Are Envarsus (tacrolimus) and Advagraf (tacrolimus) interchangeable?

Tacrolimus Brand Interchangeability: Envarsus and Advagraf

Envarsus (tacrolimus) and Advagraf (tacrolimus) are not interchangeable and should not be substituted for one another without physician supervision due to significant differences in bioavailability and pharmacokinetic profiles. 1

Pharmacokinetic Differences

Envarsus and Advagraf are both once-daily prolonged-release formulations of tacrolimus, but they have important differences:

• Bioavailability: Envarsus has approximately 30% greater relative bioavailability compared to Advagraf 2
• Dosing requirements:
  • Conversion from Advagraf to Envarsus typically requires a 30-40% dose reduction 2, 3
  • Conversion from Advagraf to Envarsus without dose adjustment could lead to tacrolimus overexposure
• Peak-to-trough fluctuation: Envarsus demonstrates approximately 30% lower peak-to-trough percentage fluctuation in blood concentration 2
• Time to maximum concentration: Envarsus has a longer time to maximum blood concentration (tmax) and lower maximum concentration (Cmax) 2

FDA Warning

The FDA has issued a black box warning specifically addressing this issue:

"Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or overexposure to tacrolimus. Tacrolimus is not interchangeable or substitutable for tacrolimus extended-release products." 1

Clinical Implications

Switching between these formulations without proper dose adjustment and monitoring can lead to:

• Underexposure: Potentially resulting in graft rejection
• Overexposure: Potentially resulting in toxicity, including:
  • Nephrotoxicity
  • Neurotoxicity
  • Hyperkalemia
  • New-onset diabetes after transplant
  • Increased risk of infections 4, 1

Recommendations for Clinical Practice

1. Changes between tacrolimus formulations must occur under physician supervision 1
2. Intense clinical and concentration monitoring is required in the first few months after any conversion to a different tacrolimus formulation 5
3. Therapeutic drug monitoring strategies applicable to one formulation may not be equally applicable to another 5
4. Patients should be educated to recognize the appearance of their tacrolimus dosage form and confirm with their healthcare provider if a different product is dispensed 1

Monitoring Requirements

When switching between formulations:

• Monitor tacrolimus trough levels more frequently (initially daily until steady levels are attained)
• Gradually increase monitoring intervals to every 1-2 weeks in the first 1-2 months
• Once stable levels are attained, monitor every 1-2 months 4
• Target trough levels are typically 5-15 ng/mL 4

Conclusion

While both Envarsus and Advagraf contain tacrolimus and are once-daily formulations, they have significantly different pharmacokinetic profiles that make them non-interchangeable. Any conversion between these formulations requires careful dose adjustment and close monitoring to ensure appropriate tacrolimus exposure and to prevent adverse outcomes.