Prograf (Tacrolimus) in Organ Transplantation
Recommended Use and Indications
Prograf (tacrolimus) is FDA-approved for prophylaxis of organ rejection in adult patients receiving allogeneic kidney, liver, or heart transplants, and in pediatric patients receiving liver transplants, always used in combination with other immunosuppressants. 1
Dosing Recommendations by Organ Type
Kidney Transplantation
- With azathioprine: Start 0.2 mg/kg/day divided every 12 hours, targeting trough levels of 7-20 ng/mL for months 1-3, then 5-15 ng/mL for months 4-12 1
- With MMF/IL-2 receptor antagonist: Start 0.1 mg/kg/day divided every 12 hours, targeting 4-11 ng/mL for months 1-12 1
- Long-term maintenance: Most patients can be maintained on 4-6 ng/mL after the first year 2, 3
Liver Transplantation
- Adults with corticosteroids: Start 0.1-0.15 mg/kg/day divided every 12 hours, targeting 5-20 ng/mL for months 1-12 1
- Pediatric patients: Start 0.15-0.2 mg/kg/day divided every 12 hours, targeting 5-20 ng/mL for months 1-12 1
- Renal-sparing regimens: Target lower levels of 6-10 ng/mL during the first month, then 4-8 ng/mL thereafter when combined with short-course corticosteroids 2
- With basiliximab and/or MMF/azathioprine: Target even lower levels of 4-7 ng/mL during the first month, followed by 3-5 ng/mL 2
Heart Transplantation
- With azathioprine or MMF: Start 0.075 mg/kg/day divided every 12 hours, targeting 10-20 ng/mL for months 1-3, then 5-15 ng/mL for month 4 and beyond 1
Critical Administration Guidelines
Administer tacrolimus capsules consistently either with or without food—never alternate—as food decreases absorption by 37% with a 77% decrease in maximum plasma concentration. 2
- Avoid grapefruit and grapefruit juice, which can significantly alter drug levels 1
- Do not interchange tacrolimus formulations (immediate-release vs. extended-release) without careful monitoring, as they are not bioequivalent and medication errors can lead to serious patient harm 1, 4
- Instruct patients to recognize the appearance of their specific tacrolimus capsules to prevent accidental substitution 1
Therapeutic Drug Monitoring Protocol
Immediate Post-Operative Period
- Monitor trough levels daily or every other day until target levels are reached 2, 5
- Continue monitoring every 2-3 days until hospital discharge 3, 5
First 3 Months
Months 4-12
Beyond First Year
- Monitor every 2-3 months once stable 2
- Increase monitoring frequency when adding or withdrawing CYP3A4-affecting medications, switching formulations, during allograft dysfunction, or when hospitalized 3, 5
Essential Laboratory Monitoring
Beyond trough levels, rigorous monitoring of multiple parameters is essential given tacrolimus's narrow therapeutic window and potential for serious toxicity. 2
- Renal function: Monitor serum creatinine regularly to detect nephrotoxicity 6, 2, 1
- Electrolytes: Monitor potassium (risk of hyperkalemia) and magnesium (risk of hypomagnesemia) closely 6, 2, 1
- Glucose: Monitor blood glucose levels regularly due to risk of new-onset diabetes after transplant 1
- Complete blood count: Monitor for bone marrow suppression, leukopenia, and anemia 6, 2, 1
- Liver function tests: Monitor hepatic function regularly 2, 1
- Blood pressure: Measure frequently, as hypertension is common and may require antihypertensive therapy 6, 1
- Lipid profile: Monitor for dyslipidemia 6
Special Populations and Dose Adjustments
Patients at Risk of Renal Dysfunction
- Use basiliximab induction with MMF or azathioprine to allow a 5-day delay in introducing tacrolimus 2, 3
- Target lower trough concentrations (4-7 ng/mL initially, then 3-5 ng/mL) when combined with other immunosuppressants 2, 3
African-American Patients
- May require dosage adjustments according to FDA labeling 1
Hepatic and Renal Impairment
- Dosage adjustments are necessary 1
Critical Drug Interactions
