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  • CLASSES

    Calcineurin Inhibitors
    Topical Calcineurin Inhibitors

    BOXED WARNING

    Immunosuppression, lymphoma, mononucleosis, new primary malignancy, post-transplant lymphoproliferative disorder (PTLD), skin cancer

    Patients receiving immunosuppressants such as oral or injectable tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients and has an association with the Epstein-Barr Virus (EBV). The risk of PTLD appears greatest in EBV negative patients. Monitor EBV serology during tacrolimus therapy. Also, immunosuppression from the use of topical tacrolimus may influence the possible development of a new primary malignancy, especially skin cancer, lymphoma, or other lymphoproliferative disorders; rare cases of malignancy (e.g., skin and lymphoma) have been reported, but a causal relationship has not been established. Some malignant conditions such as cutaneous T-cell lymphoma may mimic atopic dermatitis; avoid the use of topical tacrolimus on premalignant and malignant skin conditions. Discontinue Protopic in the presence of acute infectious mononucleosis, and do not use Protopic in patients who are immunocompromised. Avoid continuous long-term use of topical calcineurin inhibitors such as tacrolimus ointment, and limit application to areas of involvement with atopic dermatitis. Only physicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Patients initiating systemic tacrolimus therapy should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.[28611][30973][55401][60497]

    Children, infants, neonates

    Tacrolimus ointment is not approved for use in neonates, infants, or children younger than 2 years old; only the lower concentration (tacrolimus 0.03%) ointment is recommended for use in non-immunocompromised pediatric patients aged 2 to 15 years. The long-term effect of tacrolimus on the developing immune system in infants and children is not known. Immediate-release capsules and granules for oral suspension are indicated for the prophylaxis of organ rejection in pediatric kidney, liver, and heart transplant patients. In general, pediatric patients require higher tacrolimus doses compared to adults; these requirements may decrease as the child grows older. If pediatric patients are converted between immediate-release formulations, perform therapeutic drug monitoring and adjust the dosage as necessary to ensure adequate tacrolimus exposure is maintained. Astagraf XL is approved in pediatric patients 4 years of age and older. The safety and efficacy of Envarsus XR have not been established in patients less than 18 years of age.

    DEA CLASS

    Rx

    DESCRIPTION

    Immunosuppressant; more potent than cyclosporine 
    Used for graft rejection prophylaxis and treatment of acute or refractory graft rejection; considered an alternative to cyclosporine; topical formulation used for atopic dermatitis
    Increased susceptibility to infections and secondary malignancy possible

    COMMON BRAND NAMES

    ASTAGRAF XL, ENVARSUS, HECORIA, Prograf, Protopic

    HOW SUPPLIED

    ASTAGRAF XL Oral Cap ER: 0.5mg, 1mg, 5mg
    ENVARSUS Oral Tab ER: 0.75mg, 1mg, 4mg
    HECORIA/Prograf/Tacrolimus Oral Cap: 0.5mg, 1mg, 5mg
    Prograf Intravenous Inj Sol: 1mL, 5mg
    Protopic/Tacrolimus Topical Ointment: 0.03%, 0.1%

    DOSAGE & INDICATIONS

    For liver transplant rejection prophylaxis.
    Oral dosage (immediate-release capsules)
    Adults

    0.1 to 0.15 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose of tacrolimus no sooner than 6 hours after transplantation.

    Children and Adolescents

    0.15 to 0.2 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose of tacrolimus no sooner than 6 hours after transplantation. For conversion from capsules to granules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.

    Oral dosage (oral suspension)
    Children and Adolescents

    0.2 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose of tacrolimus no sooner than 6 hours after transplantation. For conversion from granules to capsules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.

    Intravenous dosage

    NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral administration. Give the first oral dose 8 to 12 hours after the IV infusion is stopped.

    Adults

    0.03 to 0.05 mg/kg/day continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations.

    Children and Adolescents

    0.03 to 0.05 mg/kg/day continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations.

    For kidney transplant rejection prophylaxis.
    NOTE: Do not administer concomitantly with cyclosporine. Additionally, use with sirolimus is not recommended in kidney transplant recipients.
    NOTE: According to renal transplant guidelines, tacrolimus is the suggested first-line calcineurin inhibitor (CNI) to be used for initial maintenance immunosuppression with an antiproliferative agent such as mycophenolate plus or minus corticosteroids. The CNI is suggested to be started before or at the time of transplantation rather than delayed until graft function onset. Further, the CNI is suggested to be continued rather than withdrawn during long-term maintenance therapy.
    In combination with azathioprine and corticosteroids.
    Oral dosage (immediate-release capsules)

    NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.

    Adults

    0.2 mg/kg/day PO in 2 divided doses given 12 hours apart in combination with azathioprine and corticosteroids. The first dose may be administered within 24 hours of transplantation but should be delayed until renal function has recovered. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Lower than the recommended initial tacrolimus doses may be adequate as maintenance therapy. Higher doses may be required in African American patients compared with Caucasian patients.[28611]

    In combination with mycophenolate mofetil, corticosteroids, and an IL-2 receptor antagonist.
    Oral dosage (immediate-release capsules)

    NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.

    Adults

    0.1 mg/kg/day PO in 2 divided doses given 12 hours apart in combination with mycophenolate mofetil, corticosteroids, and daclizumab or basiliximab induction therapy. The first dose may be administered within 24 hours of transplantation but should be delayed until renal function has recovered. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Lower than the recommended initial tacrolimus doses may be adequate as maintenance therapy. Higher doses may be required in African American patients compared with Caucasian patients.[28611]

    Oral dosage (extended-release capsules; Astagraf XL)

    NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.

    Adults

    0.15 to 0.2 mg/kg/dose PO once daily (on an empty stomach) in the morning in combination with mycophenolate mofetil, corticosteroids, and basiliximab induction therapy. The first dose should be given prior to or within 48 hours after transplant completion. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Higher doses may be required in African American patients compared with Caucasian patients.[55401]

    Children and Adolescents 4 to 17 years

    0.3 mg/kg/dose PO once daily (on an empty stomach) in the morning in combination with mycophenolate mofetil, corticosteroids, and basiliximab induction therapy. The first dose should be given within 24 hours after reperfusion. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Higher doses may be required in African American patients compared with Caucasian patients.[55401]

    In combination with mycophenolate mofetil and corticosteroids.
    Oral dosage (extended-release capsules)

    NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.

    Adults

    0.1 mg/kg/dose PO once daily (on an empty stomach) pre-operatively (first dose given 12 hours prior to reperfusion) and 0.2 mg/kg/dose PO once daily post-operatively (first dose given within 12 hours after reperfusion but at least 4 hours after the pre-operative dose) in combination with mycophenolate mofetil and corticosteroids. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Higher doses may be required in African American patients compared with Caucasian patients.[55401]

    In combination with other immunosuppresants.
    NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily,) and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
    Oral dosage (extended-release tablets; Envarsus XR)
    Adults

    Initial dose is 0.14 mg/kg/day as a once daily dose taken on an empty stomach at the same time of day, preferably in the morning, in combination with other immunosuppressants. Measure tacrolimus whole blood trough concentrations at least 2 times on separate days during the first week after initiation of therapy and following any dosage change, any change in coadministration of CYP3A inducers and/or inhibitors, or a change in renal or hepatic function. Titrate dose based on clinical assessment of rejection and tolerability. Target trough concentrations during the first month of therapy are 6 to 11 ng/mL and 4 to 11 ng/mL after the first month. Higher doses may be required in African American patients compared with Caucasian patients to attain target trough concentrations.[60497]

    For conversion from tacrolimus immediate-release products in combination with other immunosuppressants.
    NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily,) and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
    Oral dosage (extended-release tablets; Envarsus XR)
    Adults

    Initially, administer at a dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Tacrolimus extended-release tablet is administered PO once daily on an empty stomach, preferably in the morning, in combination with other immunosuppressants. Measure tacrolimus whole blood trough concentrations at least 2 times on separate days during the first week after initiation of therapy and following any dosage change, any change in coadministration of CYP3A inducers and/or inhibitors, or a change in renal or hepatic function. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations of 4 to 11 ng/mL. Higher doses may be required in African American patients compared with Caucasian patients to achieve target trough concentrations.[60497]

    Intravenous dosage

    NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral administration.

    Adults

    0.03 to 0.05 mg/kg/day as a continuous IV infusion. The infusion may begin within 24 hours of transplantation but should be delayed until renal function has recovered. Adjust the dose based on tacrolimus trough whole blood concentrations. Concomitant corticosteroid therapy is recommended during the early post-transplantation period. When the patient is able to tolerate oral therapy, give the first oral dose 8 to 12 hours after discontinuing the infusion.

    Children† and Adolescents†

    Experience in pediatric renal transplantation patients is limited. In a prospective study comparing tacrolimus and cyclosporine, pediatric patients received tacrolimus 0.1 mg/kg/day IV as an infusion over 24 hours, then 0.3 mg/kg/day PO in divided doses. At 1 year, patient and graft survival rates were 100% and 96%, respectively.[24938] In another study, 0.3 mg/kg/day PO was given as 2 divided doses (every 12 hours); doses were adjusted to achieve whole blood trough concentrations of 10 to 20 ng/mL for the first 30 days and 5 to 10 ng/mL thereafter. Continuous IV infusion of 0.06 mg/kg/day was required initially in 36 patients; the mean duration of IV receipt was 4.1 +/- 2.9 days.[35708]

    Oral dosage (immediate-release capsules or oral suspension)
    Children and Adolescents

    0.3 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose within 24 hours of transplantation, but delay until renal function has recovered. For conversion from capsules to granules or vice versa, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.

    For heart transplant rejection prophylaxis.
    NOTE: Tacrolimus is recommended to be used in conjunction with azathioprine or mycophenolate mofetil. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.
    Oral dosage (immediate-release capsules)
    Adults

    0.075 mg/kg/day PO in 2 divided doses, every 12 hours. The initial dose should be administered no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations. According to guidelines, lower concentrations should be sought when used with mycophenolate mofetil as compared with azathioprine because use of lower tacrolimus concentrations with mycophenolate mofetil is safe and is associated with lower rejection rates and improved renal function. Trial data suggest that tacrolimus-based regimens may be associated with lower rejection rates but not with superior survival as compared with cyclosporine-based regimens. Conversion from cyclosporine to tacrolimus 0.05 to 0.15 mg/kg/day PO in 2 divided doses titrated to troughs of 5 to 12 ng/mL led to reductions in rejection episodes among patients with refractory or persistent rejection. After conversion to tacrolimus, the number of treated episodes of rejection decreased from 1.2 +/- 1 to 0.3 +/- 0.5 episodes per patient per year. In another study, replacement of cyclosporine with tacrolimus led to a mean number of rejection episodes Grade 3A or higher of 0.7 +/- 0.8 as compared with 3.2 +/- 0.4 before the switch to tacrolimus.

    Children and Adolescents

    0.3 mg/kg/day PO in 2 divided doses, every 12 hours. If cell depleting induction treatment is administered, initiate tacrolimus at 0.1 mg/kg/day PO. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose no sooner than 6 hours after transplantation. For conversion from capsules to granules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.

    Oral dosage (oral suspension)
    Children and Adolescents

    0.3 mg/kg/day PO in 2 divided doses, every 12 hours. If cell depleting induction treatment is administered, initiate tacrolimus at 0.1 mg/kg/day PO. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose no sooner than 6 hours after transplantation. For conversion from granules to capsules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.

    Intravenous dosage

    NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral tacrolimus administration. Give the first oral dose 8 to 12 hours after the IV infusion is stopped.

    Adults

    0.01 mg/kg/day as a continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust the dose based on tacrolimus trough whole blood concentrations. According to guidelines, monotherapy with early corticosteroid withdrawal may be considered in highly selected patients. Lower tacrolimus concentrations should be sought when used with mycophenolate mofetil as compared with azathioprine because use of lower tacrolimus concentrations with mycophenolate mofetil is safe and is associated with lower rejection rates and improved renal function. Trial data suggest that tacrolimus-based regimens may be associated with lower rejection rates but not with superior survival as compared with cyclosporine-based regimens.

    Infants†, Children†, and Adolescents†

    Experience in pediatric heart transplantation patients is limited. Tacrolimus dosage 0.03 to 0.05 mg/kg/day continuous IV infusion to achieve whole blood concentrations of 15 to 20 ng/mL has been studied. In a retrospective review, doses less than 0.05 mg/kg/day IV may have resulted in a clinically important delay in reaching therapeutic concentrations. Frequent monitoring of whole blood concentrations is recommended during the first 48 hours, especially when the initial concentration is more than 10 ng/mL to avoid toxicity. According to heart transplant guidelines, maintenance therapy for all pediatric heart transplant recipients should include a calcineurin inhibitor (CNI) such as tacrolimus, and tacrolimus monotherapy is acceptable for patients with a benign rejection history. Tacrolimus is the preferred CNI for those considered to be at high immunologic risk such as sensitized recipients with evidence of donor-specific antibody. Also, patients with preformed alloantibodies and a positive donor-specific cross-match should get tacrolimus, corticosteroids, and either mycophenolate mofetil or a mTOR inhibitor such as sirolimus or everolimus.

    For the treatment of atopic dermatitis.
    For short-term or intermittent long-term treatment of moderate-to-severe atopic dermatitis.
    NOTE: Topical tacrolimus is a second line agent to treat atopic dermatitis in patients unresponsive to or intolerant of other first line agents; long-term safety has not been established.
    NOTE: If no improvement occurs after 6 weeks of treatment or if exacerbation of atopic dermatitis occurs, treatment should be stopped and other therapeutic options considered.
    Topical dosage (0.03% and 0.1% ointment)
    Adults and Adolescents 16 years and older

    Apply a thin layer to the affected areas twice daily. Rub in gently and completely. Treatment should continue for one week after clearing of signs and symptoms. Do not use under occlusive dressings. A European study revealed that topical tacrolimus (0.03%, 0.1%, and 0.3%) every 12 hours for 3 weeks was an effective treatment for atopic dermatitis and statistically superior to vehicle alone.

    Topical dosage (0.03% ointment)
    Children and Adolescents 2 to 17 years

    Apply a thin layer to the affected areas twice daily. Rub in gently and completely. Treatment should continue for one week after clearing of signs and symptoms. Do not use under occlusive dressings.

    Children younger than 2 years†

    A retrospective study reported that 12 patients (younger than 2 years of age) treated with topical tacrolimus 0.1% or 0.03% had significant improvement in their atopic dermatitis without adverse effects. No measurable serum tacrolimus concentrations were reported. Randomized, placebo-controlled studies are needed. A thin layer of ointment should be applied to the affected areas twice daily. Rub in gently and completely. Treatment should continue for one week after clearing of signs and symptoms. Do not use under occlusive dressings.

    For the maintenance of disease stabilization† in patients with moderate-to-severe atopic dermatitis.
    NOTE: Precautions apply to the chronic use of topical tacrolimus in children and adolescents; FDA-approved labeling warns against continuous long-term use of topical calcineurin inhibitors in any age group.
    Topical dosage (0.03% ointment)
    Children and Adolescents 2 to 17 years

    Limited data suggest tacrolimus 0.03% ointment applied topically once daily 3 times weekly to normal-appearing skin previously affected by atopic dermatitis may be effective. In a double-blind, placebo-controlled study, 105 patients ages 2 to 15 years with stabilized moderate-to-severe atopic dermatitis were randomized to tacrolimus 0.03% ointment or vehicle applied once daily, 3 times per week to normal-appearing skin previously affected by atopic dermatitis for up to 40 weeks. The tacrolimus-treated patients experienced a significantly greater number of disease-free days compared to vehicle (174 vs. 107, p = 0.0008), significantly longer time to first relapse (116 days vs. 31 days, p = 0.04), and significantly fewer relapse days (47 vs. 76, p = 0.04). In addition, the number of relapses per patient was limited to 3 or less in the tacrolimus group compared to up to 6 in the vehicle group. The severity of relapse was considered mild in the majority of the tacrolimus-treated patients; whereas, the severity was moderate in greater than 50% of the vehicle-treated patients. The incidence of application-site adverse effects was similar between the groups (12% for tacrolimus vs. 11% for vehicle).

    For the treatment of acute liver transplant rejection†.
    Intravenous and Oral dosage
    Adults

    Tacrolimus has been widely studied for rescue therapy in patients who do not tolerate cyclosporine, have cyclosporine-refractory rejection or chronic rejection. Doses studied include 0.075—0.15 mg/kg/day continuous IV infusion, then 0.3 mg/kg/day PO in divided doses. In one study, patients with uncontrolled rejection or complications related to cyclosporine were given tacrolimus 0.15 mg/kg/day IV as a continuous infusion over 24 hours, followed by 0.3 mg/kg/day PO in 2 divided doses every 12 hours. Of the 39 patients meeting criteria for tacrolimus rescue therapy, all but 12 responded to therapy as demonstrated by histopathologic findings and liver function. In a follow-up report, patients receiving cyclosporine were changed to tacrolimus because of failure of the conventional immunosuppressive therapy. The tacrolimus dosage was 0.075—0.15 mg/kg IV given over 4 hours, followed by 0.3 mg/kg/day PO in divided doses.

