: Abscess, bacterial infection (may be serious) (table 7), BK virus (including nephropathy) (table 8), candidiasis, cytomegalovirus disease (including CMV viremia) (table 9), Epstein-Barr infection, herpes simplex infection, herpes zoster infection, infection (table 10) (including serious infection) (table 11), opportunistic infection (table 12), polyomavirus infection (table 13), sepsis (children & adolescents)
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
8% |
12% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
30% |
N/A |
Adults |
N/A |
N/A |
Heart transplant |
331 |
N/A |
|
13% |
18% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
7% |
5% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
162 |
162 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
6% |
9% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
15% |
24% |
Children & adolescents |
Granules |
N/A |
Liver transplant |
91 |
90 |
|
10% |
12% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
32% |
30% |
Adults |
N/A |
N/A |
Heart transplant |
157 |
157 |
|
11% |
9% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
2% |
1% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
162 |
162 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
25% |
29% |
Children & adolescents |
Granules |
N/A |
Liver transplant |
91 |
90 |
|
56% |
N/A |
Children & adolescents |
N/A |
N/A |
N/A |
76 |
N/A |
|
69% |
69% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
24% |
21% |
Adults |
N/A |
N/A |
Heart transplant |
157 |
157 |
|
70% |
65% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
46% |
48% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
162 |
162 |
|
45% |
49% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
22% |
23% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
26% |
24% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
8% |
9% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
162 |
162 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
15% |
N/A |
Adults |
N/A |
N/A |
Heart transplant |
331 |
N/A |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
3% |
5% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
Nervous system: Abnormal dreams, agitation, amnesia, anxiety, asthenia, ataxia, changes in thinking, chills, confusion, depression, dizziness, drowsiness, emotional lability, encephalopathy, falling, fatigue, flaccid paralysis, hallucination, headache (table 14), hypertonia, hypoesthesia, impaired mobility, insomnia (table 15), intolerance to temperature, intracranial hemorrhage, mood elevation, myasthenia, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, nightmares, pain, paralysis (monoparesis, quadriparesis, quadriplegia), paresthesia, peripheral neuropathy, psychomotor disturbance, psychosis, seizure, tremor (table 16), vertigo, voice disorder, writing difficulty
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
14% |
N/A |
Children & adolescents |
N/A |
N/A |
N/A |
76 |
N/A |
|
24% |
25% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
22% |
24% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
64% |
60% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
44% |
38% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
15% |
10% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
30% |
21% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
24% |
28% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
64% |
68% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
32% |
30% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
13% |
11% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
35% |
34% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
34% |
20% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
56% |
46% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
15% |
6% |
Adults |
N/A |
N/A |
Heart transplant |
157 |
157 |
|
54% |
34% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
19% |
17% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
Neuromuscular & skeletal: Arthralgia, back pain, gout, lower limb cramp, muscle cramps, muscle spasm, myalgia, osteoporosis
Ophthalmic: Amblyopia, blurred vision, conjunctivitis, visual disturbance
Otic: Otalgia, otitis media, tinnitus
Renal: Acute kidney injury, hydronephrosis, increased blood urea nitrogen, increased serum creatinine (table 17), kidney failure, kidney impairment, nephrotoxicity (table 18), renal tubular necrosis
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
46% |
N/A |
Children & adolescents |
Extended release |
Immediate release |
Kidney transplant |
13 |
N/A |
|
23% |
23% |
Adolescents & adults |
N/A |
N/A |
Kidney transplant |
212 |
212 |
|
19% |
23% |
Adolescents & adults |
Extended release |
Immediate release |
Kidney transplant |
214 |
212 |
|
39% |
25% |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
45% |
