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]])

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Pharmacology

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

Metabolism

• Hepatic CYP3A Enzymes

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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

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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

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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]