Tacrolimus is metabolized through the hepatic CYP3A4 system, making it highly susceptible to drug interactions that can dramatically alter levels. 6, 3
- CYP3A4 inhibitors (e.g., azole antifungals, macrolide antibiotics, calcium channel blockers) will increase tacrolimus levels 6
- CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) will decrease tacrolimus levels 6
- Cannabidiol can interact with tacrolimus 1
- Mycophenolic acid products: Switching from cyclosporine to tacrolimus can increase MPA exposure; monitor for MPA-related adverse reactions 1
- Tacrolimus itself inhibits CYP3A4 and may reduce clearance of digoxin, colchicine, and HMG-CoA reductase inhibitors 6
Infection Prophylaxis Requirements
Prophylaxis against Pneumocystis jiroveci must be implemented with tacrolimus use. 6, 2
- Consider antifungal prophylaxis in patients receiving steroids for neurotoxicity treatment 2
- Long-term antiviral therapy is recommended to prevent CMV and EBV infections 6
- Use molecular diagnostic tests (PP65 for CMV, PCR) for early viral replication detection with prompt preemptive therapy 6
Major Toxicities and Black Box Warnings
The FDA has issued a black box warning for increased susceptibility to serious infections and possible development of lymphoma and other malignancies that may lead to hospitalization or death. 1
Common Serious Adverse Effects (>15% incidence):
- Nephrotoxicity (acute and/or chronic)—reduce dose and use caution with other nephrotoxic drugs 1
- Neurotoxicity including tremor, headache, paresthesia, and risk of Posterior Reversible Encephalopathy Syndrome (PRES)—monitor for neurologic abnormalities and reduce or discontinue if severe 1
- New-onset diabetes after transplant—monitor blood glucose closely 1
- Hyperkalemia—monitor serum potassium and consider carefully before using with other agents associated with hyperkalemia 1
- Hypertension—may require antihypertensive therapy 1
- Hypomagnesemia 1
Other Significant Toxicities:
- Myocardial hypertrophy—consider dose reduction or discontinuation 1
- Pure red cell aplasia—consider discontinuation 1
- Thrombotic microangiopathy (including hemolytic uremic syndrome and thrombotic thrombocytopenic purpura), especially with infections and certain concomitant medications 1
- Anaphylactic reactions with IV formulation—observe patients for signs and symptoms 1
Important Contraindications and Precautions
- Contraindicated in patients with hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil) 1
- Not recommended for use with sirolimus in liver and heart transplant due to increased risk of serious adverse reactions 1
- Avoid live vaccines during tacrolimus therapy 1
- Not interchangeable with extended-release tacrolimus products without appropriate dose adjustments and monitoring 1
Long-Term Management Considerations
- Monitor for donor-specific antibodies combined with liver enzymes and non-invasive tests to identify patients at risk of subclinical rejection 2, 5
- Many long-term survivors can maintain normal function with tacrolimus levels substantially lower than initial targets, but weigh benefits against risk of subclinical rejection 2
- Conversion to CNI-free everolimus-based regimens can be achieved in more than 50% of patients beyond the first year 2
Common Pitfalls to Avoid
- Never switch between tacrolimus formulations (brand to generic, immediate-release to extended-release) without increasing monitoring frequency, as bioavailability differences can precipitate rejection 5, 4
- Trough levels may not always correlate well with overall drug exposure (AUC), particularly with extended-release formulations 4
- Do not assume therapeutic drug monitoring strategies for one formulation apply equally to another 4
- Recognize that tacrolimus has higher rates of diabetes mellitus and neurotoxicity compared to cyclosporine, while cyclosporine has higher rates of hypertension, hyperlipidemia, hirsutism, and gingival hyperplasia 6, 7, 8, 9