Envarsus

Warnings and Precautions, Cannabidiol Drug Interactions ( 5.13 ) 7/2023 Warnings and Precautions ( 5.5 , 5.9 , 5.10 , 5.14 ) 4/2024

1 INDICATIONS AND USAGE 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 ) The prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants ( 1.2 ) 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) ]. 1.2 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) ].

2 DOSAGE AND ADMINISTRATION Take once daily on empty stomach at the same time of the day, preferably in the morning. ( 2.1 ) Avoid eating grapefruit or drinking grapefruit juice or alcohol. ( 2.1 ) African-American patients may need to be titrated to higher dosages to achieve the target tacrolimus concentrations. ( 2.4 ) Patients with severe hepatic impairment may require a lower starting dose. ( 2.4 ) Frequent monitoring of trough concentrations is recommended. ( 2.5 ) 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 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) ]. 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 ). Table 1. Recommended Tacrolimus Whole Blood Trough Concentration Ranges in Kidney Transplant Patients with Antibody Induction Time Period Post Transplant Target Tacrolimus Whole Blood Trough Concentration Ranges During Month 1 6 to 11 ng/mL > Month 1 4 to 11 ng/mL 2.3 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 a dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole blood trough concentrations and titrate ENVARSUS XR dosage to achieve whole blood trough concentration ranges of 4 to 11 ng/mL. 2.4 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 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) ]. 2.5 Therapeutic Drug Monitoring Measure tacrolimus whole blood tr …

3 DOSAGE FORMS AND STRENGTHS 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. Extended-release tablets: 0.75 mg, 1 mg, 4 mg ( 3 )

4 CONTRAINDICATIONS ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus or to any of the ingredients in ENVARSUS XR. Known hypersensitivity to tacrolimus or any of the ingredients ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are discussed in greater detail in other sections of the labeling: Lymphoma and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.1) ] Serious Infections [see Boxed Warning, Warnings and Precautions (5.2) ] New Onset Diabetes after Transplant [see Warnings and Precautions (5.4) ] Nephrotoxicity due to ENVARSUS XR and Drug Interactions [see Warnings and Precautions (5.5) ] Neurotoxicity [see Warnings and Precautions (5.6) ] Hyperkalemia [see Warnings and Precautions (5.7) ] Hypertension [see Warnings and Precautions (5.8) ] QT Prolongation [see Warnings and Precautions (5.10) ] Pure Red Cell Aplasia [see Warnings and Precautions (5.12) ] Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.13) ] De novo kidney transplant patients: Most common adverse reactions (incidence ≥15%) include: diarrhea, anemia, urinary tract infection, hypertension, tremor, constipation, diabetes mellitus, peripheral edema, hyperkalemia and headache. ( 6.1 ) Conversion of kidney transplant patients from immediate-release to extended-release tacrolimus: Most common adverse reactions (incidence ≥10%) include: diarrhea and blood creatinine increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Veloxis Pharmaceuticals, Inc. at 1-844-VELOXIS (1-844-835-6947) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below. Study 1- Phase 3 Clinical Study in De Novo Kidney Transplant Recipients Study 1 (NCT 01187953), was a Phase 3 randomized study in de novo kidney transplant patients that were treated with ENVARSUS XR (N=268) or tacrolimus [immediate-release] capsules (N=275) and concomitant immunosuppressants in a double-blind, randomized, multinational study [see Clinical Studies (14.1) ]. The proportion of patients who discontinued treatment due to adverse reactions was 8.6% and 9.8% in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the ENVARSUS XR treatment group were esophagitis, polyomavirus-associated nephropathy, graft dysfunction, complications of transplanted kidney, and diabetes mellitus, each resulting in 0.7% discontinuations among ENVARSUS XR treatment patients. In Study 1, de novo kidney transplant patients who received a starting dose of 0.17 mg/kg/day, which is higher than the recommended ENVARSUS XR starting dose of 0.14 mg/kg/day, exceeded the recommended target tacrolimus trough concentrations as high as 57 ng/mL during the first 1 to 2 weeks post-transplant [see Dosage and Administration (2.2) ]. Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in de novo kidney transplant recipients treated with ENVARSUS XR or tacrolimus [immediate-release] capsules in Study 1 are shown in Table 2 . Table 2 Percentage of Patients with Infections Through 1 Year Post-Kidney Transplant in Study 1 a MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprine a Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table. b BK virus-associated nephropathy (BKVAN) occurred in 1.5% (4/268) and 0.7% (2/275) in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively. ENVARSUS XR ± steroids, IL-2 recepto …

