Envarsus Xr

1.1 Prophylaxis of Organ Rejection in De Novo Kidney Transplant Patients

ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants [see Clinical Studies (14.1)].

Prophylaxis of Organ Rejection in Stable Kidney Transplant Patients Converting from Immediate-Release Formulations

ENVARSUS 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)].

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 themorning to ensure consistent and maximum possible drug exposure, at least 1 hour before a meal or at least 2 hoursafter 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. Beyondthe 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 ENVARSUSXR [see Drug Interactions (7.2)].

2.2 Dosing in De Novo Kidney Transplant Patients

The recommended starting dose of ENVARSUS XR in de novo kidney transplant patients is 0.14 mg/kg/day. Titrate ENVARSUS XR dosage based on clinical assessments of rejection and tolerability and to achieve whole blood trough concentration ranges (see Table 1).

Dosing for Conversion from Tacrolimus Immediate-Release Formulations

To convert from a tacrolimus immediate-release product to ENVARSUS XR, administer ENVARSUS XR once daily at adose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole bloodtrough concentrations and titrate ENVARSUS XR dosage to achieve whole blood trough concentration ranges of 4 to 11ng/mL.

Dosing Adjustments in African-American Patients, Patients with Hepatic Impairment, Drug Interactions

African-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages toattain 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) thesepatients 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 orCYP3A inhibitors or cannabidiol [see Warnings and Precautions (5.9, 5.13), Drug Interactions (7.2, 7.3)].

Therapeutic Drug Monitoring

Measure 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-performanceliquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity oftacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites aswell as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may benumerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole bloodtacrolimus trough concentrations of patients to those described in the prescribing information and other publishedliterature must be made with knowledge of the assay method(s) employed.

Pregnancy

Pregnancy Exposure Registry

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.

Risk Summary

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance andTPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies,low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated withmaternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinicallyrelevant doses (0.7 to 3.7 times the recommended clinical dose [0.14 mg/kg/day], on a mg/m² basis). Administration oforal tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects onparturition, reduced pup viability and reduced pup weight at clinically relevant doses (1.2 to 3.7 times the recommendedclinical dose, on a mg/m² basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation andlactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reducedpup 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 offspringthat died [see Animal Data].

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. generalpopulation, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2to 4 % and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes conferadditional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associatedwith 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 withapproximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-termeffects on the offspring were reported.

Maternal Adverse Reactions

ENVARSUS XR may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitormaternal blood glucose levels regularly [see Warnings and Precautions (5.4)].

ENVARSUS XR may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control bloodpressure [see Warnings and Precautions (5.7, 5.8)].

Fetal/Neonatal Adverse Reactions

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery ininfants of mothers taking ENVARSUS XR.

Labor or Delivery

There is an increased risk for premature delivery (<37 weeks) following transplantation and maternal exposure toENVARSUS XR.

Data

Human Data

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 anincreased risk for miscarriage, pre-term delivery (<37 weeks), low birth weight (<2500 g), birth defects/congenitalanomalies 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 Table 8. In the table below, the number of recipientsexposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimesterperiods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may alsocause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewingthe data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations,renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.

*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 duringpregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidneyrecipients and 16.2% of liver recipients.

Animal Data

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at0.32 mg/kg (0.7 times the recommended clinical dose based on body surface area). At 1 mg/kg (2.3 times therecommended clinical dose) embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septaldefect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) wereobserved. Administration of 3.2 mg/kg oral tacrolimus (3.7 times the recommended clinical dose) to pregnant ratsthroughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight inthe offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams thatdelivered.

In a peri/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (afterorganogenesis) and throughout lactation produced maternal toxicity, effects of parturition, and reduced pup viability at3.2 mg/kg (3.7 times the recommended clinical dose); among these pups that died early, an increased incidence of kidneyhydronephrosis 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 maternaltoxicity/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 offspringthat died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (1.2 times therecommended clinical dose) [see Nonclinical Toxicology (13.1)].

Lactation

Risk Summary

Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present inhuman milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus isexcreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated withdevelopmental toxicity in the offspring at clinically relevant doses [see Pregnancy (8.1), Nonclinical Toxicology (13.1)].

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need forENVARSUS XR and any potential adverse effects on the breastfed child from ENVARSUS XR or from the underlyingmaternal condition.

Females and Males of Reproductive Potential

Contraception

ENVARSUS XR can cause fetal harm when administered to pregnant women. Advise female and male patients ofreproductive potential to speak with their healthcare provider on family planning options including appropriatecontraception prior to starting treatment with ENVARSUS XR [see Use in Specific Populations (8.1), NonclinicalToxicology (13.1)].

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with ENVARSUS XR [see Nonclinical Toxicology (13.1)].

Pediatric Use

The safety and effectiveness of ENVARSUS XR in pediatric patients have not been established.

Geriatric Use

Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whetherthey respond differently from younger patients. In Studies 1, 2 and 3, there were 37 patients 65 years of age and older,and no patients were over 75 years [see Clinical Studies (14)]. Other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients. In general, dose selection for an elderly patient shouldbe cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended [see Dosage and Administration (2.4)]. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

Race

African-American patients may need to be titrated to higher ENVARSUS XR dosages to attain comparable troughconcentrations compared to Caucasian patients. The pharmacokinetics of ENVARSUS XR were evaluated in a study of46 stable African-American kidney transplant recipients converted from tacrolimus immediate-release to ENVARSUSXR and indicated that an 80% conversion factor is appropriate for African-American patients [see Dosage andAdministration (2.4), Clinical Pharmacology (12.3)].

African-American and Hispanic kidney transplant patients are at an increased risk for new onset diabetes after transplant.Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)].