42% |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
|
12% |
14% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
12% |
N/A |
Adults |
Extended release |
Immediate release |
Kidney transplant |
162 |
162 |
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
40% |
N/A |
Adolescents & adults |
N/A |
N/A |
Liver transplant |
250 |
250 |
|
56% |
N/A |
Adults |
N/A |
N/A |
Heart transplant |
157 |
157 |
|
52% |
N/A |
Adults |
N/A |
N/A |
Kidney transplant |
205 |
207 |
Respiratory: Acute respiratory distress syndrome, asthma, atelectasis, bronchitis, decreased lung function, dyspnea, flu-like symptoms, increased cough, pharyngitis, pleural effusion, pneumonia, pneumothorax, productive cough, pulmonary edema, pulmonary emphysema, respiratory tract infection, rhinitis, sinusitis
Miscellaneous: Abnormal healing, crying, fever, postoperative wound complication, ulcer, wound healing impairment
1% to 10%:
Gastrointestinal: Gastrointestinal infection
Infection: Fungal infection (table 19)
|
Drug (Tacrolimus) |
Comparator (various) |
Population |
Dosage Form (Tacrolimus) |
Dosage Form (Comparator) |
Indication |
Number of Patients (Tacrolimus) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|---|
|
9% |
8% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
268 |
275 |
|
4% |
4% |
Adults |
Extended release |
Immediate release |
Kidney transplant |
162 |
162 |
Respiratory: Upper respiratory tract infection
Postmarketing:
Cardiovascular: Abnormal T waves on ECG, acute myocardial infarction, coronary artery vasospasm (Samer 2022), glomerular capillary thrombosis (Holman 1993), hypertrophic cardiomyopathy (Noda 2017), ischemic heart disease, pericardial effusion (including cardiac tamponade) (Doobay 2018), premature ventricular contractions, prolonged QT interval on ECG (Hodak 1998), pulmonary embolism, supraventricular extrasystole (Kim 2013), supraventricular tachycardia (Kim 2013), torsades de pointes (Hodak 1998), ventricular fibrillation
Dermatologic: Epidermal cyst of skin (Tiwari 2021), hyperpigmentation, malignant melanoma, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria (Kamata 2009)
Endocrine & metabolic: Diabetic ketoacidosis (Maruyama 2019), hot flash, weight loss
Gastrointestinal: Biliary obstruction, colitis, delayed gastric emptying, enterocolitis, gastric ulcer, increased serum amylase, oral mucosa ulcer, pancreatitis (including acute pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis) (Ding 2022; Xu 2019)
Genitourinary: Glycosuria, hemorrhagic cystitis, hypercalciuria (Farouk 2020)
Hematologic & oncologic: Agranulocytosis, decreased serum fibrinogen, disseminated intravascular coagulation, febrile neutropenia, hemolytic-uremic syndrome (Lin 2003), hepatosplenic T-cell lymphomas, immune thrombocytopenia (Gipson 2021), increased INR, leukemia, lymphoproliferative disorder (DiGiuseppe 1996), malignant lymphoma (Sekiguchi 2012), pancytopenia, prolonged partial thromboplastin time, pure red cell aplasia (Watanabe 2020), thrombotic thrombocytopenic purpura
Hepatic: Hepatic cirrhosis, hepatic cytolysis, hepatic failure, hepatic necrosis, hepatic sinusoidal obstruction syndrome (Shen 2015), hepatitis C (reactivation) (Liu 2014), liver steatosis
Immunologic: Epstein-Barr-associated lymphoproliferative disorder (Caillard 2006), graft- versus-host disease
Infection: Reactivation of HBV (Ridruejo 2010)
Nervous system: Aphasia (Reyes 1990), carpal tunnel syndrome, cerebral infarction (Kwun 2011), coma (Junna 2007), dysarthria (Vearrier 2011), encephalitis (autoimmune) (Spindel 2020), hemiparesis, jitteriness, leukoencephalopathy (Junna 2007), mutism (Vearrier 2011), neurotoxicity (Coe 2020), parkinsonism (Gmitterova 2018), progressive multifocal leukoencephalopathy (including JC virus-associated) (Bianchi 2020; Ischii 2019), reversible posterior leukoencephalopathy syndrome (including mental status changes) (Loar 2013), status epilepticus (Junna 2007)
Neuromuscular & skeletal: Inflammatory polyarthropathy, limb pain (including calcineurin-inhibitor induced pain syndrome) (Ayyala 2016), rhabdomyolysis
Ophthalmic: Blindness, cortical blindness (Steg 1999), optic atrophy, optic neuropathy (Nanda 2021), photophobia
Otic: Hearing loss (Gulleroglu 2013, Lakshmi 2020)
Respiratory: Allergic rhinitis, interstitial lung disease, pulmonary hypertension, pulmonary infiltrates, respiratory distress, respiratory failure
Miscellaneous: Multiorgan failure
Hypersensitivity to tacrolimus, polyoxyl 60 hydrogenated castor oil (HCO-60), or any other component of the formulation.
Concerns related to adverse events:
• 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.
• 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.
Concurrent drug therapy:
• 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. Concurrent use may also increase the risk of thrombotic microangiopathy.
