Dosage & Administration
| Recommended ENVARSUS XR Initial Dosage | ||
| Initial Oral Dosage | Whole Blood Trough Concentration Range | |
De novo kidney transplantation with antibody induction | 0.14 mg/kg/day | Month 1: 6-11 ng/mL >Month 1: 4-11 ng/mL |
Conversion from tacrolimus immediate-release formulations | 80% of the pre-conversion dose of tacrolimus immediate-release | Titrate to 4-11 ng/mL |
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Envarsus XR Prescribing Information
Immunosuppressants, including ENVARSUS XR, increase the risk of developing lymphomas and other malignancies,
particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to
the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV
light by wearing protective clothing and using a sunscreen with a high protection factor.
Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in
immunosuppressed organ transplant patients. The risk of PTLD appears greatest in those individuals who are EBV
seronegative. Monitor EBV serology during treatment.
Immunosuppressants, including ENVARSUS XR, increase the risk of developing bacterial, viral, fungal, and protozoal
infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious
viral infections reported include:
- Polyomavirus-associated nephropathy (especially due to BK virus infection),
- JC virus-associated progressive multifocal leukoencephalopathy (PML), and
- Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV
seropositive donor are at highest risk of CMV viremia and CMV disease.
Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection
Warnings and Precautions, Cannabidiol Drug Interactions (5.13 Cannabidiol Drug Interactions When cannabidiol and ENVARSUS XR are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ENVARSUS XR should be considered as needed when ENVARSUS XR is co-administered with cannabidiol [ see Dosage and Administration (2.4, 2.5), Drug Interactions (7.3) ]. | 7/2023 |
Warnings and Precautions (ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration. The risk for nephrotoxicity may increase when ENVARSUS XR is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with CYP3A inhibitors or other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use [see Adverse Reactions (6.1, 6.2)and Drug Interactions (7.2)]. The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10)]. Therefore, adjustENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when co-administering ENVARSUS XR with strong CYP3A inhibitors (e.g., including but not limited to telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including but not limited to rifampin, rifabutin) [see Dosage and Administration (2.4, 2.5), Drug Interactions (7.2)] . A rapid, sharp rise in tacrolimus levels has been reported after co-administration with strong CYP3A4 inhibitors despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended[see Drug Interactions (7.2)]. ENVARSUS XR may prolong the QT/QTc interval and cause Torsades de pointes . Avoid ENVARSUS XR in patientswith congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia). When co-administering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended [see Dosage and Administration (2.5), Drug Interactions (7.2)] .Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ENVARSUS XR. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA. In patients with signs and symptoms of TMA, consider ENVARSUS XR as a risk factor. Concurrent use of ENVARSUS XR and mTOR inhibitors may contribute to the risk of TMA. | 4/2024 |
ENVARSUS XR is a calcineurin-inhibitor immunosuppressant indicated for:
- The prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants ()
1.1 Prophylaxis of Organ Rejection in De Novo Kidney Transplant PatientsENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants
[see Clinical Studies (14.1)]. - The prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants ()
1.2 Prophylaxis of Organ Rejection in Stable Kidney Transplant Patients Converting from Immediate-Release FormulationsENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants
[see Clinical Studies (14.2)].
- Take once daily on empty stomach at the same time of the day, preferably in the morning. ()
2.1 Important Administration Instructions- ENVARSUS XR (tacrolimus extended-release tablets) is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules, and tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions[see Warnings and Precautions (5.3)].ENVARSUS XR should not be used without the supervision of a physician with experience in immunosuppressive therapy.
- ENVARSUS XR should be taken on an empty stomach consistently at the same time of the day, preferably in the
morning to ensure consistent and maximum possible drug exposure, at least 1 hour before a meal or at least 2 hours
after a meal[see Clinical Pharmacology (12.3)]. - Advise patients to swallow ENVARSUS XR tablets whole with fluid (preferably water); patients must not chew,
divide, crush or dissovle the tablets. - If a dose is missed, instruct the patient to take it as soon as possible within 15 hours after missing the dose. Beyond
the 15-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular daily dose.
Instruct the patient not to double the next dose. - Patients should avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking ENVARSUS
XR[see Drug Interactions (7.2)].
- ENVARSUS XR (tacrolimus extended-release tablets) is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules, and tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions
- Avoid eating grapefruit or drinking grapefruit juice or alcohol. ()
2.1 Important Administration Instructions- ENVARSUS XR (tacrolimus extended-release tablets) is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules, and tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions[see Warnings and Precautions (5.3)].ENVARSUS XR should not be used without the supervision of a physician with experience in immunosuppressive therapy.
- ENVARSUS XR should be taken on an empty stomach consistently at the same time of the day, preferably in the
morning to ensure consistent and maximum possible drug exposure, at least 1 hour before a meal or at least 2 hours
after a meal[see Clinical Pharmacology (12.3)]. - Advise patients to swallow ENVARSUS XR tablets whole with fluid (preferably water); patients must not chew,
divide, crush or dissovle the tablets. - If a dose is missed, instruct the patient to take it as soon as possible within 15 hours after missing the dose. Beyond
the 15-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular daily dose.
Instruct the patient not to double the next dose. - Patients should avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking ENVARSUS
XR[see Drug Interactions (7.2)].