7 DRUG INTERACTIONS Risk of rejection with strong CYP3A inducers and risk of serious adverse reactions with strong CYP3A inhibitors: Adjust dose and monitor tacrolimus concentrations. ( 2.4 , 5.9 , 7.2 ) Therapeutic drug monitoring and dose reduction for ENVARSUS XR should be considered when ENVARSUS XR is co-administered with cannabidiol ( 2.5 , 5.13 , 7.3 ). See Full Prescribing Information for clinically significant drug interactions. ( 7.1 , 7.2 ) 7.1 Mycophenolic Acid When ENVARSUS XR is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with ENVARSUS XR co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA associated adverse reactions and reduce the dose of concomitantly administered MPA products as needed. 7.2 Effects of Other Drugs/Substances on ENVARSUS XR Table 7. Effects of Other Drugs/Substances on ENVARSUS XR a, d a ENVARSUS XR dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology (12.3) ] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to immediate-release tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate) d A drug interaction study with voriconazole was conducted for ENVARSUS XR [see Clinical Pharmacology (12.3) ] . No other drug-drug interaction studies were conducted with ENVARSUS XR. Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice b May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 , 5.9 , 5.10) ]. Avoid grapefruit or grapefruit juice. Alcohol May modify the rate of tacrolimus release. Avoid alcoholic beverages. Strong CYP3A Inducers c, such as: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.9) ]. Increase ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Strong CYP3A Inhibitors c, , such as: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir or ritonavir containing products), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, Schisandra sphenanthera extracts, cobicistat May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions (5.6, 5.9, 5.10) ]. Reduce ENVARSUS XR dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions (5.9)] . Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethiny …

8 USE IN SPECIFIC POPULATIONS ­Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) 8.1 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 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 [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 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 [see Animal Data]. 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. 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 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. Maternal Adverse Reactions ENVARSUS XR may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal 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 blood pressure [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 in infants of mothers taking ENVARSUS XR. Labor or Delivery There is an increased risk for premature delivery (10) compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12 …

12.1 Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

11 DESCRIPTION Tacrolimus is the active ingredient in ENVARSUS XR. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3 S -[3 R *[ E (1 S *,3 S *,4 S *)],4 S *,5 R *,8 S *,9 E ,12 R *,14 R *,15 S *,16 R *,18 S *,19 S *,26a R *]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c ][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. ENVARSUS XR is available for oral administration as extended-release tablets containing the equivalent of 0.75 mg, 1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF. chemical-structure

10 OVERDOSAGE Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included: nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence) gastrointestinal disturbances (nausea, vomiting, and diarrhea) abnormal renal function (increased blood urea nitrogen and elevated serum creatinine) urticaria hypertension peripheral edema, and infections (one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus extended-release capsules overdose). Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING ENVARSUS XR is supplied in round HDPE bottles with twist-off caps (see Table 12 ); the statement ‘ONCE-DAILY’ appears on its labels. Table 12. Strengths of ENVARSUS XR Strength Description NDC 0.75 mg Oval, white to off-white uncoated extended-release tablet, debossed with “0.75” on one side and “TCS” on the other side. 30-count (NDC 68992-3075-3) 100-count (NDC 68992-3075-1) 1 mg Oval, white to off-white uncoated extended-release tablet, debossed with “1” on one side and “TCS” on the other side. 30-count (NDC 68992-3010-3) 100-count (NDC 68992-3010-1) 4 mg Oval, white to off-white uncoated extended-release tablet, debossed with “4” on one side and “TCS” on the other side. 30-count (NDC 68992-3040-3) 100-count (NDC 68992-3040-1) Store and Dispense Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].