Tacrolimus (FK-506, Fujimycin, Prograf, Advagraf, Protopic)

Indications

Transplantation

Other


Pharmacology

Metabolism

  • Hepatic CYP3A Enzymes

Administration

  • PO (Hecoria, Prograf, Generic):
  • PO-Extended Release (Astagraf XL):
  • IV-Continuous Infusion (Prograf):

Dose Adjustment

  • Hepatic: decreased tacrolimus clearance with serum bilirubin >2 mg/dL -> lower dose may be considered
  • Renal: decrease dose
    • Oliguric Renal Transplant: start tacrolimus between 6-24 hrs post-transplant (although may be delayed until graft function recovers)
    • Hemodialysis: tacrolimus is not cleared by hemodialysis, no dose adjustment is necessary
    • Peritoneal Dialysis: unlikely to affect tacrolimus clearance

Drug Interactions

Interaction with Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil, [[Mycophenolate Mofetil]])

  • Tacrolimus Does Not Interfere with the Enterohepatic Circulation of Mycophenolate (Like Cyclosporine A Does): therefore, crossover from cyclosporine A to tacrolimus (with concomitant mycophenolate mofetil administration) may result in higher mycophenolate mofetil concentrations

Drugs/Supplements/Foods Which Decrease Tacrolimus Level

  • Carbamazepine (Tegretol) (see Carbamazepine, [[Carbamazepine]]): induces CYP3A enzyme
  • Caspofungin (see Caspofungin, [[Caspofungin]]): induces CYP3A enzyme
  • Phenobarbital (see Phenobarbital, [[Phenobarbital]]): induces CYP3A enzyme
  • Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]]): induces CYP3A enzyme
    • Concomitant phenytoin and tacrolimus administration may also increase phenytoin levels
  • Rifampin (see Rifampin, [[Rifampin]]): induces CYP3A enzyme
  • St. John’s Wort (see St. John’s Wort, [[St Johns Wort]]): induces CYP3A enzyme

Drugs/Supplements/Foods Which Increase Tacrolimus Level

  • Azole Anti-Fungals: inhibit CYP3A enzyme
  • Calcium Channel Blockers (see Calcium Channel Blockers, [[Calcium Channel Blockers]]): inhibit CYP3A enzyme
  • Chloramphenicol (see Chloramphenicol, [[Chloramphenicol]]): inhibits CYP3A enzyme
  • Grapefruit Juice: inhibits CYP3A enzymes
  • Macrolides (see Macrolides, [[Macrolides]]): inhibit CYP3A enzyme
  • Metoclopramide (Reglan (see Metoclopramide, [[Metoclopramide]]): inhibits CYP3A enzyme

Monitoring

  • Tacrolimus Level

Avoid Live Vaccines During Tacrolimus Therapy

  • Live Bacillus Calmette-Guerin (BCG) Vaccine
  • Live Influenza Vaccine
  • Live Measles Vaccine
  • Live Mumps Vaccine
  • Live Oral Polio Vaccine
  • Live Rubella Vaccine
  • Live TY21a Typhoid Vaccine
  • Live Varicella Vaccine
  • Live Yellow Fever Vaccine

Adverse Effects

Allergic/Immunologic Adverse Effects

Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]])

  • Epidemiology
    • Associated with intravenous tacrolimus formulation
      • Cross-reactive with other intravenous drugs formulated with castor oil derivatives

Cardiovascular Adverse Effects

Hypertension (see Hypertension, [[Hypertension]])

  • Epidemiology: common

Myocardial Hypertrophy

  • Epidemiology: has bee reported (particularly with high tacrolimus levels)
  • Diagnosis
    • Echocardiogram: concentric hypertrophy of left ventricular posterior wall and intraventricular septum
  • Treatment: reversible with discontinuation of tacrolimus

Q-T Prolongation/Torsade (see Torsade, [[Torsade]])

  • Epidemiology: with definite association with torsade

Endocrinologic Adverse Effects

Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])

  • Epidemiology: new-onset diabetes mellitus has been reported

Drug-Induced Hyporeninemic Hypoaldosteronism (see Hypoaldosteronism, [[Hypoaldosteronism]])

  • Physiology: drug-induced hypoaldosteronism
    • Decreased renin release -> decreased secretion of aldosterone (i.e. hyporeninemic hypoaldosteronism) -> inhibition of potassium secretion in the renal collecting duct
    • Decreased responsiveness to aldosterone (likely due to decreased mineralocorticoid receptor expression) -> inhibition of potassium secretion in the renal collecting duct