    Children

    Dosages studied include tacrolimus 0.15 mg/kg/day continuous IV infusion, then 0.15—0.33 mg/kg/day PO in divided doses. In children whose immunosuppressive therapy was changed to tacrolimus therapy after early or late graft rejection on conventional immunosuppression, the tacrolimus dosage was 0.15 mg/kg/day IV as a slow infusion, followed by 0.15 mg/kg PO every 12 hours. After a mean follow-up of 150 days, 3 patients had died and 7 patients had retransplantations. In another study, patients were changed from cyclosporine to tacrolimus because of uncontrollable acute rejection, chronic rejection, or nonspecific hepatitis. Patients received a dosage of 0.15 mg/kg IV as a continuous infusion for 4—19 days, then 0.2—0.33 mg/kg/day PO in divided doses or oral therapy starting on day 4. Of the 18 patients with acute rejection, 11 had a complete response and 7 did not respond. Five patients developed a lymphoproliferative syndrome.

    For the treatment of acute kidney transplant rejection†.
    Intravenous and Oral dosage
    Adults

    Tacrolimus has been widely studied for rescue therapy in patients who do not tolerate cyclosporine, have cyclosporine-refractory rejection, or chronic rejection. Tacrolimus dosages studied include 0.02—0.1 mg/kg/day IV, followed by 0.3 mg/kg/day PO in 2 divided doses to maintain tacrolimus 12-hour whole blood trough levels of 1—2 ng/ml. In one study, 57 of 77 patients (74%) were successfully rescued with tacrolimus therapy and still had functioning allografts with a mean follow-up of 14 months. Renal transplant guidelines mention consideration of a switch from cyclosporine to tacrolimus for severe or steroid-resistant acute rejection, if applicable.

    For pancreas transplant rejection prophylaxis†.
    For the management of pancreas/kidney or solitary pancreas transplant rejection prophylaxis† and refractory kidney and/or pancreas transplant rejection†.
    Intravenous and Oral dosage
    Adults

    Numerous trials have studied the use of tacrolimus in patients receiving pancreas transplant alone, simultaneous pancreas/kidney transplant, and pancreas transplant after kidney transplant. These studies have shown that tacrolimus is effective both as part of primary immunosuppressive therapy and in patients who do not tolerate cyclosporine or develop refractory rejection. For rejection prophylaxis dosages of 4—10 mg/day PO in divided doses have been used to maintain tacrolimus whole blood concentrations at an average of 12 ng/ml. In patients who switched to tacrolimus for rejection or rescue therapy the median dose was 10 mg/day PO in divided doses with a median whole blood concentration of 11 ng/ml.

    For islet transplantation rejection prophylaxis†.
    Intravenous and Oral dosage
    Adults

    In seven patients, immunosuppression with daclizumab, sirolimus, and low-dose tacrolimus 1 mg PO twice daily was begun immediately prior to islet transplantation. The tacrolimus dose was adjusted to maintain a whole blood trough concentration at 12 hours of 3—6 ng/ml. No corticosteroids were used as immunosuppression. All patients remain free of the need for exogenous insulin and no episodes of acute rejection have been observed with median follow-up of 11.9 months.

    For the management of heart transplant rejection†.
    Oral dosage
    Adults

    Conversion from cyclosporine to tacrolimus may reduce the severity of a rejection episode. For example, 14 of 15 patients who got oral tacrolimus rescue therapy (target 12-hour trough of 10—20 ng/ml) for grade 3A or higher refractory rejection converted from at least grade 3A to grade 2 or lower rejection.]

    For the rescue treatment for lung transplant rejection† or the management of lung transplant rejection prophylaxis†.
    Intravenous and Oral dosage
    Adults

    Tacrolimus has been studied as primary immunosuppression and as rescue therapy in patients undergoing lung transplantation. In a randomized study comparing tacrolimus with cyclosporine, the initial tacrolimus dose was 0.025 mg/kg/day continuous IV infusion, which was increased to 0.075 mg/kg/day IV, and then changed to 0.15 mg/kg/day PO in divided doses to maintain a 12-hour trough whole blood concentration of 1—1.5 ng/ml.

    Children and Adolescents

    In a study comparing tacrolimus and cyclosporine, 11 pediatric patients (ages 3—18 years) received an initial tacrolimus dose of 0.05 mg/kg/day IV, followed by 0.3 mg/kg/day PO in 2 divided doses to maintain whole blood trough concentrations of 1—2 ng/ml.

    For the management of small bowel transplant rejection prophylaxis†.
    Intravenous and Oral dosage
    Adults, Adolescents, and Children

    In one report, adults and children received tacrolimus 0.1—0.15 mg/kg/day IV, followed by 0.3 mg/kg/day PO in divided doses for either small-bowel, small-bowel and liver, or multivisceral transplantation. In a subsequent report of 15 patients who received tacrolimus 0.1—0.15 mg/kg/day IV, followed by 0.3 mg/kg/day PO in divided doses for small-bowel, with or without the colon, transplantation, actuarial patient survival rates at 6, 12, and 18 months were 100%, 88%, and 70%, respectively. The overall incidence of rejection was 94%.

    For the treatment of graft-versus-host disease (GVHD)† in combination with other immunosuppressants.
    NOTE: Tacrolimus has been designated an orphan drug by the FDA for this indication.
    Intravenous dosage
    Adults and Adolescents

    A dosage of 0.1 mg/kg/day IV in 2 divided doses has been studied. The dose should be adjusted based on tacrolimus trough whole blood concentrations. The responsiveness of steroid-refractory graft-versus-host disease to tacrolimus is marginal. Tacrolimus has also been used successfully in the treatment of chronic graft-versus-host disease.

    Children

    A dosage of 0.1 mg/kg/day continuous IV infusion has been utilized.

    Oral dosage
    Adults and Adolescents

    Doses of 0.3 mg/kg/day PO in 2 divided doses, starting when the patient can tolerate oral medications have been given. The dose should be adjusted based on tacrolimus trough whole blood concentrations.

    Children

    See dosage for adults and adolescents. Children may require higher doses to maintain therapeutic whole blood trough concentrations of tacrolimus.

    For graft-versus-host disease (GVHD) prophylaxis†.
    Intravenous dosage
    Adults, Adolescents, and Children

    Doses of 0.03 mg/kg/day continuous IV infusion, starting 1—2 days prior to bone marrow transplantation (day -1 or -2) have been recommended. Beginning tacrolimus on day -2 may be of benefit in pediatric patients. The dose should be adjusted based on tacrolimus trough whole blood concentrations. Usually given in combination with methotrexate.

    Oral dosage
    Adults, Adolescents, and Children

    Doses of 0.12 mg/kg/day PO in 2 divided doses, starting when the patient is able to tolerate oral medications have been recommended. The dose should be adjusted based on tacrolimus trough whole blood concentrations. Usually given in combination with methotrexate. Children may require higher doses to maintain therapeutic whole blood trough concentrations of tacrolimus.

    For the treatment of chronic allergic contact dermatitis†.
    Topical dosage (0.1% ointment)
    Adults

    A randomized, double-blind, vehicle-controlled trial was conducted using daily exposure to nickel allergen as a model. Patients applied nickel patches to each arm for 4 to 8 hours daily, and were then randomly assigned to apply 0.1% tacrolimus ointment to the patch site of one arm and a vehicle to the patch site of the other arm twice daily for 8 weeks. After 8 weeks, 45% of patients achieved clear or almost clear dermatitis with tacrolimus compared to 1% with vehicle; 31% of patients achieved success as early as day 8 with tacrolimus. There was no statistical difference in the occurrence of adverse events between the treatments. Adverse events occurred in 2% or fewer of the patients and were reported as application site reactions including edema, pruritus, erythema, pain, burning and bruising.

    For the treatment of psoriasis†.
    For the treatment of severe, recalcitrant, plaque-type psoriasis†.
    Oral dosage
    Adults

    0.05 to 0.15 mg/kg/day PO tacrolimus (n = 27) was shown to be more effective than placebo (n = 23) in a small study. Patients with severe, recalcitrant, plaque-type psoriasis were given tacrolimus initially as 0.05 mg/kg/day PO and was increased to 0.1 mg/kg/day PO at week 3 and to 0.15 mg/kg/day PO at week 6 if necessary. By the end of the study at week 9, tacrolimus-treated patients had a significantly greater reduction in the Psoriasis Area and Severity Index than did placebo-treated patients (-83 vs. -47; p < 0.02).

    For the treatment of facial or intertriginous psoriasis.
    NOTE: According to the American Academy of Dermatology (AAD), topical tacrolimus is not generally effective for the treatment of chronic plaque psoriasis.
    Topical dosage
    Adults and Adolescents >= 16 years

    Apply 0.1% tacrolimus ointment topically twice daily to psoriatic lesions of the face and intertriginous areas. In a clinical trial of 167 patients with facial and intertriginous psoriasis, a statistically significantly greater number of patients were clear or almost clear after 8 weeks of twice daily application of tacrolimus 0.1% ointment compared with vehicle (65% vs. 31%; p < 0.0001). Adverse events were similar between the 2 groups and were primarily reported as burning/stinging, hyperesthesia, and itching. In a clinical trial comparing tacrolimus ointment to calcitriol ointment in patients with intertriginous and facial psoriasis, tacrolimus produced a significantly greater reduction in mean target area score (67% vs. 51%; p < 0.05) with significantly more patients achieving clear or almost complete clearance by Physician's Global Assessment (60% vs. 33%; p < 0.05).

    For the treatment of severe, refractory uveitis†.
    Oral dosage
    Adults

    In patients with refractory uveitis, a dose of 0.1—0.15 mg/kg/day PO in 2 divided doses given for 12 weeks was effective in 60—83% of patients. Higher doses of 0.2 mg/kg/day PO have also been used; however, an increase in adverse effects has been reported with these dosages. A tacrolimus whole blood trough concentration of 15—25 ng/ml has been recommended.

    For the treatment of steroid- and cyclosporine-resistant nephrotic syndrome†.
    Oral dosage
    Adults, Adolescents, and Children

    In a pilot study, 7 patients with steroid-resistant nephrotic syndrome received a dose of 0.1 mg/kg/day PO for at least 3 months. This dose was effective in decreasing proteinuria to 50% to normal protein levels. In the management of cyclosporine- and steroid- resistant nephrotic syndrome after renal transplantation, the use of tacrolimus may only be useful in a small group of patients (i.e., patients with de novo nephrotic syndrome following transplantation). Patients with chronic rejection should not be changed from cyclosporine to tacrolimus to treat post-transplantation nephrotic syndrome.

    For the induction of remission of moderately to severely active ulcerative colitis† in patients with either steroid-dependent or steroid-resistant disease.
    NOTE: Most patients used medications containing 5-aminosalicylic acid or steroids.
    Oral dosage
    Adults

    0.025 mg/kg PO twice daily for 2 weeks with dose titration to a trough serum concentration of 10—15 ng/ml led to at least a 4 point improvement on the disease activity index score with all categories improved in 13 of 19 patients versus in 2 of 20 placebo recipients. Further, 20% of tacrolimus recipients had clinical remission, and 78.9% had mucosal healing; no patient had a complete response.

    For the treatment of vulvar lichen sclerosus†.
    Topical dosage (0.03% and 0.1% ointment)
    Adult females

    In a pilot study, 16 women with biopsy-proven lichen sclerosus were treated with twice daily applications of 0.1% tacrolimus ointment for three months; responders then received twice daily applications of 0.03% tacrolimus ointment. Sixty percent of patients reported a partial response, and two had a complete response. Further investigation is needed.

    For the treatment of lupus nephritis†.
    Oral dosage
    Adults

    0.05 mg/kg/day PO in 2 divided doses titrated to achieve a trough of 5—10 ng/ml plus prednisone for induction led to a complete response in 22 of 42 patients. In contrast, 15 of 39 recipients of cyclophosphamide 750 mg/m2 IV adjusted to 500—1000 mg/m2 every 4 weeks for a total of 6 doses plus prednisone met the endpoint. Data are limited by the small sample size and follow-up duration of 6 months. Tacrolimus is not a recommended induction agent, and consensus was not reached regarding the use of calcineurin inhibitors in patients whose nephritis fails to improve or worsens after 6 months of induction with cyclophosphamide, mycophenolate mofetil, or both. Tacrolimus may be a consideration if nephritis is worsening in patients treated for 3 months with glucocorticoids plus either cyclophosphamide or mycophenolate mofetil.]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.

    Elderly

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.

    Adolescents

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.

    Children

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    A lower dosage may be necessary in patients with severe hepatic impairment (Child-Pugh class C score greater than 10) due to reduced tacrolimus clearance and a prolonged half-life in these patients.  Liver transplant recipients with post-transplant severe hepatic impairment may have an increased risk of developing renal impairment related to high tacrolimus trough concentrations; consider lower doses in these patients.

    Renal Impairment

    Kidney transplant recipients: In patients with post-operative oliguria, administer the first dose no sooner than 6 hours and within 24 hours for immediate-release capsules or 48 hours in adults and 24 hours in pediatric patients for extended-release capsules (Astagraf XL). For immediate-release capsules, delay starting therapy until there is evidence of renal function recovery. The dosage may need to be reduced in patients with renal impairment. Consider switching to a different immunosuppressant therapy in patients who experience persistent serum creatinine concentration elevations despite a tacrolimus dose reduction.[28611] [55401] [60497]
     
    Liver and heart transplant recipients: Consider starting at the lower end of the dosing range in patients who have pre-existing renal impairment. Further dosage reduction below the targeted range may be necessary in some patients. Consider switching to a different immunosuppressant therapy in patients who experience persistent serum creatinine concentration elevations despite a tacrolimus dose reduction.[28611]

    ADMINISTRATION

    Oral Administration

    Administer at approximately the same time each day.
    Do not administer with grapefruit or grapefruit juice.
    Immediate-release formulations (capsules and granules for oral suspension, administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.

    Oral Solid Formulations

    Conventional immediate-release capsules
    To minimize variations in bioavailability, administer consistently with or without food.
     
    Extended-release capsules (Astagraf XL)
    Take in the morning, preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
    Swallow whole; do not chew, divide, or crush capsules.
    Do not administer with an alcoholic beverage.
    If a dose is missed up to 14 hours from the scheduled time, take the dose. If a dose is missed at more than 14 hours from the scheduled time, skip the dose and take the next dose at the regularly scheduled time.
     
    Extended-release tablets (Envarsus XR)
    Take in the morning, preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
    Swallow whole; do not chew, divide, or crush capsules.
    Do not administer with an alcoholic beverage.
    If a dose is missed up to 15 hours from the scheduled time, take the dose. If a dose is missed at more than 15 hours from the scheduled time, skip the dose and take the next dose at the regularly scheduled time.

    Oral Liquid Formulations

    Granules for oral suspension
    To minimize variations in bioavailability, administer consistently with or without food.
    Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the dose is not covered by the whole number of packets, use 1 additional 0.2 mg packet to round up the dose.
    Do not use tubing, syringes, or other equipment (e.g., cups) containing PVC to prepare or administer tacrolimus.
    Do not sprinkle the granules on food.
    Wearing disposable gloves is recommended when preparing the oral suspension or when wiping spills. Avoid inhalation or direct contact with skin or mucous membranes. If contact occurs, wash the skin thoroughly with soap and water. If ocular contact occurs, rinse the eyes with water. Wipe the surface with a wet paper towel if a spill occurs; throw the paper towel away in the trash and wash your hands well.
    To prepare the dose, empty the entire packet contents into a glass cup. Add 15 to 30 mL of room temperature drinking water and mix the entire contents of the cup. The granules will not completely dissolve. Give the suspension immediately after preparation. The suspension can be drawn up via a non-PVC oral syringe that is dispensed with the prescription. Rinse the cup or syringe with 15 to 30 mL of water and administer this to the patient to ensure all the medication is taken.

    Extemporaneous Compounding-Oral

    Extemporaneous compounding preparation†
    A 0.5 mg/mL suspension can be made by mixing the contents of six 5-mg immediate-release tacrolimus capsules with equal amounts of Ora-Plus and Simple Syrup, NF to make a final volume of 60 mL. When stored at room temperature in either glass or plastic amber bottles, the suspension is stable for 56 days. Shake well before each use.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Because of the risk of hypersensitivity reactions, IV administration should be reserved for patients who cannot take tacrolimus orally. Oral therapy should replace IV therapy as soon as possible.
    Observe patients for 30 minutes after beginning the infusion and frequently thereafter for possible hypersensitivity reactions.
    Due to chemical instability, tacrolimus should not be mixed or infused with solutions with a pH of 9 or more (e.g., acyclovir or ganciclovir).
     
