EVEROLIMUS

Everolimus tablets are a macrolide immunosuppressant. The chemical name of everolimus USP is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1- [(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30 dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 ]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C 53 H 83 NO 14 and the molecular weight is 958.24 g/mol. The structural formula is: Everolimus tablets are supplied for oral administration containing 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg of everolimus USP together with butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate and poloxamer 188 as inactive ingredients. Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye). Everolimus structural formula (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1, 18-dihydroxy-12 -{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-11, 36-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2, 3,10,14,20-pentaone.

Everolimus is an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients: • Kidney Transplant: at low-moderate immunologic risk. Use in combination with basiliximab, cyclosporine (reduced doses) and corticosteroids ( 1.1 ) • Liver Transplant: Administer no earlier than 30 days posttransplant. Use in combination with tacrolimus (reduced doses) and corticosteroids ( 1.2 , 5.5 ) Limitations of Use : Safety and efficacy have not been established in the following: • Kidney transplant patients at high immunologic risk ( 1.3 ) • Recipients of transplanted organs other than kidney or liver ( 1.3 , 5.7 ) • Pediatric patients (less than 18 years) ( 1.3 ) 1.1 Prophylaxis of Organ Rejection in Kidney Transplantation Everolimus tablets are indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunologic risk receiving a kidney transplant [ see Clinical Studies (14.1)] . Everolimus tablets are to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus and cyclosporine is recommended for all patients receiving these products [ see Dosage and Administration (2.2 , 2.3)] . 1.2 Prophylaxis of Organ Rejection in Liver Transplantation Everolimus tablets are indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Everolimus tablets are to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [ s ee Warnings and Precautions (5. 5 ) , Clinical Studies (14.2) ] . TDM of everolimus and tacrolimus is recommended for all patients receiving these products [ s ee Dosage and Administration (2.3 , 2.5)] . 1.3 Limitations of Use The safety and efficacy of everolimus tablets has not been established in the following populations: Kidney transplant patients at high immunologic risk. Recipients of transplanted organs other than kidney and liver [see Warnings and Precautions (5.7)] . Pediatric patients (less than 18 years).

Patients receiving everolimus tablets may require dose adjustments based on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of everolimus tablets should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is required if the trough concentration is below 3 ng/mL. The total daily dose of everolimus tablets should be doubled using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg). Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of everolimus tablets should be decreased by 0.25 mg twice daily [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)] . • Kidney Transplantation: starting oral dose of 0.75 mg twice daily as soon as possible after transplantation ( 2.1 ) • Liver Transplantation: starting oral dose of 1 mg twice daily starting 30 days after transplantation ( 2.2 ) • Monitor Everolimus Concentrations: Adjust maintenance dose to achieve trough concentrations within the 3 to 8 ng/mL target range using LC/MS/MS assay method ( 2.1 , 2.2 , 2.3 ) • Administer consistently with or without food at the same time as cyclosporine or tacrolimus ( 2.6 , 12.3 ) • Mild Hepatic Impairment: Reduce initial daily dose by one-third ( 2.7 ) • Moderate or Severe Hepatic Impairment: Reduce initial daily dose by one-half ( 2.7 , 12.6 ) 2.1 Dosage in Adult Kidney Transplant Patients An initial everolimus tablets dose of 0.75 mg orally twice daily (1.5 mg per day) is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine, administered as soon as possible after transplantation [ s ee Dosage and Administration ( 2.3 , 2.4 ) , Clinical Studies (14.1) ] . Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft. 2.2 Dosage in Adult Liver Transplant Patients Start everolimus tablets at least 30 days posttransplant. An initial dose of 1 mg orally twice daily (2 mg per day) is recommended for adult liver transplant patients in combination with reduced-dose tacrolimus [ s ee Dosage and Administration (2.3 , 2.5), Clinical Studies (14.2)] . Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft. 2.3 Therapeutic Drug Monitoring (TDM) - Everolimus Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients. The recommended everolimus therapeutic range is 3 to 8 ng/mL [ s ee Clinical Pharmacology (12. 7 ) ] . Careful attention should be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor everolimus blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or inhibitors or cannabidiol, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to recommended target concentrations [ s ee Drug Interactions (7), Clinical Pharmacology (12. 7 , 12. 8 )] . There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus, everolimus concentrations do not decrease if the tacrolimus exposure is reduced [see Drug Interactions (7.2)]. The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. 2.4 Therapeutic Drug Monitoring (TDM) - Cyclosporine in Kidney Transplant Patients Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the risk of nephrotoxicity [ s ee Warnings and Precautions ( 5.6 ) , Drug Interactions (7.2), Clinical Pharmacology (12. 8 )] . The recommended cyclosporine therapeutic ranges when administered with everolimus tablets are 100 to 200 ng/mL through Month 1 posttransplant, 75 to 150 ng/mL at Months 2 and 3 posttransplant, 50 to 100 ng/mL at Month 4 posttransplant, and 25 to 50 ng/mL from Month 6 through Month 12 posttransplant. The median trough concentrations observed in the clinical trial ranged between 161 to 185 ng/mL through Month 1 posttransplant and between 111 to 140 ng/mL at Months 2 and 3 posttransplant. The median trough concentration was 99 ng/mL at Month 4 posttransplant and ranged between 46 to 75 ng/mL from Months 6 through Month 12 posttransplant [ s ee Clinical Pharmacology (12. 8 ) , Clinical Studies (14.1)] . Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as possible, and no later than 48 hours after reperfusion of the graft and dose adjusted to target concentrations from Day 5 onwards. If impairment of renal function is progressive, the treatment regimen should be adjusted. In renal transplant patients, the cyclosporine dose should be based on cyclosporine whole blood trough concentrations [ s ee Clinical Pharmacology (12 . 8 )] . In renal transplantation, there are limited data regarding dosing everolimus tablets with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Everolimus tablets have not been evaluated in clinical trials with other formulations of cyclosporine. Prior to dose reduction of cyclosporine, it should be ascertained that steady-state everolimus whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced [see Drug Interactions (7.2)] . 2.5 Therapeutic Drug Monitoring (TDM) - Tacrolimus in Liver Transplant Patients Both tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the potential risk of nephrotoxicity [ see Warnings and Precautions (5.6) , Clinical Pharmacology (12.9) ]. The recommended tacrolimus therapeutic range when administered with everolimus tablets are whole blood trough (C- 0h ) concentrations of 3 to 5 ng/mL by three weeks after the first dose of everolimus tablets (approximately Month 2) and through Month 12 posttransplant. The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2 and 4 posttransplant (prior to initiation of everolimus). The median tacrolimus trough concentrations ranged between 7 to 8.1 ng/mL at Weeks 5 and 6 posttransplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 posttransplant, and between 4.3 to 4.9 ng/mL between Months 4 and 12 posttransplant [ see Clinical Pharmacology (12.9), Clinical Studies (14.2) ]. Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be avoided. In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations [ see Clinical Pharmacology (12.9 ) ]. In liver transplantation, there are limited data regarding dosing everolimus tablets with reduced tacrolimus trough concentrations of 3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus, it should be ascertained that the steady-state everolimus whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and everolimus, tacrolimus does not affect everolimus trough concentrations, and consequently, everolimus concentrations do not decrease if the tacrolimus exposure is reduced. 2.6 Administration Everolimus tablets should be swallowed whole with a glass of water and not crushed before use. Administer everolimus tablets consistently approximately 12 hours apart with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus [ s ee Clinical Pharmacology (12. 3 ) ] . 2.7 Hepatic Impairment Whole blood trough concentrations of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the initial daily dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [ s ee Clinical Pharmacology (12. 6 )] .

Hypersensitivity to everolimus, sirolimus, or to components of the drug product ( 4 ) 4.1 Hypersensitivity Reactions Everolimus tablets are contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug product.