• Sirolimus combination therapy: ER tacrolimus in combination with sirolimus is not recommended in renal transplant recipients; the safety and efficacy of IR 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 recipients, as well as increased risk of renal impairment, wound healing complications, and PTDM in heart transplant recipients. Concurrent use may also increase the risk of thrombotic microangiopathy.
Special populations:
• Patients with systemic lupus erythematosus (SLE) undergoing hip or knee replacement surgery: Patients with severe SLE (referring to patients with severe organ manifestations such as nephritis) should not interrupt therapy when undergoing hip or knee replacement surgery. For patients with SLE without severe disease, hold tacrolimus for at least 1 week prior to surgery to reduce infection risk; therapy can be restarted once surgical wound shows evidence of healing (eg, no swelling, erythema, or drainage), sutures/staples are removed, and no ongoing nonsurgical site infections (typically ~14 days to reduce infection risk) (ACR/AAHKS [Goodman 2022]).
Dosage form specific issues:
• 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) (Nicolai 2012). 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: IR and ER capsules are NOT interchangeable or substitutable. The ER formulation is a once-daily preparation; and IR formulation is intended for twice-daily administration. Serious adverse events, including organ rejection, may occur if inadvertently substituted.
• 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).
Prograf injection contains polyoxyl 60 hydrogenated castor oil (HCO-60)
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, peg-60 hydrog castor oil(cremophor rh60)]
Tablet Extended Release 24 Hour, Oral:
Envarsus XR: 0.75 mg, 1 mg, 4 mg
May be product dependent
Capsule ER 24 Hour Therapy Pack (Astagraf XL Oral)
0.5 mg (per each): $3.37
1 mg (per each): $6.73
5 mg (per each): $33.65
Capsules (Prograf Oral)
0.5 mg (per each): $4.31
1 mg (per each): $8.62
5 mg (per each): $43.10
Capsules (Tacrolimus Oral)
0.5 mg (per each): $1.26 - $2.23
1 mg (per each): $1.64 - $6.95
5 mg (per each): $10.80 - $22.30
Pack (Prograf Oral)
0.2 mg (per each): $6.24
1 mg (per each): $9.31
Solution (Prograf Intravenous)
5 mg/mL (per mL): $297.12
Tablet, 24-hour (Envarsus XR Oral)
0.75 mg (per each): $6.03
1 mg (per each): $8.04
4 mg (per each): $32.15
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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:
Advagraf: 0.5 mg, 1 mg, 3 mg, 5 mg
Solution, Intravenous:
Prograf: 5 mg/mL (1 mL) [contains alcohol, usp, polyoxyl/peg-35 castor oil(cremophor el)]
Tablet Extended Release 24 Hour, Oral:
Envarsus PA: 0.75 mg, 1 mg, 4 mg
Note: Tacrolimus is also available as granules for oral suspension.
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).
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).
Dose conversion from cyclosporine to tacrolimus: Very limited data: Based on data reported in 58 pediatric heart transplant recipients on stable doses, the following conversion factor has been suggested. Note: This is only applicable to patients already stabilized on a consistent dose (Notaro 2014).
Children <2 years: Use conversion factor of 60.
Children and Adolescents ≥2 years: Use conversion factor of 42.
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); do not administer with grapefruit juice; do not administer within 2 hours before or after antacids. 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 administered in the morning; however, some data suggests that the larger dose should be given in the evening since tacrolimus exposure may be reduced in the evening due to diurnal variation (Ref). If dosed 3 times daily, separate doses by 8 hours.
Oral granules for suspension: Empty the contents of each packet into a glass cup and mix with 15 to 30 mL of room temperature drinking water. Use whole packet(s) to prepare, adding additional 0.2 mg packets if necessary. The granules will not dissolve completely. Administer immediately after preparation. Dosing syringe or cup should be rinsed with an additional 15 to 30 mL of room temperature water to ensure all granules are taken. Do not use PVC-containing dosing cups or oral syringes to prepare. Do not sprinkle directly on food.
Oral capsules:
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 (Ref). Note: If patient receiving an extended-release formulation, convert to an appropriate dose of the immediate release. 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 : Recommendations include opening capsules and applying contents under the tongue. Patient should be advised not to swallow for 5 to 15 minutes and eating or drinking anything for up to 30 minutes (Ref).
Extended release: Administer on an empty stomach at least 1 hour before or 2 hours after a meal. Swallow whole; do not chew, crush, or divide. Take once daily in the morning at a consistent time each day.