- ENVARSUS XR (tacrolimus extended-release tablets) is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules, and tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions
- African-American patients may need to be titrated to higher dosages to achieve the target tacrolimus concentrations. ()
2.4 Dosing Adjustments in African-American Patients, Patients with Hepatic Impairment, Drug InteractionsAfrican-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to
attain comparable trough concentrations[see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].Due to reduced clearance and prolonged half-life seen in patients with severe hepatic impairment (Child-Pugh ≥10) these
patients may require a lower starting dosage of ENVARSUS XR[see Clinical Pharmacology (12.3)].Dose adjustments of ENVARSUS XR may be necessary when administered concomitantly with CYP3A inducers or
CYP3A inhibitors or cannabidiol[see Warnings and Precautions (5.9, 5.13), Drug Interactions (7.2, 7.3)]. - Patients with severe hepatic impairment may require a lower starting dose. ()
2.4 Dosing Adjustments in African-American Patients, Patients with Hepatic Impairment, Drug InteractionsAfrican-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to
attain comparable trough concentrations[see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].Due to reduced clearance and prolonged half-life seen in patients with severe hepatic impairment (Child-Pugh ≥10) these
patients may require a lower starting dosage of ENVARSUS XR[see Clinical Pharmacology (12.3)].Dose adjustments of ENVARSUS XR may be necessary when administered concomitantly with CYP3A inducers or
CYP3A inhibitors or cannabidiol[see Warnings and Precautions (5.9, 5.13), Drug Interactions (7.2, 7.3)]. - Frequent monitoring of trough concentrations is recommended. ()
2.5 Therapeutic Drug MonitoringMeasure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors or cannabidiol
[see Drug Interactions (7)],or after a change in renal or hepatic function[see Use in Specific Populations (8.6, 8.7)]. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ENVARSUS XR dose.Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high-performance
liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of
tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as
well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be
numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood
tacrolimus trough concentrations of patients to those described in the prescribing information and other published
literature must be made with knowledge of the assay method(s) employed.
| Recommended ENVARSUS XR Initial Dosage | ||
| Initial Oral Dosage | Whole Blood Trough Concentration Range | |
De novo kidney transplantation with antibody induction | 0.14 mg/kg/day | Month 1: 6-11 ng/mL >Month 1: 4-11 ng/mL |
Conversion from tacrolimus immediate-release formulations | 80% of the pre-conversion dose of tacrolimus immediate-release | Titrate to 4-11 ng/mL |
Oval, white to off-white uncoated extended-release tablets debossed with “TCS” on one side:
- 0.75 mg extended-release tablet: debossed with “0.75” on the other side.
- 1 mg extended-release tablet: debossed with “1” on the other side.
- 4 mg extended-release tablet: debossed with “4” on the other side.
Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk
to the fetus. (
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ENVARSUS XR during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.
Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and
TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies,
low birth weight, and fetal distress
Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with
maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically
relevant doses (0.7 to 3.7 times the recommended clinical dose [0.14 mg/kg/day], on a mg/m² basis). Administration of
oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on
parturition, reduced pup viability and reduced pup weight at clinically relevant doses (1.2 to 3.7 times the recommended
clinical dose, on a mg/m² basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and
lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced
pup viability at clinically relevant doses (1.2 to 3.7 times the recommended clinical dose, on a mg/m² basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring
that died
The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
to 4 % and 15 to 20%, respectively.
Risks during pregnancy are increased in organ transplant recipients.
The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer
additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated
with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.
Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with
approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term
effects on the offspring were reported.
ENVARSUS XR may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor
maternal blood glucose levels regularly
ENVARSUS XR may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood
pressure
Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in
infants of mothers taking ENVARSUS XR.
There is an increased risk for premature delivery (<37 weeks) following transplantation and maternal exposure to
ENVARSUS XR.
There are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy.
Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an
increased risk for miscarriage, pre-term delivery (<37 weeks), low birth weight (<2500 g), birth defects/congenital
anomalies and fetal distress.
TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus,
respectively. The TPRI pregnancy outcomes are summarized in
exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester
periods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may also
cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing
the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations,
renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.
| Kidney | Liver | |
Pregnancy Outcomes* | 462 | 253 |
Miscarriage | 24.5% | 25% |
Live births | 331 | 180 |
| Pre-term delivery (< 37 weeks) | 49% | 42% |
| Low birth weight (< 2500 g) | 42% | 30% |
| Birth defects | 8%† | 5% |
*Includes multiple births and terminations.
†Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.
Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during
pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney
recipients and 16.2% of liver recipients.
Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at
0.32 mg/kg (0.7 times the recommended clinical dose based on body surface area). At 1 mg/kg (2.3 times the
recommended clinical dose) embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal
defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were
observed. Administration of 3.2 mg/kg oral tacrolimus (3.7 times the recommended clinical dose) to pregnant rats
throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in
the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that
delivered.
In a peri/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after
organogenesis) and throughout lactation produced maternal toxicity, effects of parturition, and reduced pup viability at
3.2 mg/kg (3.7 times the recommended clinical dose); among these pups that died early, an increased incidence of kidney
hydronephrosis was observed. Reduced pup weight was observed at 1mg/kg (1.2 times the recommended clinical dose).
Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal
toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (3.7 times the recommended clinical dose).
Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring
that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (1.2 times the
recommended clinical dose)
ENVARSUS XR can cause fetal harm when administered to pregnant women. Advise female and male patients of
reproductive potential to speak with their healthcare provider on family planning options including appropriate
contraception prior to starting treatment with ENVARSUS XR
Toxicology (13.1)].
Based on findings in animals, male and female fertility may be compromised by treatment with ENVARSUS XR