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

Indications

Transplantation

Anti-Rejection Agent for Solid Organ Transplant
- Cardiac Transplant (see Cardiac Transplant, [[Cardiac Transplant]])
- Lung Transplant (see Lung Transplant, [[Lung Transplant]])
- Liver Transplant (see Liver Transplant, [[Liver Transplant]])
- Renal Transplant (see Renal Transplant, [[Renal Transplant]])
Bone Marrow Transplant-Related Graft vs Host Disease (see Graft vs Host Disease, [[Graft vs Host Disease]]): off-label use

Other

Myasthenia Gravis (see Myasthenia Gravis, [[Myasthenia Gravis]])
Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[Rheumatoid Arthritis]])

Pharmacology

Calcineurin Inhibitor (see Calcineurin Inhibitors, [[Calcineurin Inhibitors]])

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
- Ketoconazole (see Ketoconazole, [[Ketoconazole]])
Calcium Channel Blockers (see Calcium Channel Blockers, [[Calcium Channel Blockers]]): inhibit CYP3A enzyme
- Diltiazem (see Diltiazem, [[Diltiazem]])
- Nicardipine (see Nicardipine, [[Nicardipine]])
- Nifedipine (see Nifedipine, [[Nifedipine]])
- Verapamil (see Verapamil, [[Verapamil]])
Chloramphenicol (see Chloramphenicol, [[Chloramphenicol]]): inhibits CYP3A enzyme
Grapefruit Juice: inhibits CYP3A enzymes
Macrolides (see Macrolides, [[Macrolides]]): inhibit CYP3A enzyme
- Clarithromycin (see Clarithromycin, [[Clarithromycin]])
- Erythromycin (see Erythromycin, [[Erythromycin]])
- Troleandomycin (see Troleandomycin, [[Troleandomycin]])
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]])
- JC Virus-Associated Progressive Multifocal Leukoencephalopathy (PML) (see Progressive Multifocal Leukoencephalopathy, [[Progressive Multifocal Leukoencephalopathy]])

Neurologic Adverse Effects

Altered Mental Status

Obtundation/Coma (see Obtundation-Coma, [[Obtundation-Coma]]): associated with high tacrolimus levels
Delirium (see Delirium, [[Delirium]]): associated with high tacrolimus levels
Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome, [[Posterior Reversible Encephalopathy Syndrome]])

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]