Missed doses: Astagraf XL: Children ≥4 years and Adolescents: May be taken up to 14 hours after scheduled time; if >14 hours, resume at next regularly scheduled time; do not double a dose to make up for a missed dose.
Parenteral: Administer by IV infusion as a continuous infusion (preferred) (generally over 24 hours) or may also be administered as an intermittent infusion given over 2 hours (Ref). Must be diluted prior to administration. Do not use PVC tubing when administering diluted solutions; PVC-free administration tubing should be used to minimize the potential for significant drug absorption onto the tubing; adsorption of the drug to PVC tubing may become clinically significant with low concentrations. 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. Continue only until oral medication can be tolerated.
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. Tacrolimus levels should not be drawn from a line that was used for a tacrolimus infusion. Falsely elevated tacrolimus levels may occur if drawn from the line used for the tacrolimus infusion; once a line (even if multi-lumen) is used for a tacrolimus IV infusion, it should be considered contaminated with tacrolimus (Ref).
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 (Ref). 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.
Bariatric surgery: Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR capsule, oral solution, and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical symptom monitoring and/or therapeutic drug monitoring is recommended in the immediate postoperative period and at regular follow-up intervals after bariatric surgery to validate drug absorption that may change with small bowel adaption or transit over time.
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 (Ref). 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 (Ref). Caregivers should don 2 pairs of gloves while handling contents of capsules (Ref). Note: Absorption of a single dose of tacrolimus suspension given by the sublingual route was inadequate (Ref).
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Injection: Prior to dilution, store at 5°C to 25°C (41°F to 77°F). Following dilution, tacrolimus is 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).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Astagraf XL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204096s011lbl.pdf#page=33
Envarsus XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206406s010lbl.pdf#page=29
Immediate release: Prograf (Oral, IV): Prevention of organ rejection in liver, kidney, lung, and heart transplant recipients in combination with other immunosuppressants (FDA approved in pediatric patients [age not specified] and adults); has also been used in the prevention of graft-versus-host disease (GVHD) and treatment of nephrotic syndrome.
Extended release:
Astagraf XL: Prevention of organ rejection in kidney transplant recipients in combination with other immunosuppressants (FDA approved in ages ≥4 years and adults).
Envarsus XR: Prevention of organ rejection in kidney transplant recipients converted from tacrolimus immediate-release formulation, in combination with other immunosuppressants (FDA approved in adults).
Prograf may be confused with Gengraf, Proscar, PROzac
Tacrolimus may be confused with everolimus, pimecrolimus, sirolimus (conventional), sirolimus (protein bound), tamsulosin, temsirolimus
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (immunosuppressant agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care and Long-Term Care Settings).
The immediate release (Prograf) and extended release (Astagraf XL, Advagraf [Canadian product]) oral formulations are not interchangeable and are not substitutable.
TAC or tac is an error-prone abbreviation (mistaken as triamcinolone; tetracaine, Adrenalin, and cocaine; Taxotere, Adriamycin, and cycloPHOSphamide)
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Adalimumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Adefovir: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Afatinib: Tacrolimus (Systemic) may increase the serum concentration of Afatinib. Management: Monitor for signs and symptoms of afatinib toxicity when these agents are combined. Consider administering tacrolimus simultaneously with, or after, the dose of afatinib. If the combination is not tolerated, consider reducing the afatinib dose by 10 mg. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Aluminum Hydroxide: May decrease the serum concentration of Tacrolimus (Systemic). Particularly, maximum concentration may decrease. Aluminum Hydroxide may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Aminoglycosides: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Amiodarone: Tacrolimus (Systemic) may enhance the QTc-prolonging effect of Amiodarone. Amiodarone may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Amphotericin B: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Azithromycin (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Betel Nut: May decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Bimekizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Bulevirtide: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Cannabidiol: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Cannabis: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Management: Reduce the tacrolimus dose and monitor tacrolimus whole blood concentrations frequently, beginning within 1 to 3 days of chloramphenicol initiation. Further tacrolimus dose adjustments should be guided by continued monitoring of tacrolimus levels. Risk D: Consider therapy modification
Cidofovir: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Cinacalcet: May decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
CISplatin: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Clotrimazole (Oral): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Clotrimazole (Topical): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Colchicine: Tacrolimus (Systemic) may increase the serum concentration of Colchicine. Risk C: Monitor therapy
Corticosteroids (Systemic): May decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase. Risk C: Monitor therapy
