Tacrolimus

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) ].

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 )

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 )

Not Interchangeable with Other Tacrolimus Products: Instruct patients or caregivers to recognize appearance of ENVARSUS XR tablets. ( 5.3 ) New Onset Diabetes after Transplant: Monitor blood glucose. ( 5.4 ) Nephrotoxicity (acute and/or chronic): May occur due to ENVARSUS XR, drug interactions or concomitant nephrotoxic drugs. Monitor renal function and tacrolimus blood concentrations; consider dosage reduction or temporary interruption of ENVARSUS. ( 5.5 ) Neurotoxicity: Including risk of posterior reversible encephalopathy syndrome (PRES); monitor for neurologic abnormalities; reduce dosage or discontinue ENVARSUS XR. ( 5.6 ) Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels. ( 5.7 ) Hypertension: May require antihypertensive therapy; monitor relevant drug interactions. ( 5.8 ) QT Prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk. ( 5.10 ) Immunizations: Avoid live vaccines. ( 5.11 ) Pure Red Cell Aplasia: Consider discontinuation. ( 5.12 ) Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.14 )

5.1 Lymphoma and Other Malignancies 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.

5.2 Serious Infections 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 [see Adverse Reactions (6.1) ] .

5.3 Not Interchangeable with Other Tacrolimus Products-Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus capsules and tacrolimus extended-release capsules were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus. ENVARSUS XR is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules or tacrolimus for oral suspension. Instruct patients and caregivers to recognize the appearance of ENVARSUS XR tablet [see Dosage Forms and Strengths (3) ] and to confirm with their healthcare provider if a different product is dispensed or if dosing instructions have changed.

5.4 New Onset Diabetes after Transplant ENVARSUS XR caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately [see Adverse Reactions (6.1) and Use in Specific Populations (8.8) ] .

5.5 Nephrotoxicity due to ENVARSUS XR and Drug Interactions 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) ].

5.6 Neurotoxicity ENVARSUS XR may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions ( 6.1 , 6.2) ]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of ENVARSUS XR if neurotoxicity occurs.

5.7 Hyperkalemia Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia [see Adverse Reactions (6.1 )]. Monitor serum potassium levels periodically during treatment.

5.8 Hypertension Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require antihypertensive therapy [see Adverse Reactions (6.1) ] . Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions (5.7) ] . Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ENVARSUS XR [see Drug Interactions (7.2) ] .

5.9 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors 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, adjust ENVARSUS 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. […]

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 receptor antagonist induction therapy, MMF/MPS or AZA N=268 Tacrolimus [immediate-release] capsules ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA N=275 All infections 70% 65% Urinary Tract Infections 29% 27% Respiratory Infections 28% 24% Bacterial Infections 13% 18% Cytomegalovirus Infections 11% 9% Fungal Infections 9% 8% Gastrointestinal Infections 6% 4% BK virus b 6% 9% Serious Infections 26% 24% New Onset Diabetes After Transplantation New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥126 mg/dL, 2-hour post-prandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on two or more consecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, or HbA 1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for Study 1 through one year post-transplant is summarized in Table 3 below [see Warnings and Precautions (5.4) ] . Table 3. Percentage of Patients with NODAT 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 Analyses restricted to patients at risk for NODAT. ENVARSUS XR ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA (N=88) Tacrolimus [immediate-release] capsules ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA (N=74) Composite NODAT b 21% 15% HbA 1c ≥6.5% 13% 8% Fasting Plasma Glucose Values ≥126 mg/dL on 2 consecutive occurrences 8% 11% Oral hypoglycemic use 7% 5% Insulin use ≥31 days 1% 4% Common Adverse Reactions 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 Table 4 . Table 4. Adverse Reactions ( ≥ 10%) in Kidney Transplant Patients Through 1 Year Post-Transplant in Study 1 a 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. Adverse Reaction ENVARSUS XR N=268 Tacrolimus [immediate-release] capsules N=275 Diarrhea 31% 34% Anemia 26% 29% Urinary Tract Infection 25% 25% Hypertension 23% 23% Tremor 19% 17% Constipation 18% 25% Diabetes Mellitus 16% 14% Peripheral Edema 16% 21% Hyperkalemia 15% 11% Headache 15% 10% Hypophosphatemia 13% 15% Leukopenia 13% 14% Nausea 13% 15% Insomnia 13% 11% Increased Blood Creatinine 12% 14% Hypomagnesemia 12% 12% Hypokalemia 12% 12% Hyperglycemia 11% 12% Study 2- Phase 2 Clinical Study in De Novo Kidney Transplant Recipients Study 2 (NCT00765661) was an open-label Phase 2 study conducted in de novo kidney transplant patients randomized to once daily ENVARSUS XR (N=32) or twice daily tacrolimus [immediate-release] capsules (N=31). The study was conducted in the US and patients received an organ from a deceased or living donor. Pharmacokinetics were evaluated during the first 2 weeks with an additional 50-week treatment and follow-up to evaluate safety and efficacy [see Clinical Studies (14.1) ]. 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 group with 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 novo kidney transplant patients. There were no deaths or graft failures in Study 2. Two patients in each arm discontinued due to adverse events. […]

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, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole, isavuconazole), imatinib, nilotinib, letermovir 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) ]. Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide 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 and 5.10) ]. Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Mild or Moderate CYP3A Inducers, such as: Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed [see Dosage and Administration (2.5) ]. Caspofungin May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed [see Dosage and Administration (2.5) ]. Direct Acting Antiviral (DAA) Therapy The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy.

7.3 Cannabidiol The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. 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 (2.5) and Warnings and Precautions (5.13) ].

­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 (<37 weeks) following transplantation and maternal exposure to ENVARSUS 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 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 Table 8. In the table below, the number of recipients 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. Table 8. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus 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. Animal Data 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) [see Nonclinical Toxicology (13.1) ].

8.2 Lactation Risk Summary Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. […]

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).