    Dilution
    The concentrate for injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration between 0.004 mg/mL and 0.02 mg/mL.
    Prepare solutions in polyethylene or glass containers to allow storage for 24 hours. Do not use polyvinyl chloride (PVC) containers because stability is decreased and the polyoxyl 60 hydrogenated castor oil in the formulation may leach phthalates from PVC containers.
     
    Intravenous Infusion
    Administer through non-PVC tubing to minimize the potential for drug adsorption onto the tubing.
    Infuse the required daily dose of the diluted IV solution over 24 hours.

    Topical Administration

    Apply tacrolimus as a thin layer and rub in gently and completely. Before applying the ointment after a bath or shower, make sure the skin is completely dry.
    Avoid the eyes and surrounding area.
    Do not use with occlusive dressings. Use of occlusive dressings may promote systemic absorption.

    STORAGE

    ASTAGRAF XL:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    ENVARSUS:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    HECORIA:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Prograf:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Protopic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tacrolimus immediate-release formulations (capsules and granules for oral suspension, administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable. Inadvertent or unintentional substitution between these formulations has resulted in serious adverse reactions including graft rejection. Therapeutic drug monitoring is recommended after conversion from 1 formulation to another.

    Fungal infection, herpes infection, infection, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Increased susceptibility to infection may occur with either systemic or topical use. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Serious viral infections reported include polyoma virus-associated nephropathy (PVAN) mostly due to BK virus infection, JC virus-associated progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) infections. CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at higher risk of developing CMV viremia and CMV disease. Reactivation of a latent viral infection, especially herpes infection, can occur with immunosuppressive therapy. Monitor for infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection. Treatment with topical tacrolimus may be associated with an increased risk of varicella zoster (chickenpox or shingles) and herpes simplex infection. In the presence of these infections, the balance of risk and benefits associated with topical therapy should be evaluated. Patients should be instructed to report signs of infection promptly. Therapy requires an experienced clinician, specifically only clinicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Administration of systemic tacrolimus requires a specialized care setting and should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.

    Immunosuppression, lymphoma, mononucleosis, new primary malignancy, post-transplant lymphoproliferative disorder (PTLD), skin cancer

    Patients receiving immunosuppressants such as oral or injectable tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients and has an association with the Epstein-Barr Virus (EBV). The risk of PTLD appears greatest in EBV negative patients. Monitor EBV serology during tacrolimus therapy. Also, immunosuppression from the use of topical tacrolimus may influence the possible development of a new primary malignancy, especially skin cancer, lymphoma, or other lymphoproliferative disorders; rare cases of malignancy (e.g., skin and lymphoma) have been reported, but a causal relationship has not been established. Some malignant conditions such as cutaneous T-cell lymphoma may mimic atopic dermatitis; avoid the use of topical tacrolimus on premalignant and malignant skin conditions. Discontinue Protopic in the presence of acute infectious mononucleosis, and do not use Protopic in patients who are immunocompromised. Avoid continuous long-term use of topical calcineurin inhibitors such as tacrolimus ointment, and limit application to areas of involvement with atopic dermatitis. Only physicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Patients initiating systemic tacrolimus therapy should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.[28611][30973][55401][60497]

    Liver transplant

    The extended-release tacrolimus formulation (Astagraf XL) is not indicated for use in liver transplant recipients due to an increased 12-month mortality rate in female patients who received Astagraf XL compared with immediate-release capsules (Prograf) in a randomized, clinical trial.

    Children, infants, neonates

    Tacrolimus ointment is not approved for use in neonates, infants, or children younger than 2 years old; only the lower concentration (tacrolimus 0.03%) ointment is recommended for use in non-immunocompromised pediatric patients aged 2 to 15 years. The long-term effect of tacrolimus on the developing immune system in infants and children is not known. Immediate-release capsules and granules for oral suspension are indicated for the prophylaxis of organ rejection in pediatric kidney, liver, and heart transplant patients. In general, pediatric patients require higher tacrolimus doses compared to adults; these requirements may decrease as the child grows older. If pediatric patients are converted between immediate-release formulations, perform therapeutic drug monitoring and adjust the dosage as necessary to ensure adequate tacrolimus exposure is maintained. Astagraf XL is approved in pediatric patients 4 years of age and older. The safety and efficacy of Envarsus XR have not been established in patients less than 18 years of age.

    Oliguria, renal disease, renal failure, renal impairment

    Rare cases of acute renal failure have been reported in patients who received topical tacrolimus ointment; use the topical ointment cautiously in patients with renal impairment.[30973] Acute and chronic nephrotoxicity may occur with systemic tacrolimus therapy, especially at high doses. Monitor renal function and consider dosage reduction in patients with elevated serum creatinine (SCr) and tacrolimus whole blood concentrations greater than the recommended range. In kidney transplant recipients, treatment initiation may need to be delayed until there is evidence of renal function recovery.[28611] [55401] [60497] In liver and heart transplant recipients, consider starting at the lower end of the dosing range in patients who have pre-existing renal disease. In patients who develop renal failure while receiving tacrolimus, echocardiographic evaluation should be considered.[28611] Monitor patients with renal impairment closely; the tacrolimus dosage may need to be reduced in these patients. Consider switching to a different immunosuppressant therapy in patients who experience persistent SCr elevations despite a tacrolimus dose reduction.[28611] [55401] Acute nephrotoxicity is usually reversible and may be related to afferent renal arteriole vasoconstriction; signs and symptoms include increased SCr concentrations and oliguria. Chronic nephrotoxicity is often progressive; signs and symptoms include increased SCr concentrations, decreased graft function life, and histologic changes on renal biopsy. The risk of nephrotoxicity is increased with concomitant administration of CYP3A inhibitors (which increase tacrolimus concentrations) and drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, and protease inhibitors); do not administer tacrolimus concomitantly with cyclosporine.[28611] [55401] [60497]

    Hepatic disease

    Hepatotoxicity has been reported with systemic tacrolimus therapy; use cautiously in patients with pre-existing hepatic disease. A lower dosage may be necessary for patients with severe hepatic impairment (Child-Pugh class C score greater than 10) due to reduced tacrolimus clearance and a prolonged half-life in these patients. Closely monitor trough concentrations in patients with hepatic impairment.[28611] [55401][60497] Liver transplant recipients with post-transplant severe hepatic impairment may have an increased risk of developing renal impairment related to high trough concentrations; consider lower doses in these patients.[28611]

    Hyperkalemia, hypertension

    Tacrolimus can cause hyperkalemia and hypertension. Use tacrolimus capsules, extended-release capsules, extended-release tablets, and injection with caution in patients with pre-existing hypertension. Antihypertensive therapy may be required, but cautious use of potassium-sparing diuretics, ACE inhibitors, and angiotensin receptor blockers is warranted.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, coronary artery disease, females, geriatric, heart failure, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Tacrolimus may cause QT prolongation and torsade de pointes; avoid use in patients with congenital long QT syndrome. Use systemic tacrolimus cautiously in patients with pre-existing cardiomyopathy or other cardiac disease associated with left ventricular dysfunction (e.g., heart failure); tacrolimus-induced myocardial hypertrophy has been reported. Consider obtaining electrocardiograms and monitoring electrolytes (i.e., magnesium, potassium, calcium) periodically during treatment for patients with congestive heart failure or bradyarrhythmias such as bradycardia. Further, use tacrolimus with caution in patients with other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Seizure disorder, seizures

    Tacrolimus may cause a variety of neurotoxicities including seizures. Symptoms may be associated with tacrolimus blood trough concentrations at or above the recommended range. Monitor concentrations closely in patients with a seizure disorder, especially in patients with concurrent renal or hepatic dysfunction. Consider dosage reduction or discontinuation if neurotoxicity occurs.

    Black patients, diabetes mellitus, hyperglycemia

    Insulin-dependent post-transplant diabetes mellitus has been reported in tacrolimus-treated renal transplant patients. Black patients and Hispanic patients post-renal transplant were at an increased risk of development of post-transplant diabetes mellitus. The risk of development of post-transplant diabetes mellitus increased with increasing whole blood trough concentrations of tacrolimus and increasing doses of corticosteroids. Patients with pre-existing hyperglycemia may require alterations in hypoglycemic therapy. Also, Black kidney transplant patients may need a higher tacrolimus dose to attain comparable trough concentrations as compared with Caucasian patients. A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted, but some data are available. For example, 30 days after renal transplantation, a tacrolimus dose of 0.17 mg/kg in Caucasians led to a trough of 12.8 ng/mL. In contrast, a trough of 12.9 ng/mL was obtained with a tacrolimus dose of 0.26 mg/kg in Black patients.

    Intravenous administration, polyoxyethylated castor oil hypersensitivity

    Tacrolimus is contraindicated for use by patients with a hypersensitivity to tacrolimus. The intravenous formulation of tacrolimus contains polyoxyl 60 hydrogenated castor oil and is contraindicated for use by patients with polyoxyethylated castor oil hypersensitivity because anaphylaxis can occur during intravenous administration of tacrolimus. Intravenous use is recommended only for those who cannot tolerate an oral formulation, and conversion is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions. Constantly observe patients for at least the first 30 minutes after the start of the infusion and at frequent intervals thereafter. If signs and symptoms of anaphylaxis occur, stop the infusion immediately. Epinephrine and a source of oxygen should be immediately available.

    Pregnancy

    Tacrolimus can cause fetal harm when administered during pregnancy. Human data suggest that infants exposed to tacrolimus in utero are at risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Advise pregnant women of the potential risk to the fetus. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants; patients can register by contacting 1-877-955-6877 or www.transplantregistry.org. Tacrolimus may increase hyperglycemia in pregnant women with diabetes, including those with gestational diabetes. In addition, exacerbation of hypertension may increase the risk of pre-eclampsia. Monitor blood glucose concentrations and blood pressure regularly and treat as appropriate. Renal dysfunction, transient neonatal hyperkalemia, and low birth weight have been reported at the time of delivery in newborns of mothers taking tacrolimus. The experience with topical tacrolimus in pregnant women is too limited to permit assessment of the safety of its use during pregnancy. Tacrolimus should be used during pregnancy only when clearly needed.[28611] [30973][55401][60497]

    Breast-feeding

    Use tacrolimus with caution during breast-feeding. Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk after systemic use. The effects of tacrolimus on the breastfed infant or milk production have not been assessed.[28611] [60497] Limited data indicate that the amount of tacrolimus excreted into breast-milk after systemic administration is low.[49424] [49425] In addition, no adverse reactions have been reported in nursing infants.[49426] The systemic absorption of tacrolimus after topical administration is minimal; 90% (1,253/1,391) of subjects in a pharmacokinetic trial with periodic blood sampling had blood concentrations of less than 2 ng/mL.[30973] Therefore, it is unlikely that a clinically significant exposure would occur via breast milk. Do not allow direct contact of the infant's skin to treated areas and do not apply to the nipple area if nursing. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Infertility, reproductive risk

    Counsel female and male patients of reproductive potential about the reproductive risk associated with tacrolimus and discuss family planning options including appropriate contraception prior to treatment initiation. Tacrolimus can cause fetal harm when administered to pregnant women. Based on animal data, infertility may occur in male and female patients receiving tacrolimus. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy to enroll in the voluntary Transplantation Pregnancy Registry International at 1-877-955-6877 or www.transplantpregnancyregistry.org.

    Vaccination

    When possible administer any needed immunizations prior to transplantation and initiation of tacrolimus therapy. Live vaccines (e.g., intranasal influenza, MMR, varicella) should not be administered during tacrolimus therapy. It is recommended that live, attenuated vaccines should not be given for >= 3 months after immunosuppressive therapy. Patients receiving any vaccination during tacrolimus therapy or in the 2 weeks prior to starting systemic therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of or in addition to vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Sunlight (UV) exposure

    Patients should minimize or avoid phototherapy or sunlight (UV) exposure (natural or artificial) during tacrolimus therapy. Patients receiving immunosuppressants are at increased risk of developing lymphomas or other malignancies, especially of the skin. Inform patients of the increased risk of cancer; advise them to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen with a high protection factor. Despite the absence of observed phototoxicity in humans, tacrolimus ointment shortened the time to skin tumor formation in an animal photocarcinogenicity study.

    Occlusive dressing, ocular exposure

    Tacrolimus ointment is for dermatologic use only. Avoid ocular exposure of tacrolimus ointment. Avoid use of any occlusive dressing. The safety of tacrolimus ointment has not been established with occlusive dressings, which may increase the systemic absorption of tacrolimus.

    Exfoliative dermatitis, ichthyosis

    The safety of tacrolimus ointment has not been established for patients with generalized erythroderma, a widespread reddening of the skin often associated with exfoliative dermatitis. The use of tacrolimus ointment in those with ichthyosis, specifically Netherton's syndrome (congenital ichthyosiform erythroderma), is not recommended due to the potential for increased systemic absorption of tacrolimus.

    Red cell aplasia

    Pure red cell aplasia (PRCA) has been reported with tacrolimus therapy. Risk factors for PRCA include parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. Consider discontinuation of tacrolimus in patients diagnosed with PRCA.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 0-45.0
    pleural effusion / Delayed / 22.0-36.0
    oliguria / Early / 0-19.0
    renal tubular necrosis / Delayed / 0-15.0
    renal failure (unspecified) / Delayed / 0-15.0
    anuria / Delayed / 0-15.0
    seizures / Delayed / 0-15.0
    atrial flutter / Early / 0-15.0
    atrial fibrillation / Early / 0-15.0
    pericardial effusion / Delayed / 15.0-15.0
    thrombotic microangiopathy / Delayed / 0-15.0
    hemolytic anemia / Delayed / 0-15.0
    anasarca / Delayed / 0-15.0
    pulmonary edema / Early / 0-15.0
    acute respiratory distress syndrome (ARDS) / Early / 0-15.0
    stroke / Early / 3.1-14.9
    bradycardia / Rapid / 3.1-14.9
    heart failure / Delayed / 3.1-14.9
    thrombosis / Delayed / 3.1-14.9
    GI bleeding / Delayed / 3.1-14.9
    GI perforation / Delayed / 3.1-14.9
    esophageal ulceration / Delayed / 3.1-14.9
    ileus / Delayed / 3.1-14.9
    coagulopathy / Delayed / 3.1-14.9
    exfoliative dermatitis / Delayed / 0-14.9
    pneumothorax / Early / 3.1-14.9
    angioedema / Rapid / 1.0-2.0
    cardiomyopathy / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    cardiac valvulopathy / Delayed / 0.2-0.9
    nephrotoxicity / Delayed / 10.0
    hemorrhagic cystitis / Delayed / Incidence not known
    optic atrophy / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    pancreatitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    post-transplant lymphoproliferative disorder (PTLD) / Delayed / Incidence not known