Most common adverse reactions were as follows: Kidney Transplantation (incidence greater than or equal to 20%): peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection (UTI), and hyperlipidemia ( 6.1 ) Liver Transplantation (incidence greater than 10%): diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, leukopenia, and hypercholesterolemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc., at 1-866-924-6266 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Serious and Otherwise Important Adverse Reactions The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity Reactions [ see Contraindications (4.1) ] Lymphomas and Other Malignancies [ see Boxed Warning, Warnings and Precautions (5.2) ] Serious Infections [ see Warnings and Precautions (5.3) ] Kidney Graft Thrombosis [ see Warnings an d Precautions ( 5.4 ) ] Hepatic Artery Thrombosis [ see Warnings and Precautions (5. 5 ) ] Everolimus and Calcineurin Inhibitor-Induced Nephrotoxicity [ see Warnings and Precautions ( 5. 6 ) ] Heart Transplantation [ see Warnings and Precautions (5.7) ] Angioedema [ see Warnings and Precautions (5. 8 ) ] Wound Healing and Fluid Accumulation [ see Warnings and Precautions ( 5. 9 ) ] Interstitial Lung Disease/Non-Infectious Pneumonitis [ see Warnings and Precautions (5. 10 ) ] Hyperlipidemia [ see Warnings and Precautions ( 5. 11 ) ] Proteinuria [ see Warnings and Precautions ( 5.1 2 ) ] Polyoma Virus Infections [ see Warnings and Precautions ( 5.1 3 ) ] Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS) [ see Warnings and Precautions ( 5.1 5 ) ] New Onset Diabetes After Transplant [ see Warnings and Precautions ( 5.1 6 ) ] Male Infertility [ see Warnings and Precautions ( 5.1 8 ) ] 6.2 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Kidney Transplantation The data described below reflect exposure to everolimus in an open-label, randomized trial of de novo kidney transplant patients of concentration-controlled everolimus at an initial everolimus starting dose of 1.5 mg per day [target trough concentrations 3 to 8 ng/mL with reduced exposure cyclosporine (N = 274) compared to mycophenolic acid (N = 273) with standard exposure cyclosporine]. All patients received basiliximab induction therapy and corticosteroids. The population was between 18 and 70 years, more than 43% were 50 years of age or older (mean age was 46 years in the everolimus group, 47 years control group); a majority of recipients were male (64% in the everolimus group, 69% control group); and a majority of patients were Caucasian (70% in the everolimus group, 69% control group). Demographic characteristics were comparable between treatment groups. The most frequent diseases leading to transplantation were balanced between groups and included hypertension/nephrosclerosis, glomerulonephritis/glomerular disease and diabetes mellitus. Significantly more patients discontinued everolimus 1.5 mg per day treatment (83/277, 30%) than discontinued the control regimen (60/277, 22%). Of those patients who prematurely discontinued treatment, most discontinuations were due to adverse reactions: 18% in the everolimus group compared to 9% in the control group (p-value = 0.004). This difference was more prominent between treatment groups among female patients. In those patients discontinuing study medication, adverse reactions were collected up to 7 days after study medication discontinuation and serious adverse reactions up to 30 days after study medication discontinuation. Discontinuation of everolimus at a higher dose (3 mg per day) was 95/279, 34%, including 20% due to adverse reactions, and this regimen is not recommended (see below). The overall incidences of serious adverse reactions were 57% (159/278) in the everolimus group and 52% (141/273) in the mycophenolic acid group. Infections and infestations reported as serious adverse reactions had the highest incidence in both groups [20% (54/274) in the everolimus group and 25% (69/273) in the control group]. The difference was mainly due to the higher incidence of viral infections in the mycophenolic acid group, mainly CMV and BK virus infections. Injury, poisoning and procedural complications reported as serious adverse reactions had the second highest incidence in both groups [14% (39/274) in the everolimus group and 12% (32/273) in the control group] followed by renal and urinary disorders [10% (28/274) in the everolimus group and 13% (36/273) in the control group] and vascular disorders [10% (26/274) in the everolimus group and 7% (20/273) in the control group]. A total of 13 patients died during the first 12 months of study; 7 (3%) in the everolimus group and 6 (2%) in the control group. The most common causes of death across the study groups were related to cardiac conditions and infections. There were 12 (4%) graft losses in the everolimus group and 8 (3%) in the control group over the 12-month study period. Of the graft losses, 4 were due to renal artery and two due to renal vein thrombosis in the everolimus group (2%) compared to two renal artery thromboses in the control group (1%) [ s ee Boxed Warning, Warnings and Precautions (5. 