COVID-19 Vaccines: Calcineurin Inhibitors (Systemic) may diminish the therapeutic effect of COVID-19 Vaccines. Management: Rheumatology guidelines recommend holding calcineurin inhibitors for 1 to 2 weeks after each vaccine dose as permitted by the underlying disease. This is specific to the use of calcineurin inhibitors for rheumatologic or musculoskeletal disease. Risk D: Consider therapy modification
CycloSPORINE (Systemic): Tacrolimus (Systemic) may enhance the nephrotoxic effect of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Tacrolimus (Systemic). Management: Monitor for decreased tacrolimus concentrations and effects when combined with strong CYP3A4 inducers. Tacrolimus dose increases will likely be needed during concomitant use. Risk D: Consider therapy modification
CYP3A4 Inducers (Weak): May decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to one-third of the original dose if starting posaconazole or voriconazole. Coadministration with nelfinavir is not generally recommended. Tacrolimus dose reductions or prolongation of dosing interval will likely be required. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Weak): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Dinutuximab Beta: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May decrease the serum concentration of Tacrolimus (Systemic). Direct Acting Antiviral Agents (HCV) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Efonidipine: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Elacestrant: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modification
Ertapenem: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Erythromycin (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Estrogen Derivatives: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Everolimus: May decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Fenofibrate and Derivatives: Tacrolimus (Systemic) may enhance the nephrotoxic effect of Fenofibrate and Derivatives. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
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. Risk D: Consider therapy modification
Foscarnet: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
Futibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Ganciclovir (Systemic): May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Givinostat: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Grapefruit Juice: May decrease the metabolism of Tacrolimus (Systemic). Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Itraconazole: May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely during therapy with itraconazole; tacrolimus dose reductions will likely be required. The magnitude of this interaction may be greater in older patients or those with one or more CYP3A5*3 alleles. Risk D: Consider therapy modification
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Consider alternatives to this combination when possible. If combined, monitor for decreased effectiveness of these CYP3A4 substrates if combined with ivosidenib. Risk D: Consider therapy modification
Ketoconazole (Systemic): May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required; empiric dose reductions of 50% have been recommended. Monitor tacrolimus concentrations and clinical response closely. Risk D: Consider therapy modification
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
LevoFLOXacin (Systemic): May enhance the QTc-prolonging effect of Tacrolimus (Systemic). LevoFLOXacin (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Magnesium Hydroxide: May increase the serum concentration of Tacrolimus (Systemic). Magnesium Hydroxide may decrease the serum concentration of Tacrolimus (Systemic). Specifically, maximum concentration may decrease. Risk C: Monitor therapy
Maribavir: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Mavacamten: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Metoclopramide: May increase the serum concentration of Tacrolimus (Systemic). Specifically, treatment of gastroparesis may increase tacrolimus concentrations. Risk C: Monitor therapy
Mifamurtide: Tacrolimus (Systemic) may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Nelfinavir: May increase the serum concentration of Tacrolimus (Systemic). Management: Avoid this combination unless benefits outweigh risks. If used, tacrolimus dose reductions will likely be required; monitor response and tacrolimus concentrations closely, beginning within 1 to 3 days of coadministration. Risk D: Consider therapy modification
Nirmatrelvir and Ritonavir: May increase the serum concentration of Tacrolimus (Systemic). Management: Consider avoiding this combination, if possible, through use of alternative anti-COVID-19 therapy. If combined, hold tacrolimus during nirmatrelvir/ritonavir treatment and for at least 2 to 3 days after completion. Monitor tacrolimus levels closely. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olutasidenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid use of olutasidenib with sensitive or narrow therapeutic index CYP3A4 substrates when possible. If concurrent use with olutasidenib is unavoidable, monitor closely for evidence of decreased concentrations of the CYP3A4 substrates. Risk D: Consider therapy modification
Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
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 beginning within 1 to 3 days of coadministration. Risk D: Consider therapy modification