Gastrointestinal Adverse Effects

Diarrhea (see Diarrhea, [[Diarrhea]])

  • Epidemiology: xxx

Gastrointestinal Perforation (see Intestinal Perforation, [[Intestinal Perforation]])

  • Epidemiology: has been reported
    • All cases were a complication of transplant surgery with accompanying infection, diverticuli, or malignant neoplasm

Hematologic/Oncologic Adverse Effects

Thrombotic Thrombocytopenic Purpura (TTP)/Hemolytic-Uremic Syndrome (HUS) (see xxxx, [[xxxx]])

  • Epidemiology: definite association
  • xxx

Increased Risk of Skin Cancer (see Skin Cancer, [[Skin Cancer]])

  • Epidemiology

Post-Transplant Lymphoproliferative Disorder (PTLD)/Lymphoma (see Lymphoma, [[Lymphoma]])

  • Epidemiology: related to the intensity and duration of immunosuppression (as opposed to the use of a specific agent)
  • Clinical

Pure Red Cell Aplasia (see xxxx, [[xxxx]])

  • Epidemiology: all cases had risk factors including parvovirus B19 infection, underlying disease, or concomitant medications which have been associated with pure red cell aplasia

Infectious Adverse Effects

Cytomegalovirus (CMV) (see Cytomegalovirus, [[Cytomegalovirus]])

  • xxx

Polyomaviruses

  • BK Virus (BK Polyomavirus) (see BK Virus, [[BK Virus]])
    • Polyomavirus-Associated Nephropathy (PVAN)
  • JC Virus (JC Polyomavirus) (see JC Virus, [[JC Virus]])

Neurologic Adverse Effects

Altered Mental Status

Headache (see Headache, [[Headache]])

  • Epidemiology:

Tremor (see Tremor, [[Tremor]])

  • Epidemiology: common

Renal Adverse Effects

Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])

  • Epidemiology
  • Physiology: vasoconstriction of afferent renal arteriole
  • Diagnosis
    • Low Fractional Excretion of Sodium (FENa)
  • Treatment: typically reversible

Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])

  • Epidemiology
  • Diagnosis
    • Renal Biopsy: characteristic changes
  • Clinical
    • Decreased Renal Allograft Lifespan
  • Treatment: typically progressive

Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])

  • Epidemiology : hyperkalemia occurs in 44-73% of transplant patients who receive cyclosporine A or tacrolimus [MEDLINE]
  • Physiology: drug-induced hypoaldosteronism (see above)
  • Treatment: fludrocortisone may be effective

Hyponatremia (see Hyponatremia, [[Hyponatremia]])

  • Epidemiology: xxx

Type 4 Renal Tubular Acidosis (RTA) (see Type 4 Renal Tubular Acidosis, [[Type 4 Renal Tubular Acidosis]])

  • Physiology: drug-induced hypoaldosteronism (see above)

Other Adverse Effects

  • xxx
  • xxx
  • xxx
  • xxx

References

  • Frequency of hyperkalemia in recipients of simultaneous pancreas and kidney transplants with bladder drainage. Transplantation 1996;62: 1174-5 [MEDLINE]
  • Cyclosporine a and FK506 inhibit transcriptional activity of the human mineralocorticoid receptor: a cell-based model to investigate partial aldosterone resistance in kidney transplantation. Endocrinology. 2002 May;143(5):1932-41 [MEDLINE]
  • Hyponatremia and hyperkalemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Nephrol Dial Transplant. 2004 Feb;19(2):444-50 [MEDLINE]
  • Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5 [MEDLINE]
  • Fludrocortisone is effective in the management of tacrolimus-induced hyperkalemia in liver transplant recipients. Transplant Proc. 2011 Sep;43(7):2664-8. doi: 10.1016/j.transproceed.2011.07.006 [MEDLINE]
  • Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am J Nephrol. 2013;37(6):602-12. doi: 10.1159/000351648. Epub 2013 Jun 18 [MEDLINE]
  • Role of fludrocortisone in the management of tacrolimus-induced hyperkalemia in a renal transplant recipient. Saudi J Kidney Dis Transpl. 2014 Jan;25(1):149-51 [MEDLINE]
  • Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015 Jan 22;125(4):616-8. doi: 10.1182/blood-2014-11-611335. Epub 2014 Nov 20 [MEDLINE]