Indications
Transplantation
- Anti-Rejection Agent for Solid Organ Transplant
- Bone Marrow Transplant-Related Graft vs Host Disease (see Graft vs Host Disease, [[Graft vs Host Disease]]): off-label use
Other
Pharmacology
Metabolism
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
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]])
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]])
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]])
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]])
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]])
Tremor (see Tremor, [[Tremor]])
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]])
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
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]