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Pretomanid: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Protease Inhibitors: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Protease Inhibitors may decrease the metabolism of Tacrolimus (Systemic). Management: Consider reducing the tacrolimus dose to 1 mg once or twice per week if coadministered with protease inhibitors that are strong inhibitors of CYP3A4. Monitor response, plasma concentrations (as appropriate), and for signs of toxicity. Risk D: 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. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Remdesivir: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Saquinavir: May increase the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Schisandra: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Sevelamer: May decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Simeprevir: May decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Simeprevir. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sirolimus Products: Tacrolimus (Systemic) may enhance the adverse/toxic effect of Sirolimus Products. Sirolimus Products may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus Products may decrease the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Sodium Zirconium Cyclosilicate: May decrease the serum concentration of Tacrolimus (Systemic). Management: Separate the administration of sodium zirconium cyclosilicate and tacrolimus by at least 2 hours. Risk D: Consider therapy modification
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Sotagliflozin: May decrease the serum concentration of Tacrolimus (Systemic). Sotagliflozin may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Sparsentan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Spironolactone: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Tacrolimus (Systemic). Management: Consider avoiding this combination. If coadministered, monitor for reduced serum concentrations of tacrolimus when St Johns Wort is initiated/dose increased, and increased serum concentrations if St Johns Wort is discontinued/dose decreased. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Taurursodiol: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk X: Avoid combination
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
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). Temsirolimus may increase the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Tenofovir Products: May enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tigecycline: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Tofisopam: May increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Tovorafenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid concurrent use whenever possible; if the combination cannot be avoided, monitor closely for reduced effectiveness of the CYP3A4 substrate. Risk D: Consider therapy modification
Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Trofinetide: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Ustekinumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vedolizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to approximately one-third of the original dose when starting concurrent voriconazole. Tacrolimus whole blood trough concentrations should be monitored closely beginning within 1 to 3 days of concomitant use. Risk D: Consider therapy modification
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Ethanol: Alcohol may increase the rate of release of extended-release tacrolimus and adversely affect tacrolimus safety and/or efficacy. Management: Avoid alcohol.
Food: Food decreases rate and extent of absorption. High-fat meals have most pronounced effect (37% and 25% decrease in AUC, respectively, and 77% and 25% decrease in Cmax, respectively, for immediately release and extended release formulations). Grapefruit juice, a CYP3A4 inhibitor, may increase serum level and/or toxicity of tacrolimus. Management: Administer with or without food (immediate release), but be consistent. Administer extended release on an empty stomach. Avoid concurrent use of grapefruit juice.
Avoid grapefruit and grapefruit juice. Avoid alcohol.
Family planning and contraceptive options for patients who can become pregnant and patients with partners who can become pregnant should be evaluated prior to starting treatment.
Tacrolimus is an acceptable immunosuppressant for use in kidney, heart, and liver transplant recipients planning a pregnancy. Conception may be considered for patients who can become pregnant who are on a stable/low maintenance dose for ≥1 year following transplant (AASLD [Lucey 2013]; EBPG 2002; ISHLT [Velleca 2023]; López 2014). Tacrolimus has also been used as an immunosuppressant in patients undergoing uterine transplant (Jones 2019).
Based on limited data, tacrolimus may be used in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant and are not able to use alternative therapies; however, BP monitoring is recommended. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).
Based on limited data, tacrolimus may be used in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Tacrolimus crosses the human placenta and is measurable in the cord blood, amniotic fluid, and newborn serum. Tacrolimus also accumulates in the placenta in concentrations that may be higher than the maternal serum (Freriksen 2018; Jain 1997). Infants with lower birth weights have been found to have higher tacrolimus concentrations, possibly due to slower metabolism (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, pregnant patients were also taking a concomitant medication known to cause adverse pregnancy outcomes. Tacrolimus may exacerbate hypertension and hyperglycemia in pregnant patients with preexisting disease. Adverse pregnancy outcomes may also be associated with an organ transplant, including preterm delivery and low birth weight in the infant and hypertension and preeclampsia in the mother. Cholestasis of pregnancy may be increased following liver transplant.
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of tacrolimus are altered. Increased monitoring of blood levels in the pregnant patient is recommended, and dosage adjustments may be required during pregnancy and immediately postpartum (AASLD [Lucey 2013]; EBPG 2002; ISHLT [Velleca 2023]; López 2014). Whole blood concentrations of tacrolimus decrease as pregnancy progresses; however, unbound tacrolimus concentrations increase. Measuring unbound concentrations may be preferred, especially in patients 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 monotherapy is the preferred immunosuppressant in patients who become pregnant following a liver transplant (AASLD [Lucey 2013]). Tacrolimus may also be used in pregnant patients who have had a kidney (EBPG 2002; López 2014), heart (ISHLT [Velleca 2023]), or uterine (Jones 2019; Perni 2022; Richards 2021; Wilson 2023) transplant.