    Moderate

    hypertension / Early / 0-89.0
    diabetes mellitus / Delayed / 10.0-75.0
    hypertriglyceridemia / Delayed / 65.0-65.0
    anemia / Delayed / 0.2-65.0
    hypercholesterolemia / Delayed / 0.2-57.0
    hypophosphatemia / Delayed / 13.0-49.0
    hypomagnesemia / Delayed / 12.0-48.0
    leukopenia / Delayed / 13.0-48.0
    hyperglycemia / Delayed / 11.0-47.0
    constipation / Delayed / 0.2-40.0
    elevated hepatic enzymes / Delayed / 0-37.0
    peripheral edema / Delayed / 0-36.0
    hyperlipidemia / Delayed / 10.0-34.0
    hypokalemia / Delayed / 0-29.0
    dyspnea / Early / 0-29.0
    erythema / Early / 9.0-28.0
    ascites / Delayed / 7.0-27.0
    thrombocytopenia / Delayed / 0-24.0
    chest pain (unspecified) / Early / 0.2-19.0
    edema / Delayed / 0.2-18.0
    conjunctivitis / Delayed / 0-15.0
    proteinuria / Delayed / 0-15.0
    hyperphosphatemia / Delayed / 0-15.0
    hyponatremia / Delayed / 0-15.0
    confusion / Early / 0-15.0
    depression / Delayed / 0-15.0
    hallucinations / Early / 0-15.0
    peripheral neuropathy / Delayed / 0-15.0
    blurred vision / Early / 0-15.0
    neurotoxicity / Early / 0-15.0
    sinus tachycardia / Rapid / 0-15.0
    hyperuricemia / Delayed / 0-15.0
    metabolic acidosis / Delayed / 0-15.0
    stomatitis / Delayed / 0-15.0
    esophagitis / Delayed / 0-15.0
    gastritis / Delayed / 0-15.0
    neutropenia / Delayed / 0-15.0
    impaired wound healing / Delayed / 0-15.0
    osteopenia / Delayed / 0-15.0
    osteoporosis / Delayed / 0-15.0
    cholestasis / Delayed / 0-15.0
    hepatitis / Delayed / 0-15.0
    vaginitis / Delayed / 0-15.0
    BK virus-associated nephropathy / Delayed / 0.7-14.9
    dysuria / Early / 3.1-14.9
    pyuria / Delayed / 3.1-14.9
    cystitis / Delayed / 3.1-14.9
    bladder spasm / Early / 3.1-14.9
    hematuria / Delayed / 3.1-14.9
    urinary retention / Early / 3.1-14.9
    hypercalcemia / Delayed / 3.1-14.9
    hypocalcemia / Delayed / 3.1-14.9
    amnesia / Delayed / 3.1-14.9
    psychosis / Early / 3.1-14.9
    encephalopathy / Delayed / 3.1-14.9
    myoclonia / Delayed / 3.1-14.9
    amblyopia / Delayed / 3.1-14.9
    peripheral vasodilation / Rapid / 0.2-14.9
    angina / Early / 3.1-14.9
    orthostatic hypotension / Delayed / 3.1-14.9
    phlebitis / Rapid / 3.1-14.9
    hypotension / Rapid / 3.1-14.9
    Cushing's syndrome / Delayed / 3.1-14.9
    hypervolemia / Delayed / 3.1-14.9
    metabolic alkalosis / Delayed / 3.1-14.9
    hypoglycemia / Early / 3.1-14.9
    dysphagia / Delayed / 3.1-14.9
    polycythemia / Delayed / 3.1-14.9
    skin ulcer / Delayed / 0.2-14.9
    dehydration / Delayed / 0.2-14.9
    heat intolerance / Early / 3.1-14.9
    gout / Delayed / 3.1-14.9
    myasthenia / Delayed / 3.1-14.9
    cholangitis / Delayed / 3.1-14.9
    jaundice / Delayed / 3.1-14.9
    hyperbilirubinemia / Delayed / 0.2-14.9
    hyperesthesia / Delayed / 0-7.0
    migraine / Early / 0.2-0.9
    blepharitis / Early / 0.2-0.9
    cataracts / Delayed / 0.2-0.9
    hypothyroidism / Delayed / 0.2-0.9
    colitis / Delayed / 0.2-0.9
    furunculosis / Delayed / 0.2-0.9
    osteomyelitis / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    delirium / Early / Incidence not known
    photophobia / Early / Incidence not known
    aphasia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    glycosuria / Early / Incidence not known
    immunosuppression / Delayed / Incidence not known