4 ) ] . The most common (greater than or equal to 20%) adverse reactions observed in the everolimus group were: peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia. Infections The overall incidence of bacterial, fungal and viral infections reported as adverse reactions was higher in the control group (68%) compared to the everolimus group (64%) and was primarily due to an increased number of viral infections (21% in the control group and 10% in the everolimus group). The incidence of CMV infections reported as adverse reactions was 8% in the control group compared to 1% in the everolimus group; and 3% of the serious CMV infections in the control group versus 0% in the everolimus group were considered serious [ see Warnings and Precautions (5.3) ] . BK Virus BK virus infections were lower in incidence in the everolimus group (2 patients, 1%) compared to the control group (11 patients, 4%). One of the two BK virus infections in the everolimus group, and two of the 11 BK virus infections in the control group were also reported as serious adverse reactions. BK virus infections did not result in graft loss in any of the groups in the clinical trial. Wound Healing and Fluid Collections Wound healing-related reactions were identified through a retrospective search and request for additional data. The overall incidence of wound-related reactions, including lymphocele, seroma, hematoma, dehiscence, incisional hernia, and infections was 35% in the everolimus group compared to 26% in the control group. More patients required intraoperative repair debridement or drainage of incisional wound complications and more required drainage of lymphoceles and seromas in the everolimus group compared to control. Adverse reactions due to major fluid collections such as edema and other types of fluid collections was 45% in the everolimus group and 40% in the control group [ see Warnings and Precautions ( 5. 9 ) ] . Neoplasms Adverse reactions due to malignant and benign neoplasms were reported in 3% of patients in the everolimus group and 6% in the control group. The most frequently reported neoplasms in the control group were basal cell carcinoma, squamous cell carcinoma, skin papilloma and seborrheic keratosis. One patient in the everolimus group who underwent a melanoma excision prior to transplantation died due to metastatic melanoma [ see Boxed Warning, Warnings and Precautions (5.2) ] . New Onset Diabetes Mellitus (NODM) NODM reported based on adverse reactions and random serum glucose values, was 9% in the everolimus group compared to 7% in the control group. Endocrine Effects in Males In the everolimus group, serum testosterone levels significantly decreased while the FSH levels significantly increased without significant changes being observed in the control group. In both the everolimus and the control groups mean testosterone and FSH levels remained within the normal range with the mean FSH level in the everolimus group being at the upper limit of the normal range (11.1 U/L). More patients were reported with erectile dysfunction in the everolimus treatment group compared to the control group (5% compared to 2%, respectively). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of greater than or equal to 10% for patients receiving everolimus with reduced dose cyclosporine or mycophenolic acid with standard dose cyclosporine. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 2. Incidence Rates of Frequent (Greater Than or Equal to 10% in Any Treatment Group) Adverse Reactions (Safety Population*) * The safety analysis population defined as all randomized kidney transplant patients who received at least one dose of treatment and had at least one post-baseline safety assessment. Adverse reactions Everolimus 1.5 mg with reduced exposure cyclosporine N = 274 n (%) Mycophenolic acid 1.44 g with standard exposure cyclosporine N = 273 n (%) Any adverse reactions * 271 (99) 270 (99) Blood lymphatic system disorders 93 (34) 111 (41) Anemia 70 (26) 68 (25) Leukopenia 8 (3) 33 (12) Gastrointestinal disorders 196 (72) 207 (76) Constipation 105 (38) 117 (43) Nausea 79 (29) 85 (31) Diarrhea 51 (19) 54 (20) Vomiting 40 (15) 60 (22) Abdominal pain 36 (13) 42 (15) Dyspepsia 12 (4) 31 (11) Abdominal pain upper 9 (3) 30 (11) General disorders and administrative-site conditions 181 (66) 160 (59) Edema peripheral 123 (45) 108 (40) Pyrexia 51 (19) 40 (15) Fatigue 25 (9) 28 (10) Infections and infestations 169 (62) 185 (68) Urinary tract infection 60 (22) 63 (23) Upper respiratory tract infection 44 (16) 49 (18) Injury, poisoning and procedural complications 163 (60) 163 (60) Incision-site pain 45 (16) 47 (17) Procedural pain 40 (15) 37 (14) Investigations 137 (50) 133 (49) Blood creatinine increased 48 (18) 59 (22) Metabolism and nutrition disorders 222 (81) 199 (73) Hyperlipidemia 57 (21) 43 (16) Hyperkalemia 49 (18) 48 (18) Hypercholesterolemia 