Based on limited data, tacrolimus may be used in pregnant patients with rheumatic and musculoskeletal diseases who are not able to use alternative therapies; however, close monitoring of blood pressure is recommended (ACR [Sammaritano 2020]). Tacrolimus is not one of the recommended agents for the treatment of myasthenia gravis during pregnancy (Sanders 2016).
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.
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.
Limited data correlating serum concentration to therapeutic efficacy/toxicity; in solid organ transplant recipients, goal levels vary depending on time from transplant, patient risk factors, concomitant immunosuppression, and time post-transplant; consult institution-specific protocols:
Heart transplant: Typical whole blood trough concentrations: Months 1 to 12 post-transplant: 5 to 20 ng/mL.
Kidney transplant: Whole blood trough concentrations:
Immediate release:
Children and Adolescents <16 years: Months 1 to 12 post-transplant: 5 to 20 ng/mL.
Adolescents ≥16 years:
In combination with azathioprine:
Months 1 to 3 post-transplant: 7 to 20 ng/mL.
Months 4 to 12 post-transplant: 5 to 15 ng/mL.
In combination with mycophenolate mofetil/IL-2 receptor antagonist (eg, daclizumab): Months 1 to 12 post-transplant: 4 to 11 ng/mL.
Extended release (Astagraf XL):
With basiliximab induction:
Children ≥4 years and Adolescents <16 years:
Month 1 post-transplant: 10 to 20 ng/mL.
>1 month post-transplant: 5 to 15 ng/mL.
Adolescents ≥16 years:
Month 1 post-transplant: 7 to 15 ng/mL.
Months 2 to 6 post-transplant: 5 to 15 ng/mL.
>6 months post-transplant: 5 to 10 ng/mL.
Without basiliximab induction:
Adolescents ≥16 years:
Month 1 post-transplant: 10 to 15 ng/mL.
Months 2 to 6 post-transplant: 5 to 15 ng/mL.
>6 months post-transplant: 5 to 10 ng/mL.
Nephrotic syndrome: Trough: 5 to 10 ng/mL (KDIGO 2021); a lower goal of 3 to 5 ng/mL has also been recommended (Bock 2013; Jahan 2015).
Liver transplant: Whole blood trough concentrations: Months 1 to 12 post-transplant: 5 to 20 ng/mL.
Lung transplant: Whole blood trough concentrations: Week 1 to 2 post-transplant: 10 to 20 ng/mL; Week 2 to Month 12: 10 to 15 ng/mL.
Prevention of graft-vs-host disease: Whole blood trough concentrations: 10 to 20 ng/mL (Uberti 1999); although some institutions use a lower limit of 5 ng/mL and an upper limit of 15 ng/mL (Przepiorka 1999; Yanik 2000).
Tacrolimus 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 recipients 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 hematopoietic cell transplant recipients 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; Vd: Mean: Infants and Children: 2.6 L/kg in liver transplant recipients; Adults: 0.85 to 1.41 L/kg in liver and kidney transplant recipients.
Protein binding: ~99% primarily to albumin and alpha-1 acid glycoprotein
Metabolism: Extensively hepatic via CYP3A4 to eight possible metabolites (major metabolite, 31-demethyl tacrolimus, shows same activity as tacrolimus in vitro)
Bioavailability: Oral: Incomplete and variable: Immediate release:
Infants and Children: Kidney transplant: 19% ± 14%, liver transplant: 31% ± 24%
Adults: Kidney transplant: 17% ± 10%, liver transplant: 22% ± 6%, heart transplant: 23% ± 9%
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 recipients; prolonged in patients with severe hepatic impairment.
Extended release: 38 ± 3 hours; prolonged in patients with severe hepatic impairment
Time to peak: Oral: 0.5 to 6 hours
Excretion: Feces (~93%); urine (<1% as unchanged drug)
Clearance: 7 to 103 mL/minute/kg (average: 30 mL/minute/kg); clearance higher in children
Hepatic function impairment: The mean clearance was substantially lower in patients with severe hepatic impairment.
Race/Ethnicity: Cmax is lower, Tmax is prolonged, and bioavailability is decreased following oral (but not IV) administration in African American kidney transplant recipients.
Cystic fibrosis: Lower tacrolimus bioavailability has been reported in patients with cystic fibrosis.
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