Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinicalstudies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the ratesobserved in practice. In addition, the clinical studies were not designed to establish comparative differences across studyarms with regards to the adverse reactions discussed below.

Study 1 (NCT 01187953), was a Phase 3 randomized study in de novo kidney transplant patients that were treated withENVARSUS XR (N=268) or tacrolimus [immediate-release] capsules (N=275) and concomitant immunosuppressants in adouble-blind, randomized, multinational study

The overall incidence of infections, serious infections, and infections with identified etiology reported in de novo kidneytransplant recipients treated with ENVARSUS XR or tacrolimus [immediate-release] capsules in Study 1 are shown in

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucosevalues ≥126 mg/dL, 2-hour post-prandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on two ormore consecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, orHbA

The incidence of adverse reactions that occurred in ≥10% of ENVARSUS XR-treated patients compared to tacrolimus[immediate-release] capsules through one year of treatment in Study 1 is shown by treatment group in

Study 2 (NCT00765661) was an open-label Phase 2 study conducted in de novo kidney transplant patients randomized toonce daily ENVARSUS XR (N=32) or twice daily tacrolimus [immediate-release] capsules (N=31). The study wasconducted in the US and patients received an organ from a deceased or living donor. Pharmacokinetics were evaluatedduring the first 2 weeks with an additional 50-week treatment and follow-up to evaluate safety and efficacy

The starting dosage was 0.14 mg/kg/day (given once daily) for ENVARSUS XR and 0.2 mg/kg/day (given twice daily)for tacrolimus [immediate-release] capsules. On Day 2 predose, the proportion of patients in the ENVARSUS XR groupwith tacrolimus trough concentration that were within, above, and below 6 to 11 ng/mL was 53%, 11%, and 37%,respectively. The starting dose of 0.14 mg/kg/day in Study 2 formed the basis of dosing recommendations in de novokidney transplant patients.

There were no deaths or graft failures in Study 2. Two patients in each arm discontinued due to adverse events. The mostcommon adverse reactions included infections and cardiovascular events, and were generally similar to those reported inStudy 1.

In Study 3 (NCT00817206) stable kidney transplant patients were treated with ENVARSUS XR (N=162) or tacrolimus[immediate-release] capsules (N=162) and concomitant immunosuppressants in an open-label, randomized, multinationalstudy

The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidneytransplant recipients treated with ENVARSUS XR or tacrolimus capsules are shown in

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucosevalues ≥126 mg/dL, 2-hour postprandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on 2 or moreconsecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, orHbA1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history ofdiabetes. The incidence of NODAT for the stable kidney transplant study through one year post-transplant is summarizedin

In Study 3, the most common (≥10%) adverse reactions observed with Envarsus XR were diarrhea (14%), and bloodcreatinine increased (12%).

The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outsidethe U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible toreliably estimate their frequency or establish a causal relationship to drug exposure. The following reactions have beenincluded due to either their seriousness, frequency of reporting or strength of causal connection to ENVARSUS XR:

Advise patients to:

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor

Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections,due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweatsor chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin

Inform patients that ENVARSUS XR can cause diabetes mellitus and should be advised to contact their physician if theydevelop frequent urination, increased thirst or hunger

Inform patients that ENVARSUS XR can have toxic effects on the kidney that should be monitored. Advise patients toattend all visits and complete all blood tests ordered by their medical team

Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, andtremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors

Inform patients that ENVARSUS XR can cause hyperkalemia. Monitoring of potassium levels may be necessary,especially with concomitant use of other drugs known to cause hyperkalemia

Inform patients that ENVARSUS XR can cause high blood pressure which may require treatment with anti-hypertensivetherapy. Advise patients to monitor their blood pressure

Inform patients that ENVARSUS XR can cause blood clotting problems. The risk of this occurring increases when patients take ENVARSUS XR and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria

Instruct patients to tell their healthcare providers when they start or stop taking any concomitant medications, includingprescription and non-prescription medicines, natural or herbal remedies, dietary supplements and vitamins. Somemedications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage ofENVARSUS XR. Advise patients to avoid grapefruit, grapefruit juice and alcoholic beverages

Inform women of childbearing potential that ENVARSUS XR can harm the fetus. Instruct male and female patients todiscuss with their healthcare provider family planning options including appropriate contraception. Also discuss withpregnant patients the risks and benefits of breastfeeding their infant

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed toimmunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. Toenroll or register, patients can call the toll-free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Based on animal studies, ENVARSUS XR may affect fertility in males and females

Inform patients that ENVARSUS XR can interfere with the usual response to immunizations and that they should avoidlive vaccines

Product of Germany

Manufactured by:

Manufactured for: