Regulatory Decision Summary for Envarsus Pa

Health Canada considers that the overall benefit-risk profile of Envarsus PA is favorable when used with other immunosuppressants for the prophylaxis of organ rejection in allogenic kidney or liver transplant adult patients.

Envarsus PA is a prolonged-release tacrolimus tablet formulation. The recommended dosage of Envarsus PA is once daily at the same time of the day, preferably in the morning an on empty stomach.

The indication for Envarsus PA is supported primarily by safety and efficacy data from one active-controlled, double-blind Phase 3 study and one open-label Phase 3 study for kidney transplant patients, and two Phase 2 studies for liver transplant patients.

Envarsus PA was demonstrated to consistently deliver tacrolimus exposure to patients in the targeted range of 4-20 ng/mL based on the clinical studies conducted in kidney and liver transplant patients (stable and de novo settings), consistent with twice daily administration of immediate release formulation.

Efficacy analysis of the Phase 3 studies for kidney transplant patients was integrated. The effectiveness of Envarsus PA was evaluated primarily on the composite endpoint of treatment failure, which was derived from graft loss, death, biopsy-proven acute rejection (BPAR) and lost to follow-up. Based on the analysis of treatment failure at 6 and 12 months, the efficacy failure rate was no worse in the Envarsus PA group compared to the immediate release formulation group, and consistent with the historical data in renal transplant patients having received tacrolimus treatment.

Results of a Phase 2 study of Envarsus PA in 49 stable liver transplant patients converted from the immediate release formulation treatment showed that were no deaths and no graft losses, and only mild biopsy-proven acute rejection (BPAR) which occurred in 1 patient during the 52-week study period. Study Envarsus PA 2018 in de novo liver transplant patients, showed no worse efficacy for Envarsus PA once daily versus twice daily immediate release tacrolimus formulation after 12 months of treatment.

The most common Treatment Emergent Adverse Events (TEAE) reported in kidney transplant patients did not reveal any important differences between treatment groups in terms of the frequency of events, and were broadly consistent with the established safety profile of other drugs in the same class. Amongst these, the most frequently reported TEAEs in ≥15% of kidney transplant patients were: diarrhea; urinary tract infection; anemia; hypertension; and constipation. The severity of the TEAEs was also similar between the treatment groups.

The most common treatment-related adverse even reported in kidney transplant patients were tremor, diabetes mellitus, blood creatinine increase and urinary tract infection, which were comparable between the two treatment groups. For the serious adverse reactions and death as well as laboratory abnormalities, there were no overall differences between the treatment groups. Similar safety results were also observed in liver transplant patients in Phase 2 studies.

Based on the data reviewed, Health Canada considers that the anticipated benefits of Envarsus PA, as an immunosuppressant, for the prophylaxis of organ rejections in adult patients with allogenic kidney or liver transplants outweigh the potential risks under the conditions of use as described in the Product Monograph of Envarsus PA at this time.