    Mild

    diarrhea / Early / 3.0-72.0
    headache / Early / 9.0-64.0
    insomnia / Early / 1.0-64.0
    abdominal pain / Early / 0-59.0
    tremor / Early / 15.0-56.0
    asthenia / Delayed / 0-52.0
    nausea / Early / 1.0-46.0
    pruritus / Rapid / 0-46.0
    fever / Early / 1.0-46.0
    infection / Delayed / 1.0-45.0
    paresthesias / Delayed / 0-40.0
    anorexia / Delayed / 0-34.0
    leukocytosis / Delayed / 0-32.0
    cough / Delayed / 1.0-31.0
    back pain / Delayed / 1.0-30.0
    vomiting / Early / 1.0-29.0
    dyspepsia / Early / 0-28.0
    arthralgia / Delayed / 0-25.0
    rash / Early / 0-24.0
    dizziness / Early / 0-19.0
    fatigue / Early / 16.0-16.0
    agitation / Early / 0-15.0
    nightmares / Early / 0-15.0
    anxiety / Delayed / 0-15.0
    hypoesthesia / Delayed / 0-15.0
    tinnitus / Delayed / 0-15.0
    flushing / Rapid / 0-15.0
    Cushingoid features / Delayed / 0-15.0
    gastroesophageal reflux / Delayed / 0-15.0
    flatulence / Early / 0-15.0
    alopecia / Delayed / 0-15.0
    acne vulgaris / Delayed / 0-15.0
    hyperhidrosis / Delayed / 0-15.0
    pharyngitis / Delayed / 3.0-14.9
    rhinitis / Early / 2.0-14.9
    influenza / Delayed / 3.1-14.9
    sinusitis / Delayed / 2.0-14.9
    urinary urgency / Early / 3.1-14.9
    nocturia / Early / 3.1-14.9
    emotional lability / Early / 3.1-14.9
    inconsolable crying / Delayed / 3.1-14.9
    psychomotor impairment / Early / 3.1-14.9
    abnormal dreams / Early / 3.1-14.9
    drowsiness / Early / 3.1-14.9
    syncope / Early / 0.2-14.9
    otalgia / Early / 0-14.9
    vertigo / Early / 0.2-14.9
    weight gain / Delayed / 3.1-14.9
    appetite stimulation / Delayed / 3.1-14.9
    ecchymosis / Delayed / 0.2-14.9
    skin discoloration / Delayed / 0.2-14.9
    hirsutism / Delayed / 3.1-14.9
    diaphoresis / Early / 0.2-14.9
    photosensitivity / Delayed / 0.2-14.9
    chills / Rapid / 0.2-14.9
    hiccups / Early / 3.1-14.9
    myalgia / Early / 0-14.9
    folliculitis / Delayed / 2.0-6.0
    urticaria / Rapid / 1.0-6.0
    vesicular rash / Delayed / 1.0-4.0
    dysmenorrhea / Delayed / 0-4.0
    xerosis / Delayed / 1.0-3.0
    maculopapular rash / Early / 0-2.0
    laryngitis / Delayed / 0.2-0.9
    ocular pain / Early / 0.2-0.9
    xerophthalmia / Early / 0.2-0.9
    dysgeusia / Early / 0.2-0.9
    seborrhea / Delayed / 0.2-0.9
    xerostomia / Early / 0.2-0.9
    epistaxis / Delayed / 0.2-0.9
    muscle cramps / Delayed / 0.2-0.9
    arthropathy / Delayed / 0.2-0.9
    weight loss / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously with other drugs that are associated with QT prolongation, such as tacrolimus.
    Acetaminophen; Butalbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Acetaminophen; Butalbital; Caffeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Acyclovir: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including acyclovir. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced .
    Adefovir: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including adefovir. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
    Afatinib: (Moderate) If the concomitant use of tacrolimus and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of tacrolimus. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. While data is conflicting, tacrolimus may be a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Albuterol: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aldesleukin, IL-2: (Moderate) Aldesleukin may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects with Aldesleukin, such as tacrolimus, may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and tacrolimus should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as alfuzosin.
    Aliskiren; Amlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Alogliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Alogliptin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Alogliptin; Pioglitazone: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Alpha-glucosidase Inhibitors: (Moderate) Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Aluminum Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Amiloride: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    Aminoglycosides: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced
    Amiodarone: (Major) Amiodarone and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4, and amiodarone is also a CYP3A4 inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
    Amitriptyline: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Amitriptyline; Chlordiazepoxide: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Amlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Benazepril: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Olmesartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Telmisartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Valsartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Concurrent administration of clarithromycin and tacrolimus may result in elevated tacrolimus concentrations resulting in nephrotoxicity. Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4; clarithromycin inhibits this isoenzyme. The manufacturer of tacrolimus states that coadministration with strong CYP3A4 inhibitors such as clarithromycin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. In addition, both clarithromycin and tacrolimus have been reported to prolong the QTc interval. Use this combination with caution. (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concurrent administration of clarithromycin and tacrolimus may result in elevated tacrolimus concentrations resulting in nephrotoxicity. Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4; clarithromycin inhibits this isoenzyme. The manufacturer of tacrolimus states that coadministration with strong CYP3A4 inhibitors such as clarithromycin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. In addition, both clarithromycin and tacrolimus have been reported to prolong the QTc interval. Use this combination with caution. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase the serum concentrations of tacrolimus.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B lipid complex (ABLC): (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B liposomal (LAmB): (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B: (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
    Amprenavir: (Major) Coadministration with strong CYP3A4 inhibitors such as amprenavir is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include tacrolimus.
    Angiotensin-converting enzyme inhibitors: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
    Apalutamide: (Moderate) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with apalutamide is necessary. Tacrolimus is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly increased tacrolimus clearance.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with apomorphine. Tacrolimus causes QT prolongation. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Major) Use caution if tacrolimus and aprepitant, fosaprepitant are used concurrently and monitor tacrolimus levels and for an increase in tacrolimus-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tacrolimus is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tacrolimus. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. Use caution if tacrolimus and aprepitant, fosaprepitant are used concurrently and monitor tacrolimus levels and for an increase in tacrolimus-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tacrolimus is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tacrolimus. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Tacrolimus causes QT prolongation. Tacrolimus should be used cautiously and with close monitoring with aripiprazole.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include tacrolimus.
    Artemether; Lumefantrine: (Major) Concurrent use of tacrolimus and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If tacrolimus must be coadministered with substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, such as artemether; lumefantrine, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitor for QT prolongation. Consider ECG monitoring if tacrolimus must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, such as asenapine. However, according to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to prolong the QT interval.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Aspirin, ASA; Omeprazole: (Moderate) Concomitant administration of omeprazole and tacrolimus may increase the serum concentrations of tacrolimus.
    Aspirin, ASA; Pravastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and pravastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of pravastatin40 mg/day is recommended.
    Atazanavir: (Moderate) Atazanavir has potential to inhibit the CYP3A4 metabolism of tacrolimus. Increased tacrolimus serum concentrations may be seen. If these drugs are coadministered, monitor tacrolimus serum concentrations in order to prevent serious drug-related adverse events such as QT prolongation.
    Atazanavir; Cobicistat: (Moderate) Atazanavir has potential to inhibit the CYP3A4 metabolism of tacrolimus. Increased tacrolimus serum concentrations may be seen. If these drugs are coadministered, monitor tacrolimus serum concentrations in order to prevent serious drug-related adverse events such as QT prolongation. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated tacrolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tacrolimus. These drugs used in combination may result in elevated tacrolimus plasma concentrations, causing an increased risk for tacrolimus-related adverse events.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include tacrolimus.
    Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity.
    Atorvastatin; Ezetimibe: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Azathioprine: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression
    Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with azithromycin. Tacrolimus causes QT prolongation, and cases of QT prolongation and TdP have been reported with the post-marketing use of azithromycin.
    Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of these medicines. When possible, avoid concomitant administration of systemic bacitracin and other nephrotoxic drugs such as tacrolimus. Use of topically administrated preparations containing bacitracin, especially when applied to large surface areas, may have additive nephrotoxic potential.
    Barbiturates: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Basiliximab: (Major) Basiliximab acts as an IL-2 receptor antagonist. Binding of basiliximab to the IL-2 receptors on activated T cells may allow circulating IL-2 to bind to IL-2 receptors on hepatic and intestinal cells, which may cause a down-regulation of CYP3A4 enzyme activity. Reduced CYP3A4 activity may increase concentrations of CYP3A4 substrates such as tacrolimus. In a retrospective evaluation, the tacrolimus dose needed to achieve a trough concentration of 15 to 20 ng/ml was lower among basiliximab recipients as compared with antithymocyte globulin recipients. Over the 60 days after transplantation, tacrolimus dose requirements were 0.16 mg/kg/day for basiliximab recipients and 0.24 mg/kg/day for antithymocyte globulin recipients. All patients initially received oral tacrolimus 0.075 to 0.15 mg/kg with the dose titrated to achieve the desired trough concentration. On day 3 after transplantation, tacrolimus trough concentrations were higher than 20 ng/ml in 6 of 12 adults who also got basiliximab 20 mg on the day of transplantation and 4 days later; three patients with an elevated trough concentration had acute tubular necrosis and underwent hemodialysis. In contrast, 2 of 8 patients who got antithymocyte globulin daily for the first 7 days had a tacrolimus trough concentration higher than 20 ng/ml - no significant adverse effects were noted. The half-life of basiliximab is 7.2 days, so the tacrolimus dose may need upward adjustment as the effects of basiliximab on IL-2 dissipate. For example, one month after transplantation, 6 of the 12 basiliximab recipients had tacrolimus trough concentrations below the targeted range of 15 to 20 ng/ml.
    Bedaquiline: (Major) Bedaquiline and tacrolimus can cause QT prolongation, and both drugs are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministering with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. The manufacturer of bedaquiline recommends obtaining obtain serum electrolyte concentrations and a baseline ECG prior to initiation of therapy. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Bepridil: (Major) Tacrolimus has been associated with a possible risk for QT prolongation and/or torsades de pointes and should be used cautiously with other drugs that may prolong the QT interval or increase the risk of torsades de pointes, including bepridil.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Monitor patients for signs and symptoms of QT prolongation with coadministration of systemic metronidazole and tacrolimus. QT prolongation has been associated with the use of both agents; therefore, concomitant use may increase this risk.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Monitor patients for signs and symptoms of QT prolongation with coadministration of systemic metronidazole and tacrolimus. QT prolongation has been associated with the use of both agents; therefore, concomitant use may increase this risk.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as tacrolimus. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Major) Tacrolimus is a substrate of the hepatic isoenzyme CYP3A4. Coadministration with strong CYP3A4 inhibitors such as boceprevir is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. In addition, frequent assessments of renal function are advised. In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9 - fold and AUC by 17 - fold compared to tacrolimus alone.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like tacrolimus; the risk of peripheral neuropathy may be additive.
    Bosentan: (Moderate) Drugs such as bosentan, which can induce cytochrome P-450 3A4, can decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations is recommended if any of the hepatic enzyme inducing agents are used concurrently with tacrolimus.
    Brigatinib: (Moderate) Monitor tacrolimus serum concentrations and watch for decreased efficacy of tacrolimus if coadministration with brigatinib is necessary; adjust the dose of tacrolimus as clinically indicated. Tacrolimus is a sensitive CYP3A substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Brodalumab: (Moderate) If brodalumab is initiated or discontinued in a patient taking tacrolimus, monitor tacrolimus concentrations; tacrolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus.
    Bromocriptine: (Minor) Bromocriptine may decrease the clearance of tacrolimus with the potential to either reduce immunosuppressant dosage requirements or cause drug-related toxicity. Close monitoring of tacrolimus concentrations is recommended if bromocriptine is coadministered.
    Budesonide; Formoterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Buprenorphine: (Major) Both buprenorphine and tacrolimus have been associated with QTc prolongation, and both are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Buprenorphine; Naloxone: (Major) Both buprenorphine and tacrolimus have been associated with QTc prolongation, and both are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Butabarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Canagliflozin: (Moderate) Tacrolimus has been reported to cause hyperglycemia, and may contribute to insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Monitor for changes in glycemic control if therapy with tacrolimus is initiated.
    Canagliflozin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia, and may contribute to insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Monitor for changes in glycemic control if therapy with tacrolimus is initiated. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Canakinumab: (Moderate) If canakinumab is initiated or discontinued in a patient taking tacrolimus, monitor tacrolimus concentrations; tacrolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during canakinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus.
    Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including tacrolimus, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Carbamazepine: (Moderate) Carbamazepine induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when carbamazepine and tacrolimus are used concomitantly.
    Carboplatin: (Moderate) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Caspofungin: (Major) Tacrolimus concentrations are reduced approximately 25% in those patients receiving concurrent caspofungin. The mechanism of this interaction has not been identified; monitor tacrolimus blood concentrations. Increased dosage of tacrolimus may be required. The pharmacokinetic parameters of caspofungin are not altered by tacrolimus.
    Ceritinib: (Major) Avoid coadministration of ceritinib with tacrolimus due to increased tacrolimus exposure; additive QT prolongation may also occur. If coadministration is unavoidable, monitor tacrolimus levels and watch for tacrolimus-related adverse reactions; a dosage adjustment may be necessary. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index and is also associated with QT prolongation.
    Chlorambucil: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Chloramphenicol: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 CYP 3A4. Drugs that inhibit this isoenzyme, such as chloramphenicol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Chloroquine: (Major) Avoid coadministration of chloroquine with tacrolimus if possible, due to the risk of QT prolongation and torsade de pointes (TdP). Chloroquine administration is associated with an increased risk of QT prolongation and TdP. Tacrolimus has also been associated with QT prolongation and TdP. Coadministration may further increase the risk of QT prolongation and torsade de pointes.
    Chlorpromazine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and chlorpromazine should be used together cautiously. Tacrolimus causes QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
    Chondroitin; Glucosamine: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Cidofovir: (Severe) The administration of cidofovir with another potentially nephrotoxic agent, such as tacrolimus is contraindicated. Tacrolimus should be discontinued at least 7 days prior to beginning cidofovir.
    Cimetidine: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 system. Drugs that inhibit this enzyme system, including cimetidine, may decrease the metabolism of tacrolimus. Subsequent increased plasma concentrations of tacrolimus may lead to nephrotoxicity.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with ciprofloxacin. Tacrolimus causes QT prolongation, and ciprofloxacin has been associated with a possible risk for QT prolongation and TdP.
    Cisapride: (Severe) Tacrolimus prolongs the QTc interval. Because of the potential for torsades de pointes (TdP), use of cisapride with tacrolimus is contraindicated.
    Cisplatin: (Moderate) Other nephrotoxic drugs, including tacrolimus, can aggravate the nephrotoxicity and electrolyte loss seen with cisplatin if given concurrently or shortly after cisplatin therapy. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
    Citalopram: (Major) Concurrent use of citalopram with tacrolimus is not recommended due to a possible risk for QT prolongation and torsade de pointes (TdP). If concurrent therapy is considered essential, ECG monitoring is recommended. Tacrolimus causes QT prolongation. Citalopram causes dose-dependent QT interval prolongation.
    Citric Acid; Potassium Citrate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Clarithromycin: (Major) Concurrent administration of clarithromycin and tacrolimus may result in elevated tacrolimus concentrations resulting in nephrotoxicity. Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4; clarithromycin inhibits this isoenzyme. The manufacturer of tacrolimus states that coadministration with strong CYP3A4 inhibitors such as clarithromycin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. In addition, both clarithromycin and tacrolimus have been reported to prolong the QTc interval. Use this combination with caution.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with tacrolimus. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Tacrolimus causes QT prolongation. Additionally, concomitant use may increase the concentration of tacrolimus, increasing the risk of adverse effects. Tacrolimus is a CYP3A4 substrate that has a narrow therapeutic range; in vitro data suggest clofazimine inhibits CYP3A4.
    Clomipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Clozapine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and clozapine should be used together cautiously. Tacrolimus causes QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation.
    Cobicistat: (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated tacrolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tacrolimus. These drugs used in combination may result in elevated tacrolimus plasma concentrations, causing an increased risk for tacrolimus-related adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated tacrolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tacrolimus. These drugs used in combination may result in elevated tacrolimus plasma concentrations, causing an increased risk for tacrolimus-related adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated tacrolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tacrolimus. These drugs used in combination may result in elevated tacrolimus plasma concentrations, causing an increased risk for tacrolimus-related adverse events.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and tacrolimus is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and tacrolimus is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include tacrolimus.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include tacrolimus.
    Colchicine: (Major) Coadministration of colchicine and tacrolimus should be avoided due to the potential for serious and life-threatening toxicity. Colchicine is a substrate of P-glycoprotein (P-gp) and tacrolimus is an inhibitor of P-gp; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore the manufacturer of Colcrys contraindicates the use of colchicine and P-gp inhibitors in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for coadministration with P-gp inhibitors are provided by the manufacturer of Colcrys.
    Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including tacrolimus, may increase serum concentrations of either drug.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tacrolimus, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tacrolimus. Treatment with tacrolimus may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Avoid coadministration of crizotinib with tacrolimus due to the risk of QT prolongation; exposure to tacrolimus may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Frequently monitor tacrolimus whole blood concentrations; adjust the dose of tacrolimus as clinically appropriate. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Tacrolimus is a sensitive CYP3A4 substrate that also causes QT prolongation.
    Cyclosporine: (Severe) Concurrent use of cyclosporine and tacrolimus may increase the risk of nephrotoxicity due to synergistic or additive effects. Concomitant tacrolimus and cyclosporine usage is not recommended. When switching patients from cyclosporine to tacrolimus, wait at least 24 hours after the last dose of cyclosporine before beginning tacrolimus therapy. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be delayed until the concentration falls into the normal range.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with tacrolimus, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE), or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like tacrolimus in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with tacrolimus, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) The concomitant use of dabrafenib and tacrolimus may lead to decreased tacrolimus concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor tacrolimus levels and for loss of tacrolimus efficacy. Dabrafenib is a moderate CYP3A4 inducer and tacrolimus is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Daclizumab: (Minor) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. In a randomized trial of daclizumab for the prevention of allograft rejection in cardiac transplant patients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving daclizumab compared to those receiving placebo (7% vs. 5%, respectively, at 6 months; 10% vs. 6%, respectively, at 12 months). Some, but not all of the increased mortality appeared to be related to a higher incidence of severe infections. Concomitant use of antilymphocyte antibody therapy may also be a factor in some of the fatal infections. In renal allograft recipients treated with daclizumab and mycophenolate mofetil, no pharmacokinetic interaction between daclizumab and mycophenolic acid (the active metabolite of mycophenolate mofetil) was observed. Very limited experience exists with the use of daclizumab concomitantly with antithymocyte globulin, antilymphocyte globulin, muromonab-CD3, or tacrolimus.
    Dalfopristin; Quinupristin: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with dalfopristin; quinupristin. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. dalfopristin; quinupristin is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Danazol: (Moderate) Danazol has been reported to increase tacrolimus whole blood concentrations. Patients receiving tacrolimus should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of tacrolimus may be necessary if danazol therapy is discontinued.
    Dapagliflozin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin.
    Dapagliflozin; Metformin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Dapagliflozin; Saxagliptin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Darunavir: (Moderate) Tacrolimus is a CYP3A4 substrate, and darunavir inhibits CYP3A4. Close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended.
    Darunavir; Cobicistat: (Moderate) Tacrolimus is a CYP3A4 substrate, and darunavir inhibits CYP3A4. Close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated tacrolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tacrolimus. These drugs used in combination may result in elevated tacrolimus plasma concentrations, causing an increased risk for tacrolimus-related adverse events.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Moderate) Tacrolimus is a CYP3A4 substrate, and darunavir inhibits CYP3A4. Close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated tacrolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tacrolimus. These drugs used in combination may result in elevated tacrolimus plasma concentrations, causing an increased risk for tacrolimus-related adverse events.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) A reduced dose of tacrolimus based on tacrolimus whole blood concentrations is recommended if coadministered with ritonavir. Concurrent administration is expected to increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions including neurotoxicity and QT prolongation. Tacrolimus is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Dasatinib: (Major) Monitor for evidence of QT prolongation during concurrent use of dasatinib and tacrolimus. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Tacrolimus causes QT prolongation.
    Deferasirox: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including tacrolimus, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly.
    Degarelix: (Major) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation that should be used cautiously with tacrolimus include degarelix.
    Delavirdine: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 CYP3A4. Drugs that inhibit this isoenzyme, such as delavirdine, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects. Monitor tacrolimus concentrations carefully if these drugs are coadministered.
    Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Desipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with tacrolimus, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Tacrolimus causes QT prolongation.
    Dexlansoprazole: (Moderate) Concomitant administration of dexlansoprazole and tacrolimus may increase serum concentrations of tracrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations, and adjust dose as needed to maintain therapeutic drug concentrations.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include tacrolimus.
    Dextromethorphan; Quinidine: (Major) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). As the risk of TdP is increased with greater QT prolongation, avoid use of quinidine with another drug that prolongs the QT interval such as tacrolimus. It should be noted that the manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as quinidine. Tacrolimus and quinidine are both metabolized by cytochrome P450 3A4.
    Diltiazem: (Moderate) Diltiazem inhibits tacrolimus metabolism via the CYP3A pathway. Tacrolimus blood concentrations should be monitored during concurrent diltiazem therapy as dosage adjustments of tacrolimus may be needed to avoid tacrolimus-induced toxicity.
    Disopyramide: (Major) Disopyramide and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
    Dofetilide: (Severe) Tacrolimus prolongs the QTc interval. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Because of the potential forTdP, use of dofetilide with tacrolimus is contraindicated.
    Dolasetron: (Major) When administering tacrolimus with dolasetron, monitoring for QT prolongation is recommended. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Tacrolimus causes QT prolongation. Concurrent use may increase the risk of QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with tacrolimus. If these drugs are coadministered, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitoring for QT prolongation. Both tacrolimus and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include tacrolimus.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include tacrolimus.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
    Doxepin: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with tacrolimus is necessary, and monitor for an increase in tacrolimus concentrations as well as tacrolimus-related adverse effects. Dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index.
    Dronedarone: (Severe) Concomitant use of dronedarone and tacrolimus is contraindicated. Tacrolimus prolongs the QTc interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4. Droperidol is also associated with torsade de pointes. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are substrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
    Drospirenone; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to tacrolimus. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. Monitor tacrolimus concentrations if dupilumab is initiated or discontinued in a patient taking tacrolimus; tacrolimus dose adjustments may be needed.
    Duvelisib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with duvelisib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range. Duvelisib is a moderate CYP3A inhibitor.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and tacrolimus may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs. Also, efavirenz induces CYP3A4 and may decrease serum concentrations of tacrolimus. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and tacrolimus may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs. Also, efavirenz induces CYP3A4 and may decrease serum concentrations of tacrolimus. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and tacrolimus may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs. Also, efavirenz induces CYP3A4 and may decrease serum concentrations of tacrolimus. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
