Does switching from Envarsus (tacrolimus) to Advagraf (tacrolimus) require a dose increase?

Switching from Envarsus to Advagraf Requires a Dose Increase

When switching from Envarsus (tacrolimus) to Advagraf (tacrolimus), a dose increase of approximately 40-50% is required to maintain similar therapeutic trough levels.

Pharmacokinetic Differences Between Formulations

Tacrolimus is a critical immunosuppressant used in solid organ transplantation that requires careful dosing due to its narrow therapeutic index. The different formulations have distinct pharmacokinetic properties:

• Envarsus: Uses MeltDose technology that improves absorption of tacrolimus, resulting in higher bioavailability
• Advagraf: A once-daily prolonged-release formulation with lower bioavailability compared to Envarsus

Bioavailability Comparison

Research demonstrates that Envarsus has approximately 30% greater relative bioavailability compared to Advagraf 1. This means:

• When converting from Envarsus to Advagraf, the dose needs to be increased to maintain similar trough concentrations
• Studies show that converting from Advagraf to Envarsus allows for a 42.9% reduction in tacrolimus dose while maintaining similar trough concentrations 2
• Therefore, the reverse conversion (Envarsus to Advagraf) would require a proportional increase in dose

Conversion Algorithm

When switching from Envarsus to Advagraf:

1. Calculate the new Advagraf dose: Increase the current Envarsus dose by approximately 40-50%
2. Monitor tacrolimus trough levels: Check levels within 3-5 days after conversion
3. Adjust as needed: Further dose adjustments may be required based on measured trough levels
4. Continue monitoring: More frequent monitoring is recommended in the first few months after conversion

Monitoring Recommendations

After conversion between tacrolimus formulations, close therapeutic drug monitoring is essential:

• Check tacrolimus trough levels 3-5 days after conversion
• Monitor levels weekly until stable
• Once stable, follow standard monitoring protocols (typically every 1-3 months)
• Target trough levels should be maintained between 5-15 ng/mL for adult patients once steady state is reached 3

Clinical Considerations

Several factors should be considered when switching between tacrolimus formulations:

• Timing: Make the switch in the morning, with the last Envarsus dose taken the day before
• Patient factors: Age, liver function, concomitant medications, and genetic polymorphisms may affect tacrolimus metabolism
• Drug interactions: Both formulations are metabolized by cytochrome P450, so drug interactions remain similar 3
• Transplant type: Different organ transplants may require different target trough levels

Potential Pitfalls

Several important caveats should be considered:

• Mistaken interchange: Accidentally interchanging different tacrolimus formulations without appropriate dose adjustment can lead to serious patient harm 4
• Transient level changes: Some studies show a transient decrease in tacrolimus levels 3-6 months after conversion between formulations, requiring closer monitoring during this period 5
• Individual variability: Response to conversion may vary between patients, emphasizing the need for individualized monitoring

Conclusion

When switching from Envarsus to Advagraf, a dose increase of approximately 40-50% is required due to the higher bioavailability of Envarsus. Close monitoring of tacrolimus trough levels is essential following conversion to ensure therapeutic levels are maintained and to prevent transplant rejection or toxicity.