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Important safety information
Indication and clinical use:
ENVARSUS® PA (tacrolimus prolonged-release tablets) is indicated in adult patients for the prophylaxis of organ rejection in allogenic kidney or liver transplant in combination with other immunosuppressants.
Pediatrics (< 18 years of age): Not indicated in pediatrics.
Geriatrics (≥ 65 years of age): There is no evidence currently available to indicate that dose should be adjusted in elderly patients solely on the basis of age. A limited number of patients 65 years of age and over were included in the clinical studies of ENVARSUS® PA.
Most serious warnings and precautions:
Serious infections, including fatal outcomes: Increased risk of developing both generalized and localized bacterial, viral, fungal, and protozoal infections, including opportunistic infections, that may lead to serious or fatal outcomes. Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection. Whenever possible, administer the complete complement of vaccines before transplantation. Avoid the use of live attenuated vaccines during treatment. Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic.
Malignancies: Increased risk of developing lymphomas and other malignancies, particularly of the skin. Examine patients for skin changes, and advise to avoid or limit exposure to sunlight and UV light. Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr virus (EBV), has been reported. Monitor EBV serology during treatment.
Prescriber restrictions and patient management requirements: Only physicians experienced in immunosuppressive therapy and management of organ transplants should prescribe ENVARSUS® PA. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient and should be consulted if a patient is converted to an alternative formulation so that therapeutic drug monitoring can be instituted.
Other relevant warnings and precautions:
Not interchangeable or substitutable on an equal dose-by-dose basis with other existing tacrolimus-containing products (immediate- or extended-release)
Contains lactose
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
CYP3A4 inducers and inhibitors
Caution during co-administration with P-glycoprotein (P-gp) inhibitors
Heart failure and ventricular hypertrophy or hypertrophy of the septum
Prolonged QT/QTc interval
Hypertension
Gastrointestinal perforation
Episodes of diarrhea
Cases of pure red cell aplasia and leukopenia
Thrombotic microangiopathy and thrombocytopenic purpura
New-onset diabetes mellitus
Neurotoxicities
Acute or chronic nephrotoxicity
Hyperkalemia
Renal insufficiency
Pregnant and breastfeeding women
Dose selection for an elderly patient should be cautious
For more information:
Please consult the Product Monograph at https://www.endodocuments.com/ENVARSUSPA/MONOGRAPH/CAN/ENG and the Dear Healthcare Professional Letter on inadvertent switching between different tacrolimus oral formulations, which could lead to graft rejection and other adverse reactions, available at https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70511a-eng.php, for important information relating to adverse reactions, drug interactions, and dosing that has not been discussed in this piece. The Product Monograph is also available by calling us at 1-888-867-7426.
Patients and study arms: De novo kidney transplant recipients were randomly assigned to 0.17 mg/kg/day ENVARSUS® PA (n=268) once daily or 0.1 mg/kg/day Prograf® (n=275) twice daily, and all patients also received matching double-dummy placebo to maintain the blind.
Dose adjustment: Study drug doses were adjusted to maintain target tacrolimus trough levels between 6 and 11 ng/mL for the first 30 days and 4 to 11 ng/mL for the remainder of the study.†
Primary efficacy endpoint: The incidence of treatment failures, which was a composite of death, graft failure, BPAR (Banff Grade ≥ 1A, using Banff 2007 criteria; based on a biopsy reading from a blinded central pathologist), or loss to follow-up within 12 months after the randomization date.
*Components of overall efficacy failure include death, graft failure, locally assessed BPAR, and loss to follow-up.
†Typical whole blood trough concentrations indicated for ENVARSUS® PA in de novo kidney transplant patients are 7–20 ng/mL from Day 1 to 90 and 5–15 ng/mL from Month 4 to 12.