    Elagolix: (Moderate) Monitor tacrolimus whole blood trough concentrations when tacrolimus is administered with elagolix; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus whole blood concentrations. Tacrolimus is metabolized mainly by CYP3A enzymes; elagolix is a weak to moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Moderate) Studies have shown plasma concentrations of tacrolimus are increased when administered concurrently with elbasvir; grazoprevir. If these drugs are use together, frequently monitor for changes in tacrolimus whole blood concentrations, renal function, and for tacrolimus-associated adverse events. Tacrolimus is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include tacrolimus.
    Emapalumab: (Moderate) Monitor for decreased efficacy of tacrolimus and adjust the dose as needed during coadministration with emapalumab. Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
    Empagliflozin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Empagliflozin; Linagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
    Empagliflozin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Emtricitabine: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with tacrolimus. If these drugs are coadministered, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitoring for QT prolongation. Both tacrolimus and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with tacrolimus. If these drugs are coadministered, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitoring for QT prolongation. Both tacrolimus and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Tenofovir alafenamide: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Enalapril; Felodipine: (Moderate) Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, tacrolimus blood concentration should be monitored and the tacrolimus dose adjusted as necessary.
    Encorafenib: (Major) Avoid coadministration of encorafenib and tacrolimus due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Coadministration may also result in increased toxicity or decreased efficacy of tacrolimus. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Tacrolimus causes QT prolongation and is a sensitive CYP3A4 substrate.
    Enflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Entecavir: (Moderate) In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of tacrolimus, entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients. Monitor renal function.
    Enzalutamide: (Major) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with enzalutamide is necessary. Tacrolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly increased tacrolimus clearance.
    Eribulin: (Major) Eribulin has been associated with QT prolongation. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as eribulin.
    Ertugliflozin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Ertugliflozin; Sitagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Erythromycin: (Major) When possible avoid concurrent erythromycin and tacrolimus therapy. However, if concomitant therapy is necessary, close monitoring of tacrolimus blood concentrations and of the QT interval is warranted. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP such as tacrolimus should be used cautiously with erythromycin. In addition, the concurrent administration of erythromycin and tacrolimus may result in elevated tacrolimus levels resulting in nephrotoxicity. In one case, the whole blood tacrolimus concentration was > 60 ng/ml following 3 days of therapy with erythromycin (prior tacrolimus level 9.8 ng/ml).
    Erythromycin; Sulfisoxazole: (Major) When possible avoid concurrent erythromycin and tacrolimus therapy. However, if concomitant therapy is necessary, close monitoring of tacrolimus blood concentrations and of the QT interval is warranted. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP such as tacrolimus should be used cautiously with erythromycin. In addition, the concurrent administration of erythromycin and tacrolimus may result in elevated tacrolimus levels resulting in nephrotoxicity. In one case, the whole blood tacrolimus concentration was > 60 ng/ml following 3 days of therapy with erythromycin (prior tacrolimus level 9.8 ng/ml).
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as tacrolimus, should be done with caution and close monitoring.
    Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Tacrolimus is a CYP3A4 substrate. Eslicarbazepine may potentially accelerate the hepatic metabolism of tacrolimus. Clinicians should be alert to decreased effectiveness of tacrolimus; dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
    Esomeprazole: (Moderate) Esomeprazole may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, nephrotoxicity, QT prolongation). Monitor tacrolimus whole blood trough concentrations and reduce the tacrolimus dose if needed. Tacrolimus is metabolized primarily by CYP3A4; esomeprazole inhibits CYP3A4 and thus may decrease CYP3A4-mediated metabolism of tacrolimus.
    Esomeprazole; Naproxen: (Moderate) Esomeprazole may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, nephrotoxicity, QT prolongation). Monitor tacrolimus whole blood trough concentrations and reduce the tacrolimus dose if needed. Tacrolimus is metabolized primarily by CYP3A4; esomeprazole inhibits CYP3A4 and thus may decrease CYP3A4-mediated metabolism of tacrolimus.
    Ethanol: (Major) Alcoholic beverages should not be consumed while taking the extended-release tacrolimus capsules (Astagraf XL). Concomitant alcohol use may increase the rate of release of tacrolimus and/or adversely alter the pharmacokinetic properties and effectiveness and safety. A flushing syndrome (alcohol intolerance) has been reported in patients treated with topical tacrolimus or pimecrolimus upon ingestion of ethanol. The flushing occurred in the face or at the sites of medication application, usually within 5-15 minutes of ethanol ingestion, and lasted for an average duration of 1 hour. Patients describe redness and warm sensations, which sometimes result in discomfort. The reaction does not appear to occur in all patients; roughly 3-7% report a notable effect. The possible mechanism of the effect is the inhibition of acetaldehyde dehydrogenase, leading to increased acetaldehyde dehydrogenase concentrations in the skin. Aspirin appears useful in attenuation of the reaction in those patients for whom the reaction is bothersome. (Major) Alcoholic beverages should not be consumed while taking the extended-release tacrolimus capsules (Astagraf XL). Concomitant alcohol use may increase the rate of release of tacrolimus and/or adversely alter the pharmacokinetic properties and effectiveness and safety. A flushing syndrome (alcohol intolerance) has been reported in patients treated with topical tacrolimus or pimecrolimus upon ingestion of ethanol. The flushing occurred in the face or at the sites of medication application, usually within 5-15 minutes of ethanol ingestion, and lasted for an average duration of 1 hour. Patients describe redness and warm sensations, which sometimes result in discomfort. The reaction does not appear to occur in all patients; roughly 3-7% report a notable effect. The possible mechanism of the effect is the inhibition of acetaldehyde dehydrogenase, leading to increased acetaldehyde dehydrogenase concentrations in the skin. Aspirin appears useful in attenuation of the reaction in those patients for whom the reaction is bothersome.
    Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Desogestrel: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norethindrone: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norgestimate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Ethinyl Estradiol; Norgestrel: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Etoposide, VP-16: (Minor) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with tacrolimus. Tacrolimus is a weak inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Etravirine: (Major) Coadministration with etravirine may result in altered tacrolimus concentrations. Coadminister these drugs with caution, carefully monitoring tacrolimus concentrations and making dosage adjustments as needed.
    Ezetimibe; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Ezogabine: (Major) Ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval, such as tacrolimus.
    Felodipine: (Moderate) Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, tacrolimus blood concentration should be monitored and the tacrolimus dose adjusted as necessary.
    Fenofibrate: (Moderate) Coadministration of fenofibrate and tacrolimus may result in deterioration of renal function. Tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and increaess in serum creatinine. Because the primary elimination route of fenofibrate is renal excretion, the benefits and risks of using fenofibrate with tacrolimus should be carefully considered, and the lowest effective dose employed with monitoring of renal function.
    Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include tacrolimus.
    Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with flecainide. Tacrolimus causes QT prolongation. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Severe) Concurrent use of fluconazole and tacrolimus is contraindicated. Both drugs can cause QTc prolongation, and their use together increases the risk of life-threatening arrhythmias such as torsade de pointes (TdP). Additionally, tacrolimus is metabolized via CYP3A4 and fluconazole inhibits this isoenzyme. Although the manufacturer of tacrolimus recommends dose adjustment and close monitoring when tacrolimus is coadministered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, fluconazole is contraindicated for use with CYP3A4 substrates that prolong the QT interval such as tacrolimus.
    Fluoxetine: (Major) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation that should be used cautiously with tacrolimus include fluoxetine. Caution and close monitoring is advised with coadministration.
    Fluoxetine; Olanzapine: (Major) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation include olanzapine. Caution and close monitoring is advised with coadministration. (Major) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation that should be used cautiously with tacrolimus include fluoxetine. Caution and close monitoring is advised with coadministration.
    Fluphenazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and fluphenazine should be used together cautiously. Tacrolimus causes QT prolongation. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and fluvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of fluvastatin of 40 mg/day is recommended.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated tacrolimus concentrations during concurrent use of fluvoxamine and tacrolimus. Tacrolimus causes QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, tacrolimus is metabolized CYP3A4 and fluvoxamine is a moderate inhibitor of CYP3A4, which may result in decreased metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Food: (Severe) The extent of absorption of tacrolimus when given orally with high-fat food is reduced as compared with administration in the fasted state. The systemic exposure (mean AUC) of tacrolimus was decreased by 37% when given with a high-fat meal. The systemic exposure was reduced to a similar extent when tacrolimus was given immediately after or 1.5 hours after meal ingestion as compared with the fasted state. While patients may take tacrolimus with food, it is critical that they always take tacrolimus consistently with or without food to ensure consistent whole blood concentrations.
    Formoterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fosamprenavir: (Moderate) Fosamprenavir inhibits CYP3A4, potentially resulting in elevated whole blood concentrations of tacrolimus and tacrolimus-related side effects, including nephrotoxicity. Close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as tacrolimus. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Tacrolimus also causes QT prolongation. Also, concurrent use may result in additive nephrotoxicity. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Moderate) Fosphenytoin can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of tacrolimus. If fosphenytoin is added to tacrolimus, the levels of tacrolimus should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if fosphenytoin is discontinued, levels of tacrolimus could increase and result in toxicity.
    Fostamatinib: (Moderate) Monitor for tacrolimus toxicities that may require tacrolimus dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a sensitive CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; tacrolimus is a sensitive substrate for CYP3A4. Coadministration of fostamatinib with another sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Ganciclovir: (Moderate) Use ganciclovir and tacrolimus together only if the potential benefits outweigh the risks. Monitor renal function when ganciclovir is coadministered with tacrolimus because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with gemifloxacin. Tacrolimus causes QT prolongation. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and tacrolimus together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Tacrolimus may cause QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with tacrolimus due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tacrolimus also causes QT prolongation.
    Glipizide; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Glucosamine: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Glyburide; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and tacrolimus may result in decreased exposure of tacrolimus. Tacrolimus is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of tacrolimus during coadministration.
    Glycopyrrolate; Formoterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Tacrolimus should be used cautiously and with close monitoring with goserelin. Tacrolimus causes QT prolongation. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), granisetron and tacrolimus should be used together cautiously. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron with drugs known to prolong the QT interval or are arrhythmogenic, may result in clinical consequences. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when administrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as granisetron.
    Grapefruit juice: (Severe) Grapefruit and grapefruit juice consumption by patients receiving tacrolimus should be avoided due to the risk of nephrotoxicity and other potential adverse reactions. Grapefruit juice inhibits tacrolimus metabolism. Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4 and grapefruit juice inhibits CYP3A4 in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level. In one case report, taking tacrolimus after consuming a large amount (1.5 kg) of grapefruit marmalade during the previous week caused a 500% greater blood concentration of the drug and acute renal dysfunction.
    Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Halofantrine: (Severe) Tacrolimus prolongs the QTc interval. Halofantrine has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP) and is contraindicated for use with tacrolimus.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Haloperidol: (Major) Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as haloperidol. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Histrelin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tacrolimus is necessary; correct any electrolyte abnormalities. Tacrolimus causes QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like tacrolimus. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and tacrolimus. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Tacrolimus causes QT prolongation.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include tacrolimus.
    Ibandronate: (Moderate) Theoretically, coadministration of intravenous ibandronate with other potentially nephrotoxic drugs like tacrolimus may increase the risk of developing nephrotoxicity.
    Ibritumomab Tiuxetan: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Tacrolimus causes QT prolongation and should be used cautiously with ibutilide.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tacrolimus, a CYP3A substrate, as tacrolimus toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should not be used with other agents also known to have this effect, such as tacrolimus. If coadministration is necessary, reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.
    Imatinib: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 CYP3A4. Drugs that inhibit this isoenzyme, such as imatinib, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Imipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like tacrolimus. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Incretin Mimetics: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Indacaterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indinavir: (Major) Coadministration with strong CYP3A4 inhibitors such as indinavir is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions.
    Infliximab: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with tacrolimus due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and tacrolimus have been associated with QT interval prolongation.
    Insulins: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Iodine; Potassium Iodide, KI: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Isavuconazonium: (Moderate) Use caution and closely monitor tacrolimus serum concentrations when administered concurrently with isavuconazonium. Use of these drugs together results in elevated tacrolimus serum concentrations and an increased risk for adverse reactions. Tacrolimus dose adjustments may be necessary and should be guided by serum concentrations during coadministration. Isavuconazole, the active moiety of isavuconazonium, is a inhibitor of hepatic isoenzyme CYP3A4; tacrolimus is metabolized by this enzyme.
    Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Isoniazid, INH: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with isoniazid. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Isoniazid is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration with strong CYP3A4-inducers such as rifampin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 +/- 6% vs. 7 +/- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with isoniazid. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Isoniazid is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Isoniazid, INH; Rifampin: (Major) Coadministration with strong CYP3A4-inducers such as rifampin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 +/- 6% vs. 7 +/- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with isoniazid. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Isoniazid is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Itraconazole: (Major) Caution is advised when administering itraconazole with tacrolimus due to the potential for additive effects on the QT interval and increased exposure to tacrolimus. Both tacrolimus and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, itraconazole (a potent CYP3A4 inhibitor) may inhibit the metabolism of tacrolimus (a CYP3A4 substrate); concurrent use may result in elevated tacrolimus plasma concentrations and an increased risk for adverse events, including QT prolongation. Closely monitor tacrolimus blood levels and adjust doses accordingly.
    Ivacaftor: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with tacrolimus due to an increased risk of QT prolongation; tacrolimus exposure may also decrease. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of tacrolimus. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Ivosidenib is a CYP3A4 inducer that has been associated with prolongation of the QTc interval and ventricular arrhythmias. Tacrolimus also causes QT prolongation and is a sensitive CYP3A4 substrate.
    Ixabepilone: (Minor) Tacrolimus is an inhibitor of P-glycoprotein (Pgp). Ixabepilone is a Pgp substrate, and concomitant use of ixabepilone with a Pgp inhibitor may cause an increase in ixabepilone concentrations. Caution is recommended if ixabepilone is coadministered with a Pgp inhibitor.
    Ixekizumab: (Moderate) If ixekizumab is initiated or discontinued in a patient taking tacrolimus, monitor tacrolimus concentrations; tacrolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during ixekizumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. These interactions remain theoretical. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with tacrolimus due to the potential for additive effects on the QT interval and increased exposure to tacrolimus. Both tacrolimus and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole (a potent CYP3A4 inhibitor) may inhibit the metabolism of tacrolimus (a CYP3A4 substrate): concurrent use may result in elevated tacrolimus plasma concentrations and an increased risk for adverse events, including QT prolongation. In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 +/- 5% vs. 30 +/- 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone. Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients. Close monitoring of tacrolimus blood levels is warranted. This interaction has been used clinically to reduce the nephrotoxicity and high cost of tacrolimus therapy.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
    Lanreotide: (Moderate) Measure tacrolimus whole blood trough concentrations at least twice during the first week after initiation of concomitant lanreotide and tacrolimus therapy; continue to monitor and adjust the dose of tacrolimus as clinically appropriate. Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index. Limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of CYP3A4 substrates, which may be due to the suppression of growth hormone; it cannot be excluded that lanreotide has this effect.
    Lansoprazole: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Lansoprazole; Naproxen: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Lapatinib: (Major) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with lapatinib is necessary. Also, monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Tacrolimus is a CYP3A4 substrate that can cause QT prolongation. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Larotrectinib: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with larotrectinib. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Larotrectinib is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with tacrolimus due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tacrolimus also causes QT prolongation.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tacrolimus; monitor for potential reduction in efficacy. Tacrolimus is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tacrolimus; monitor for potential reduction in efficacy. Tacrolimus is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) Frequently monitor tacrolimus whole blood concentrations during concurrent treatment and after discontinuation of letermovir, and adjust the tacrolimus dose accordingly. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of letermovir increased the AUC and Cmax of tacrolimus by 2.42-fold and 1.57-fold, respectively. Tacrolimus is a sensitive CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include tacrolimus.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include tacrolimus.
    Levalbuterol: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Concomitant use of levofloxacin with tacrolimus may result in increased serum concentrations of tacrolimus. In renal transplant patients stabilized on tacrolimus, the addition of levofloxacin resulted in reduced tacrolimus metabolism. Higher AUC values for tacrolimus were observed, but increased adverse reactions and supratherapeutic serum concentrations were not noted. Serum concentrations of tacrolimus should be monitored and dosage changes made only if adverse reactions or supratherapeutic concentrations occur. Also, concomitant use of tacrolimus and levofloxacin may increase the risk of cardiac arrhythmias since both drugs are associated with QT prolongation.
    Levomethadyl: (Major) Levomethadyl is associated with an established risk of QT prolongation and/or torsades de pointes and is contraindicated in combination with other agents that may prolong the QT interval, such as tacrolimus.
    Linagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
    Linagliptin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
    Lithium: (Major) Lithium should be used cautiously with tacrolimus. Both lithium and tacrolimus have been associated with QT prolongation.
    Live Vaccines: (Severe) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with tacrolimus due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tacrolimus causes QT prolongation.
    Lomefloxacin: (Moderate) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as tacrolimus, should be used cautiously when given concurrently with lomefloxacin.
    Long-acting beta-agonists: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like tacrolimus, should be used cautiously and with close monitoring with loperamide.
    Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like tacrolimus, should be used cautiously and with close monitoring with loperamide.
    Lopinavir; Ritonavir: (Major) Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as lopinavir; ritonavir. In one case, lopinavir; ritonavir was added to a patients' tacrolimus-containing medication regimen. Three days after initiating lopinavir; ritonavir, tacrolimus concentrations rose to toxic concentrations. Subsequently, the tacrolimus dosage was decreased from 5 mg twice daily to 0.5 mg once weekly to maintain appropriate tacrolimus blood concentrations. (Moderate) A reduced dose of tacrolimus based on tacrolimus whole blood concentrations is recommended if coadministered with ritonavir. Concurrent administration is expected to increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions including neurotoxicity and QT prolongation. Tacrolimus is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Lorlatinib: (Moderate) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with lorlatinib is necessary. Tacrolimus is a sensitive CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer may significantly increase tacrolimus clearance.
    Lovastatin: (Major) Guidelines recommend avoiding coadministration of lovastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Lovastatin; Niacin: (Major) Guidelines recommend avoiding coadministration of lovastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of tacrolimus and lumacaftor; ivacaftor is not recommended. Lumacaftor; ivacaftor may decrease the systemic exposure of tacrolimus. If concurrent use cannot be avoided, monitor tacrolimus whole blood trough concentrations closely and adjust the dose accordingly. Tacrolimus is a substrate of CYP3A, and lumacaftor; ivacaftor is a potent CYP3A inducer.
    Lumacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as tacrolimus. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Tacrolimus causes QT prolongation.
    Magnesium Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
    Maprotiline: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and maprotiline should be used together cautiously. Tacrolimus causes QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Maraviroc: (Minor) Use caution and careful monitoring with the coadministration of maraviroc and tacrolimus as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); tacrolimus may be an inhibitor of P-gp. Conflicting data exist regarding any interaction between tacrolimus and P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with mefloquine. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as tacrolimus. Additionally, both tacrolimus and mefloquine are CYP3A4 substrates. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates of CYP3A4 that also have the potential to prolong the QT interval.
    Meglitinides: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Melphalan: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include tacrolimus.
    Mephobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Mesoridazine: (Severe) Tacrolimus prolongs the QTc interval. Mesoridazine has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP) and is contraindicated for use with tacrolimus.
    Metaproterenol: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Metformin; Pioglitazone: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Metformin; Repaglinide: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Metformin; Rosiglitazone: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
    Metformin; Saxagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Metformin; Sitagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as tacrolimus, should be done with extreme caution and a careful assessment of treatment risks versus benefits. When coadministering tacrolimus with other substrates of CYP3A, especially those that also have the potential to prolong the QT interval, such as methadone, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Consider obtaining electrocardiograms (ECGs) and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in at-risk patients. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Tacrolimus may also prolong the QT interval and has been reported to cause TdP.
    Methohexital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Methylprednisolone: (Major) Patients receiving tacrolimus and systemic corticosteroids concomitantly should be carefully monitored for alterations in tacrolimus whole blood concentrations. According to the manufacturer of tacrolimus, methylprednisolone may increase tacrolimus blood concentrations. The mechanism of the interaction is unclear. Tacrolimus is a CYP3A4 substrate, but methylprednisolone does not appear to have an inhibitory effect on CYP3A4 activity. For example, the pharmacokinetics and pharmacodynamics of the CYP3A4 substrate triazolam were determined in a three-phase cross-over study; the three treatment periods were placebo, methylprednisolone 32 mg PO 1 hour before triazolam 0.25 mg PO, and methylprednisolone 8 mg PO daily for 9 days before triazolam 0.25 mg PO. The single methylprednisolone dose did not significantly affect CYP3A4 activity. Methylprednisolone receipt for 9 days led to slightly reduced maximum triazolam concentrations, which may have been due to an inducing effect on the CYP3A4-mediated first-pass metabolism of triazolam.
    Metoclopramide: (Major) Increased tacrolimus whole blood concentrations may be observed if a GI prokinetic agent like metoclopramide is added to therapy. Monitor tacrolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
    Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving tacrolimus, drug concentration monitoring should be performed and the tacrolimus dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as tacrolimus.
    Metronidazole: (Major) Monitor patients for signs and symptoms of QT prolongation with coadministration of systemic metronidazole and tacrolimus. QT prolongation has been associated with the use of both agents; therefore, concomitant use may increase this risk.
    Micafungin: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as tacrolimus concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with these medications. Concurrent administration of micafungin and tacrolimus did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on tacrolimus pharmacokinetic parameters
    Midostaurin: (Major) The concomitant use of midostaurin and tacrolimus may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There are post-marketing reports of QT prolongation and torsade de pointes with systemic tacrolimus administration.
    Mifepristone: (Severe) Coadministration of systemic tacrolimus is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome. Mifepristone, a CYP3A4 inhibitor, is likely to increase tacrolimus concentrations and adverse effects, since tacrolimus is a CYP3A4 substrate with a narrow therapeutic index. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tacrolimus. Coadminister with caution. Tacrolimus causes QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Use caution if mitotane and tacrolimus are used concomitantly, and monitor for decreased efficacy of tacrolimus and a possible change in dosage requirements. Monitor tacrolimus whole blood trough concentrations and adjust the dose of tacrolimus as necessary. Mitotane is a strong CYP3A4 inducer and tacrolimus is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tacrolimus. Concomitant administration of immediate-release tacrolimus and another strong CYP3A inducer, rifampin, resulted in a significant decrease in the mean tacrolimus bioavailability (from 14% to 7%) and a significant increase in the mean tacrolimus clearance (from 0.035 L/hr/kg to 0.053 L/hr/kg) compared with tacrolimus alone in 6 healthy subjects. In another pharmacokinetic study in 22 healthy male subjects, the administration of a single 10 mg dose of extended-release tacrolimus (Astagraf XL) following 12 days of rifampin 600 mg/day decreased mean tacrolimus AUC and Cmax values by 56% and 46%, respectively.
    Moxifloxacin: (Major) Concurrent use of tacrolimus and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tacrolimus causes QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Mycophenolate: (Minor) Tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase. As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with tacrolimus.
    Nefazodone: (Major) Nefazodone (a potent CYP3A4 inhibitor) decreases the elimination of tacrolimus (a CYP3A4 substrate). Delirium, renal failure, and high tacrolimus serum concentrations (46.4 ng/ml) were reported in a patient receiving tacrolimus and nefazodone. The patient discontinued nefazodone and was started on paroxetine instead. Three days after stopping the nefazodone the tacrolimus level was 10.2 ng/ml. In a separate report, a patient on stable doses of tacrolimus for 2 years developed headache, confusion and 'gray areas' in her vision without ophthalmologic findings 1 week after switching from sertraline to nefazodone for persistent depression. Her serum creatinine increased 1.5 mg/dl from baseline and her 12-hour trough tacrolimus level was > 30 ng/ml. The tacrolimus was held for 4 days and the patient restarted on sertraline with resolution of symptoms. Because of the potential toxicity of tacrolimus, nefazodone should be used cautiously, if at all, in patients receiving tacrolimus. Monitoring of serum tacrolimus concentrations is recommended.
    Nelfinavir: (Moderate) Nelfinavir is a potent inhibitor of CYP3A4 and is expected to inhibit the metabolism of tacrolimus, thus increasing whole blood concentrations of tacrolimus and leading to the potential for nephrotoxicity or other tacrolimus-related side effects. In a clinical study in 5 liver transplant patients, concomitant use of immediate-release tacrolimus and nelfinavir resulted in significantly increased tacrolimus blood concentrations which required an average of a 16-fold tacrolimus dosage reduction to maintain mean trough concentrations of 9.7 nanograms/ml. Avoid concomitant use of tacrolimus with nelfinavir unless the benefits outweigh the risks. If used together, close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions is warranted.
    Nevirapine: (Major) Nevirapine induces CYP3A4, and thus, can decrease whole blood concentrations of tacrolimus, a CYP3A4 substrate. Monitoring tacrolimus whole blood concentrations and appropriate dose adjustments are recommended if used concurrently with nevirapine.
    Niacin; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Nicardipine: (Moderate) Coadministration of nicardipine and tacrolimus may result in elevated plasma tacrolimus concentrations. Monitor plasma concentrations of tacrolimus closely, and adjust the dose as necessary. Tacrolimus is metabolized by CYP3A4; nicardipine is an inhibitor of CYP3A4.
    Nifedipine: (Moderate) Tacrolimus is metabolized by CYP3A4 isoenzyme. CYP3A4 is the major isoenzyme that metabolizes nifedipine. When coadministered with nifedipine, tacrolimus whole blood trough concentrations are increased. In a retrospective study of liver transplant patients with hypertension, nifedipine decreased the daily and cumulative dosage requirements of tacrolimus by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage for patients who did not receive nifedipine. It is recommended that tacrolimus blood concentrations be closely monitored when nifedipine and tacrolimus are administered concomitantly.
    Nilotinib: (Major) Nilotinib and tacrolimus both prolong the QT interval. Additionally, tacrolimus is metabolized by CYP3A4 and nilotinib inhibits this isoenzyme. Coadministration of nilotinib and a drug that prolongs the QT interval is not advised, as nilotinib prolongs the QT interval. If concurrent administration with tacrolimus is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. The manufacturer of tacrolimus advises reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as nilotinib. Tacrolimus concentrations and thus other adverse reactions may also be increased during concomitant administration.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with norfloxacin. Tacrolimus causes QT prolongation. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Octreotide: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), octreotide and tacrolimus should be used together cautiously; tacrolimus exposure may also increase. Monitor tacrolimus whole blood trough concentrations and reduce the tacrolimus dose if necessary. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index and has been associated with QT prolongation. Somatostatin analogs like octreotide decrease growth hormone secretion which in turn may inhibit 3A4 enzyme function. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with ofloxacin. Tacrolimus causes QT prolongation. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation include olanzapine. Caution and close monitoring is advised with coadministration.
    Olodaterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) A reduced dose of tacrolimus based on tacrolimus whole blood concentrations is recommended if coadministered with ritonavir. Concurrent administration is expected to increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions including neurotoxicity and QT prolongation. Tacrolimus is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with tacrolimus is contraindicated due to the potential for severe immunosuppressant-associated adverse events. When administered concurrently with ombitasvir; paritaprevir; ritonavir, the maximum plasma concentration (peak), minimum plasma concentration (trough), and systemic exposure of tacrolimus are significantly increased.
    Omeprazole: (Moderate) Concomitant administration of omeprazole and tacrolimus may increase the serum concentrations of tacrolimus.
    Omeprazole; Sodium Bicarbonate: (Major) Addition of tacrolimus to solutions containing sodium bicarbonate or magnesium oxide will result in pH-dependent degradation of tacrolimus.Separation of the oral tacrolimus and antacid doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase the serum concentrations of tacrolimus.
    Ondansetron: (Major) ECG monitoring is recommended if ondansetron and tacrolimus must be coadministered. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Tacrolimus also causes QT prolongation.
    Oritavancin: (Moderate) Avoid use of oritavancin with drugs that have a narrow therapeutic window, such as tacrolimus.Tacrolimus is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of tacrolimus may be reduced if these drugs are administered concurrently. Monitor for lack of tacrolimus efficacy.
    Osimertinib: (Major) Avoid coadministration of tacrolimus with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tacrolimus also causes QT prolongation.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tacrolimus with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Tacrolimus causes QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxcarbazepine: (Moderate) The effectiveness of immunosuppressive medications such as tacrolimus could be decreased by the co-administration of oxcarbazepine. Monitoring of tacrolimus whole blood concentrations is recommended if oxcarbazepine is used concurrently with tacrolimus.
    Palbociclib: (Moderate) Monitor tacrolimus concentrations and watch for an increase in tacrolimus-related adverse reactions if coadministration with palbociclib is necessary. The tacrolimus dose may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A and tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as tacrolimus. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Pamidronate: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include tacrolimus.
    Pasireotide: (Major) Tacrolimus causes QT prolongation and should be used cautiously with pasireotide as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and tacrolimus have been reported to prolong the QT interval. If pazopanib and tacrolimus must be continued, closely monitor the patient for QT interval prolongation. Also, reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tacrolimus, a CYP3A4 substrate, may cause an increase in systemic concentrations of tacrolimus. Use caution when concurrent administration is necessary.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include tacrolimus. Tacrolimus has been associated with a possible risk for QT prolongation.
    Pentobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Perindopril; Amlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Perphenazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and perphenazine should be used together cautiously. Tacrolimus causes QT prolongation. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and perphenazine should be used together cautiously. Tacrolimus causes QT prolongation. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Phenobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include tacrolimus.
    Phenytoin: (Moderate) Phenytoin can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of tacrolimus. If phenytoin is added to tacrolimus, the levels of tacrolimus should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if phenytoin is discontinued, levels of tacrolimus could increase and result in toxicity.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as tacrolimus. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of tacrolimus with pimozide is contraindicated.
    Pirbuterol: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Pitavastatin: (Major) Guidelines recommend avoiding coadministration of pitavastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Polymyxin B: (Minor) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including Polymixin B. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
    Polymyxins: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including tacrolimus, may increase serum concentrations of either drug.
    Posaconazole: (Major) Posaconazole and tacrolimus can cause QTc prolongation. Also, tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4, and posaconazole inhibits this isoenzyme and can thus, decrease the metabolism of tacrolimus. When coadministering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Also, consider monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. In a pharmacokinetic study in healthy subjects, the administration of a single 0.05 mg/kg dose of immediate-release tacrolimus after 7 days of posaconazole 400 mg PO every 12 hours increased tacrolimus AUC and Cmax values by 4.5-fold and 2-fold, respectively, compared with tacrolimus alone. When initiating therapy with posaconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the original dose and make subsequent tacrolimus dose adjustments based on the tacrolimus whole blood concentrations.
    Potassium Acetate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium Bicarbonate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium Chloride: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium Citrate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium Gluconate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium Iodide, KI: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium Phosphate; Sodium Phosphate: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as tacrolimus. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium-sparing diuretics: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    Pramlintide: (Moderate) Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Monitor for worsening of glycemic control.
    Pravastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and pravastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of pravastatin40 mg/day is recommended.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include tacrolimus.
    Primidone: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Procainamide: (Major) Tacrolimus should be used cautiously and with close clinical monitoring with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP) and tacrolimus causes QT prolongation.
    Prochlorperazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and prochlorperazine should be used together cautiously. Tacrolimus causes QT prolongation. Phenothiazines have been reported to prolong the QT interval. Concurrent use of drugs that are associated with a possible risk for QT prolongation and torsade de pointes (TdP) with prochlorperazine should be approached with caution. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include tacrolimus.
    Propafenone: (Major) Concurrent use of tacrolimus and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tacrolimus prolongs the QT interval. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, both drugs are metabolized by CYP3A4. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are substrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of TdP may be increased.
    Protriptyline: (Major) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Quetiapine: (Major) Concurrent use of quetiapine and tacrolimus should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Tacrolimus also causes QT prolongation. Additionally, both tacrolimus and quetiapine are substrates for CYP3A4. When coadministrating tacrolimus with other substrates of CYP3A4, it is recommended to reduce the tacrolimus dose and closely monitor tacrolimus whole blood concentrations.
    Quinidine: (Major) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). As the risk of TdP is increased with greater QT prolongation, avoid use of quinidine with another drug that prolongs the QT interval such as tacrolimus. It should be noted that the manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as quinidine. Tacrolimus and quinidine are both metabolized by cytochrome P450 3A4.
    Quinine: (Major) Concurrent use of quinine and tacrolimus should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Tacrolimus also causes QT prolongation. In addition, concentrations of tacrolimus may be increased with concomitant use of quinine. Tacrolimus is a CYP3A4 substrate and quinine is a CYP3A4 inhibitor. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with inhibitors of CYP3A4 that also have the potential to prolong the QT interval.
    Rabeprazole: (Moderate) According to the FDA-approved labeling, concomitant use of tacrolimus and rabeprazole may result in increased exposure to tacrolimus, particularly in transplant patients who are intermediate or poor metabolizers of CYP2C19. The rabeprazole manufacturer recommends monitoring tacrolimus plasma concentrations during coadministration; dose adjustments may be needed to maintain therapeutic drug concentrations. However, in drug interaction studies, rabeprazole had little effect on tacrolimus drug concentrations. Rabeprazole uses a non-enzymatic pathway in addition to the CYP system and does not compete with tacrolimus for CYP3A4 compared with other PPIS; additionally, the effects of CYP2C19 polymorphism on rabeprazole are minimal compared to other PPIs.
    Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tacrolimus.
    Ribociclib: (Major) Avoid coadministration of ribociclib with tacrolimus due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of tacrolimus may also be increased resulting in an increase in tacrolimus-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Tacrolimus is a sensitive CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with tacrolimus due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of tacrolimus may also be increased resulting in an increase in tacrolimus-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Tacrolimus is a sensitive CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rifabutin: (Major) Coadministration with strong CYP3A4-inducers such as rifabutin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus.
    Rifampin: (Major) Coadministration with strong CYP3A4-inducers such as rifampin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 +/- 6% vs. 7 +/- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration.
    Rifapentine: (Major) Coadministration with strong CYP3A4-inducers such as rifapentine is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage.
    Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with tacrolimus. If these drugs are coadministered, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitoring for QT prolongation. Both tacrolimus and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) Use tacrolimus and risperidone together with caution since there is an increased risk for QT prolongation and torsade de pointes (TdP). Monitor patients with known risk factors for cardiac disease or arrhythmia closely during coadministration. Tacrolimus causes QT prolongation. Risperidone has also been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Moderate) A reduced dose of tacrolimus based on tacrolimus whole blood concentrations is recommended if coadministered with ritonavir. Concurrent administration is expected to increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions including neurotoxicity and QT prolongation. Tacrolimus is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when tacrolimus is coadministered with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as romidepsin. In addition, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Rosuvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and rosuvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of rosuvastatin of 5 mg/day is recommended.
    Rucaparib: (Moderate) Frequently monitor tacrolimus levels and watch for an increase in tacrolimus-related adverse reactions if coadministration with rucaparib is necessary. Tacrolimus is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as tacrolimus, may occur during concurrent use with rufinamide.
    Salicylates: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
    Salmeterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Saquinavir: (Severe) Concurrent administration of tacrolimus and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as tacrolimus. In addition to the potential for arrhythmias, inhibition of CYP3A4 by saquinavir boosted with ritonavir may increase the whole blood concentrations of tacrolimus and lead to other tacrolimus-related side effects such as nephrotoxicity.
    Saxagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Secobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking tacrolimus, monitor tacrolimus concentrations; tacrolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. These interactions remain theoretical. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4.
    Sertraline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tacrolimus causes QT prolongation.
    Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of tacrolimus from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because tacrolimus has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
    Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Short-acting beta-agonists: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sildenafil: (Moderate) Consider initiating sildenafil at a low dose (25 mg) in kidney transplant recipients receiving tacrolimus. In a study of renal transplant patients, coadministration of tacrolimus with a single 50 mg dose of sildenafil resulted in an increase in the AUC, Cmax, and half-life of sildenafil. Decreases in blood pressure were also observed. No significant effect on the pharmacokinetic parameters of tacrolimus were observed.
    Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Simvastatin; Sitagliptin: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Sirolimus: (Moderate) The concomitant use of sirolimus with a calcineurin inhibitor, such as tacrolimus, may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. In addition to a potential increased risk of thrombotic microangiopathy, sirolimus may decrease the blood concentration of tacrolimus.
    Sitagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Sodium Bicarbonate: (Major) Addition of tacrolimus to solutions containing sodium bicarbonate or magnesium oxide will result in pH-dependent degradation of tacrolimus.Separation of the oral tacrolimus and antacid doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with tacrolimus. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); tacrolimus is an inhibitor of both P-gp and BCRP.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with tacrolimus. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); tacrolimus is an inhibitor of both P-gp and BCRP.
    Solifenacin: (Major) Monitor for evidence of QT prolongation during concurrent use of tacrolimus and solifenacin. Tacrolimus causes QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with tacrolimus is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT prolongation.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Tacrolimus causes QT prolongation and should be used cautiously with sotalol.
    Sparfloxacin: (Severe) Tacrolimus prolongs the QTc interval. Sparfloxacin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP) and is contraindicated for use with tacrolimus.
    Spironolactone: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum may increase the metabolism of tacrolimus through induction of the hepatic CYP3A4 isoenzyme and decreased serum concentrations of tacrolimus would be expected if St. John's Wort was co-administered. St. John's Wort in all forms, including teas, should be avoided in patients treated with tacrolimus.
    Streptogramins: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with dalfopristin; quinupristin. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. dalfopristin; quinupristin is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Sulfonylureas: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Sunitinib: (Major) Monitor patients for QT prolongation if coadministration of tacrolimus with sunitinib is necessary. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Tacrolimus also causes QT prolongation.
    Talazoparib: (Major) Avoid coadministration of tacrolimus with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and tacrolimus is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen and tacrolimus due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Tacrolimus also causes QT prolongation.
    Teduglutide: (Moderate) Teduglutide may increase absorption of tacrolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of tacrolimus is recommended.
    Telaprevir: (Major) Coadministration with strong CYP3A4-inhibitors such as telaprevir is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. In addition, frequent assessments of renal function are advised. Tacrolimus is a substrate of the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Increased tacrolimus concentrations could potentially result in adverse events such as QT interval prolongation.
    Telavancin: (Major) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as tacrolimus may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance. In addition, telavancin has been associated with QT prolongation. According to the manufacturer, telavancin should be used with caution when prescribing other agents known to prolong the QT interval such as tacrolimus.
    Telbivudine: (Moderate) Drugs that alter renal function such as tacrolimus may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Telithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with tacrolimus. Telithromycin is associated with QT prolongation and TdP. Tacrolimus has also been associated with a possible risk for QT prolongation and/or TdP based on a few case reports. Additionally, telithromycin is a strong inhibitor of CYP3A4, and tacrolimus is a CYP3A4 substrate. Coadministration may result in increased tacrolimus plasma concentrations and could increase or prolong both the therapeutic and adverse effects. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended during coadministration.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and tacrolimus is necessary, as the systemic exposure of tacrolimus may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of tacrolimus as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of tacrolimus if necessary. Tacrolimus is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and tacrolimus is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Tenofovir Alafenamide: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir Alafenamide: (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir, PMPA: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
    Terbutaline: (Minor) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval. Caution is advisable during concurrent use of other agents associated with a possible risk for QT prolongation and TdP including tacrolimus.
    Tezacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events. (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of tacrolimus. Appropriate monitoring should be used; adjust tacrolimus dosage as necessary. Tacrolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp.
    Theophylline, Aminophylline: (Moderate) Addition of aminophylline to tacrolimus therapy may result in increased concentrations of tacrolimus. Monitor serum tacrolimus and creatinine concentrations and renal function in patents who are stabilized on tacrolimus if aminophylline is added. (Moderate) Addition of theophylline to tacrolimus therapy may result in increased concentrations of tacrolimus. Closely monitor serum tacrolimus concentrations, serum creatinine concentrations, and renal function in patents who are stabilized on tacrolimus if theophylline is added, changed or discontinued.
    Thiazolidinediones: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Thiopental: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
    Thioridazine: (Severe) The use of thioridazine with tacrolimus is contraindicated due to the risk for QT prolongation and torsade de pointes (TdP). Thioridazine is also associated with a well-established risk of QT prolongation and TdP. Tacrolimus has been associated with QT prolongation.
    Ticagrelor: (Minor) Coadministration of ticagrelor and tacrolimus may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate. Tacrolimus may be a P-gp inhibitor; however, data are conflicting. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tinidazole: (Minor) Tinidazole may increase tacrolimus serum concentrations when administered concomitantly. Although this interaction has not been studied, a similar interaction has been reported with the concomitant use of metronidazole (a chemically similar nitroimidazole) and tacrolimus. Patients should be monitored for signs of toxicity during coadministration.
    Tiotropium; Olodaterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tipranavir: (Major) Coadministration with strong CYP3A4 inhibitors such as tipranavir is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions.
    Tocilizumab: (Moderate) Closely observe patients for signs of infection, altered clinical response, or drug toxicity. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. If tocilizumab is initiated or discontinued in a patient taking tacrolimus, check the drug concentration; tacrolimus dose adjustment may be needed.
    Tofacitinib: (Major) Avoid use of tofacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Tolterodine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tolterodine should be used together cautiously. Tacrolimus causes QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
    Topotecan: (Major) Avoid coadministration of tacrolimus with oral topotecan due to increased topotecan exposure; tacrolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and tacrolimus is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Toremifene: (Major) Avoid coadministration of tacrolimus with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tacrolimus also causes QT prolongation.
    Trandolapril; Verapamil: (Moderate) Verapamil, a CYP3A4 substrate, may inhibit tacrolimus metabolism by inhibiting CYP3A4 intestinal metabolism. If verapamil is added to tacrolimus therapy, blood trough concentrations of tacrolimus should be monitored and dose adjustments may be necessary.
    Trazodone: (Major) Tacrolimus causes QT prolongation and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Triamterene: (Major) Simultaneous use of a potassium-sparing diuretic with tacrolimus can increase the risk of hyperkalemia, and is generally not recommended. If these drugs are used concomitantly, serum potassium should be monitored frequently.
    Trifluoperazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and trifluoperazine should be used together cautiously. Tacrolimus causes QT prolongation. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Trimipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include tacrolimus.
    Umeclidinium; Vilanterol: (Moderate) Tacrolimus causes QT prolongation. Other agents associated with a possible risk for QT prolongation that should be used cautiously with tacrolimus include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Valganciclovir: (Moderate) Use valganciclovir and tacrolimus together only if the potential benefits outweigh the risks. Monitor renal function when valganciclovir is coadministered with tacrolimus because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Vancomycin: (Moderate) Concomitant use of parenteral vancomycin with other nephrotoxic drugs, such as tacrolimus, can lead to additive nephrotoxicity. Monitor renal function closely and adjust vancomycin or tacrolimus doses according to serum concentrations.
    Vandetanib: (Major) Avoid coadministration of vandetanib with tacrolimus due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Tacrolimus also causes QT prolongation.
    Vardenafil: (Major) Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as vardenafil. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Vemurafenib: (Major) Tacrolimus causes QT prolongation. Vemurafenib has also been associated with QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation (including ECG monitoring) is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as vemurafenib.
    Venlafaxine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and venlafaxine should be used together cautiously. Tacrolimus causes QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    Verapamil: (Moderate) Verapamil, a CYP3A4 substrate, may inhibit tacrolimus metabolism by inhibiting CYP3A4 intestinal metabolism. If verapamil is added to tacrolimus therapy, blood trough concentrations of tacrolimus should be monitored and dose adjustments may be necessary.
    Voriconazole: (Major) Caution is advised when administering voriconazole with tacrolimus due to the potential for additive effects on the QT interval and increased exposure to tacrolimus. Use of these drugs together has resulted in a 2-fold and 3-fold increase in the maximum plasma concentrations and systemic exposure of tacrolimus, respectively. If these drugs must be used together, the manufacturer recommends reducing the tacrolimus dose by two-thirds (i.e., administer one-third of the pre-voriconazole dose). Tacrolimus concentrations should be frequently assessed. When voriconazole is discontinued, tacrolimus concentrations should be carefully monitored and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Major) Vorinostat therapy is associated with a risk of QT prolongation. Vorinostat should be used with caution if given with other agents that may prolong the QT interval including tacrolimus.
    Zileuton: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and could potentially compete with other CYP3A4 substrates, including tacrolimus. Clinical documentation of interactions is lacking; the manufacturer recommends appropriate clinical monitoring if these drugs are used concomitantly due to the lack of data.
    Ziprasidone: (Severe) Concomitant use of ziprasidone and tacrolimus is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Tacrolimus causes QT prolongation.
    Zoledronic Acid: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs, such as tacrolimus, may increase serum concentrations of either zoledronic acid and/or tacrolimus.

    PREGNANCY AND LACTATION

    Pregnancy

    Tacrolimus can cause fetal harm when administered during pregnancy. Human data suggest that infants exposed to tacrolimus in utero are at risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Advise pregnant women of the potential risk to the fetus. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants; patients can register by contacting 1-877-955-6877 or www.transplantregistry.org. Tacrolimus may increase hyperglycemia in pregnant women with diabetes, including those with gestational diabetes. In addition, exacerbation of hypertension may increase the risk of pre-eclampsia. Monitor blood glucose concentrations and blood pressure regularly and treat as appropriate. Renal dysfunction, transient neonatal hyperkalemia, and low birth weight have been reported at the time of delivery in newborns of mothers taking tacrolimus. The experience with topical tacrolimus in pregnant women is too limited to permit assessment of the safety of its use during pregnancy. Tacrolimus should be used during pregnancy only when clearly needed.[28611] [30973][55401][60497]

    Use tacrolimus with caution during breast-feeding. Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk after systemic use. The effects of tacrolimus on the breastfed infant or milk production have not been assessed.[28611] [60497] Limited data indicate that the amount of tacrolimus excreted into breast-milk after systemic administration is low.[49424] [49425] In addition, no adverse reactions have been reported in nursing infants.[49426] The systemic absorption of tacrolimus after topical administration is minimal; 90% (1,253/1,391) of subjects in a pharmacokinetic trial with periodic blood sampling had blood concentrations of less than 2 ng/mL.[30973] Therefore, it is unlikely that a clinically significant exposure would occur via breast milk. Do not allow direct contact of the infant's skin to treated areas and do not apply to the nipple area if nursing. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Tacrolimus induces immunosuppression by inhibiting the first phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early proteins (e.g., interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon gamma) that allow T-cells to progress from the G0- to G1-phase. Tacrolimus binds to an immunophilin termed FK binding protein (FKBP), specifically FKBP12. Immunophilins (cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein activation. The tacrolimus-FK binding protein complex binds to and inhibits the phosphatase activity of calcineurin. The calcineurin enzyme catalyzes critical dephosphorylation reactions necessary for early lymphokine gene transcription. Calcineurin inhibition results in blockade of signal transduction by the cytosol component of the nuclear factor of activated T-cells (NF-AT), which results in a failure to activate NF-AT regulated genes. NF-AT activated genes include those required for B-cell activation (e.g., IL-4 and CD40 ligand) and those required for T-cell activation (e.g., IL-2, TNF-alpha, and interferon gamma). Reduced circulating levels of T-cell activators result in inhibition of T-cell proliferative responses to antigens and mitogens including mixed lymphocyte reactivity and cytotoxic T-cell generation. Compared to cyclosporine, tacrolimus is about 100-times more potent in inhibiting T-cell proliferative responses.In atopic dermatitis, topical tacrolimus acts to inhibit inflammation primarily by inhibiting T-cells. Tacrolimus may also bind to cell surface steroid receptors, inhibit the release of mast cell mediators, down-regulate IL-8 receptors, and decrease intracellular adhesion molecule-1 and E-selectin lesional blood vessel expression. These activities lead to decreased antigen recognition and down-regulation of the entire inflammatory cascade leading to a clinical response. Topical tacrolimus does not inhibit collagen synthesis and, therefore, does not cause skin atrophy as seen with corticosteroid therapy.

    PHARMACOKINETICS

    Tacrolimus is administered topically, parenterally, and orally. Due to high lipophilicity, tissue distribution of tacrolimus after oral or parenteral therapy is extensive. Tacrolimus crosses the placenta creating fetal cord plasma concentrations that are 35% of the maternal plasma concentration. The drug is also excreted in breast milk with concentrations similar to those in plasma. Protein binding is approximately 99%. Tacrolimus is mainly bound to albumin and alpha1-acid glycoprotein. Erythrocytes bind 75% to 80% of the drug resulting in whole blood concentrations that are 10- to 30-times higher than plasma concentrations. The distribution of tacrolimus between erythrocytes and plasma is dependent upon tacrolimus concentration, hematocrit, and temperature. Metabolism of tacrolimus is mainly by demethylation and hydroxylation via the hepatic cytochrome P450 enzyme 3A family. Genetic polymorphisms in CYP3A5 are known to influence tacrolimus dose requirements. In a study, patients with at least 1 CYP3A5(1) allele had lower tacrolimus area under the time versus blood concentration curves or lower trough concentrations as compared with data from CYP3A5 nonexpressors. Specifically, after administration of 0.1 mg/kg/dose twice a day, the median systemic exposure was 2.1- to 2.6-fold higher in nonexpressors. Patients with at least 1 CYP3A5(1) allele may need a higher tacrolimus loading dose.[34513] The formation of 8 possible metabolites has been proposed. The major metabolite identified in vitro is 13-demethyl tacrolimus, which in vitro has been reported to have the same activity as tacrolimus. After IV tacrolimus administration, the mean volume of distribution was 1.91 L/kg in healthy subjects, 1.41 L/kg in kidney transplant patients, and 0.85 L/kg in adult liver transplant patients and the mean clearance was 0.04 L/kg/hour in healthy subjects, 0.083 L/kg/hour in kidney transplant patients, 0.053 L/kg/hour in adult liver transplant patients, and 0.51 L/kg/hour in heart transplant patients. Less than 1% of the dose was excreted unchanged in the urine. After the administration of radiolabeled IV tacrolimus to 6 healthy volunteers, fecal elimination accounted for 92.4% of the radioactivity. After radiolabeled oral tacrolimus, fecal and urinary elimination accounted for 92.6% and 2.3% of the radioactivity, respectively. After IV tacrolimus administration, the mean elimination half-life was 34.2 hours in healthy subjects, 18.8 hours in kidney transplant patients, 11.7 hours in adult liver transplant patients, and 23.6 hours in heart transplant patients.[28611] The mean elimination half-life was 37.9 +/- 3.4 hours in 24 healthy subjects after the administration of tacrolimus extended-release capsules (Astagraf XL) 4 mg PO for 10 days.[55401] The mean elimination half-life was 31 +/- 8.1 hours in 25 healthy subjects after administration of tacrolimus extended-release tablets (Envarsus XR) 2 mg PO for 10 days.[60497]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
     
    Tacrolimus is a substrate of CYP3A4. It may be an inhibitor of P-glycoprotein (P-gp); however, conflicting data exist regarding any interaction between tacrolimus and P-gp.[52498] In vitro data suggest that tacrolimus is neither a substrate nor an inhibitor of P-gp.[34512] Monitor tacrolimus whole blood trough concentrations and adjust the dose as needed if tacrolimus is used together with a strong CYP3A4 inhibitor or inducer as concomitant use may result in increased or decreased tacrolimus concentrations. Also monitor for increased adverse reactions, including QT prolongation, if tacrolimus is administered with a strong CYP3A4 inhibitor.[28611] [55401] Based on the extent of topical absorption, concomitant administration of tacrolimus ointment with systemically administered drugs is unlikely to result in an interaction; however, use tacrolimus ointment and known CYP3A4 inhibitors with caution in patients with widespread and/or erythrodermic disease.[30973]

    Oral Route

    Immediate-release capsules:
    Oral tacrolimus absorption is poor and variable with the absolute bioavailability ranging from 17% to 23%. The pharmacokinetics of immediate-release tacrolimus have been studied in healthy subjects (n = 16; 5 mg PO), kidney transplant patients (n = 26; 0.2 mg/kg/day and 0.3 mg/kg/day), liver transplant patients (n = 17; 0.3 mg/kg/day), and heart transplant patients (n = 11, 0.075 mg/kg/day; n = 14, 0.15 mg/kg/day). In these patient populations, the mean Cmax ranged from 14.7 to 68.5 ng/mL; the mean Tmax ranged from 1.5 to 3 hours; and the AUC values (measuring times varied between populations) ranged from 82.7 to 3,300 ng x hour/mL.
     
    Food effects: The presence of food can alter both the rate and the extent of tacrolimus absorption; administer immediate-release tacrolimus consistently with or without food. When immediate-release tacrolimus was administered with a high-fat meal in 15 healthy volunteers, the mean AUC and Cmax values were decreased by 37% and 77%, respectively; the Tmax increased 5-fold. Tacrolimus administered with a high carbohydrate meal decreased the mean AUC and Cmax by 28% and 65%, respectively. When immediate-release tacrolimus was administered 15 minutes after a high-fat meal to 11 liver transplant patients, the mean AUC and Cmax values were decreased by 27% and 50%, respectively.[28611]
     
    Immediate-release granules for oral suspension:
    In healthy adult volunteers, the systemic exposure to tacrolimus (AUC = 320 ng x hour/mL) for the granules was approximately 16% higher than that for tacrolimus capsules when administered as single doses. Maximum concentrations (Cmax = 35.6 ng/mL) were attained 1.3 hours after administration. Half-life was approximately 32 hours.[28611]
     
    Extended-release capsules (Astagraf XL):
    In 24 healthy subjects who received extended-release tacrolimus 4 mg/day for 10 days, the mean Cmax, mean trough concentration prior to the next dose (Ctrough), and AUC values were 11.6 ng/mL, 4.7 ng/mL, and 155 ng x hour/mL, respectively. The median Tmax was 2 hours (range, 1 to 3 hours). In 17 de novo kidney transplant patients who received tacrolimus extended-release capsules 5.4 mg/day for 14 days, the mean Cmax, Ctrough, and AUC values were 32.7 ng/mL, 11.2 ng/mL, and 412 ng x hour/mL, respectively. The median Tmax was 2 hours (range, 1 to 4 hours). In 60 kidney transplant patients at least 6 months post-transplant who received tacrolimus extended-release capsules (dose range, 0.18 to 0.2 mg/kg/day), the mean Cmax, Ctrough, and AUC values were 16.1 ng/mL, 6.7 ng/mL, and 222 ng x hour/mL, respectively, on day 14; the Tmax was 2 hours (range, 1 to 6 hours).
     
    On day 1 post-kidney transplant, the dose-adjusted 24-hour AUC was 16% lower with once-daily tacrolimus extended-release capsules (Astagraf XL) compared with twice-daily tacrolimus immediate-release capsules (Prograf). The dose-adjusted 24-hour AUC (AUC24) was similar between the 2 formulations by day 3 post-transplant and was 21% higher with Astagraf XL on day 14 post-transplant (with comparable trough concentrations).
     
    Food effects: The presence of food can alter both the rate and the extent of tacrolimus absorption; administer extended-release tacrolimus capsules on an empty stomach at least 1 hour prior to or 2 hours after a meal. When extended-release capsules were administered immediately after a high-fat meal in 24 healthy subjects, the mean AUC and Cmax values were both decreased by about 25%; the Tmax increased from 2 hours to 4 hours.
     
    Chronopharmacokinetic effect: A diurnal effect on absorption has been observed with tacrolimus; take extended-release capsules at the same time daily in the morning. In 23 healthy subjects, the AUC value was decreased by 35% when extended-release capsules were taken in the evening relative to a morning dose.[55401]
     
    Extended-release tablets (Envarsus XR):
    On day 1 post-kidney transplant, the AUC24 for 21 de novo adult kidney transplant patients given extended-release tacrolimus 0.14 mg/kg/day, was up to 10% lower than that of twice-daily, immediate-release tacrolimus at a dose of 0.1 mg/kg/day; trough concentrations were similar. Typically, steady-state was achieved within 7 days of stable extended-release tacrolimus dosing. At steady-state, trough concentrations were comparable between the 2 formulations, but AUC24 was approximately 15% higher with extended-release tacrolimus compared to immediate-release. In 47 adults more than 6 months post-kidney transplant given 67% to 80% of the daily dose of tacrolimus immediate-release capsules, AUC24 (216 +/- 63 ng x hour/mL) and tacrolimus trough concentrations (7 +/- 2.3 ng/mL) achieved with extended-release tablets were similar to AUC and trough concentrations prior to the switch. The mean Cmax was 30% lower after the switch and the median Tmax was prolonged with the extended-release formulation (6 hours vs. 2 hours).[60497]
     
    Chronopharmacokinetic effect: In 26 healthy subjects, administration of extended-release tablets in the evening produced an AUC that was 15% lower and tacrolimus trough concentrations that were 20% lower compared to morning dosing.[60497]

    Topical Route

    The absolute bioavailability of tacrolimus applied topically is unknown. After topical administration of single or multiple doses of the 0.1% ointment to adults, peak tacrolimus blood concentrations ranged from undetectable to 20 ng/mL. Most patients had peak blood concentrations less than 5 ng/mL. In pediatric patients, application of the 0.1% ointment resulted in peak blood concentrations below 1.6 ng/mL. There is no evidence that tacrolimus accumulates systemically after topical administration. The lowest tacrolimus blood concentration that may elicit systemic effects is unknown.