47 (17) 34 (13) Dyslipidemia 41 (15) 24 (9) Hypomagnesemia 37 (14) 40 (15) Hypophosphatemia 35 (13) 35 (13) Hyperglycemia 34 (12) 38 (14) Hypokalemia 32 (12) 32 (12) Musculoskeletal and connective tissue disorders 112 (41) 105 (39) Pain in extremity 32 (12) 29 (11) Back pain 30 (11) 28 (10) Nervous system disorders 92 (34) 109 (40) Headache 49 (18) 40 (15) Tremor 23 (8) 38 (14) Psychiatric disorders 90 (33) 72 (26) Insomnia 47 (17) 43 (16) Renal and urinary disorders 112 (41) 124 (45) Hematuria 33 (12) 33 (12) Dysuria 29 (11) 28 (10) Respiratory, thoracic and mediastinal disorders 86 (31) 93 (34) Cough 20 (7) 30 (11) Vascular disorders 122 (45) 124 (45) Hypertension 81 (30) 82 (30) Adverse reaction that occurred with at least a 5% higher frequency in the everolimus 1.5 mg group compared to the control group were: peripheral edema (45% compared to 40%), hyperlipidemia (21% compared to 16%), dyslipidemia (15% compared to 9%), and stomatitis/mouth ulceration (8% compared to 3%). A third treatment group of everolimus 3 mg per day (1.5 mg twice daily; target trough concentrations 6 to 12 ng/mL) with reduced exposure cyclosporine was included in the study described above. Although as effective as the lower dose everolimus group, the overall safety was worse and consequently higher doses of everolimus cannot be recommended. Out of 279 patients, 95 (34%) discontinued the study medication with 57 (20%) doing so because of adverse reactions. The most frequent adverse reactions leading to discontinuation of everolimus when used at this higher dose were injury, poisoning and procedural complications (everolimus 1.5 mg: 5%, everolimus 3 mg: 7%, and control: 2%), infections (2%, 6%, and 3%, respectively), renal and urinary disorders (4%, 7%, and 4%, respectively), and gastrointestinal disorders (1%, 3%, and 2%). The combination of fixed-dose everolimus and standard doses of cyclosporine in previous kidney clinical trials resulted in frequent elevations of serum creatinine with higher mean and median serum creatinine values observed than in the current study with reduced exposure cyclosporine. These results indicate that everolimus increases the cyclosporine-induced nephrotoxicity, and, therefore, should only be used in a concentration-controlled regimen with reduced exposure cyclosporine [ see Boxed Warning, Indications and Usage (1. 1 ) , Warnings and Precautions (5. 6 ) ] . Liver Transplantation The data described below reflect exposure to everolimus starting 30 days after transplantation in an open-label, randomized trial of liver transplant patients. Seven hundred and nineteen (719) patients who fulfilled the inclusion/exclusion criteria [ see Clinical Studies (14.2 ) ] were randomized into one of the three treatment groups of the study. During the first 30 days prior to randomization, patients received tacrolimus and corticosteroids, with or without mycophenolate mofetil (about 70% to 80% received MMF). No induction antibody was administered. At randomization, MMF was discontinued and patients were randomized to everolimus initial dose of 1 mg twice per day (2 mg daily) and adjusted to protocol specified target trough concentrations of 3 to 8 ng/mL with reduced exposure tacrolimus [protocol-specified target troughs 3 to 5 ng/mL] (N = 245) [ see Clinical Pharmacology (12.7, 12.9)] or to a control group of standard exposure tacrolimus [protocol specified target troughs 8 to 12 ng/mL up to Month 4 posttransplant, then 6 to 10 ng/mL Month 4 through Month 12 posttransplant] (N = 241). A third randomized group was discontinued prematurely [ see Clinical Studies (14.2) ] and is not described in this section. The population was between 18 and 70 years, more than 50% were 50 years of age (mean age was 54 years in the everolimus group, 55 years in the tacrolimus control group); 74% were male in both everolimus and control groups, respectively, and a majority were Caucasian (86% everolimus group, 80% control group). Demographic characteristics were comparable between treatment groups. The most frequent diseases leading to transplantation were balanced between groups. The most frequent causes of end-stage liver disease (ESLD) were alcoholic cirrhosis, hepatitis C, and hepatocellular carcinoma and were balanced between groups. Twenty-seven percent (27%) discontinued study drug in the everolimus group compared with 22% for the tacrolimus control group during the first 12 months of study. The most common reason for discontinuation of study medication was due to adverse reactions (19% and 11%, respectively), including proteinuria, recurrent hepatitis C, and pancytopenia in the everolimus group. At 24 months, the rate of discontinuation of study medication in liver transplant patients was greater for the everolimus group (42%) compared to tacrolimus control group (33%). The overall incidences of serious adverse reactions were 50% (122/245) in the everolimus group and 43% (104/241) in the control group at 12 months and similar at 24 months (56% and 54%, respectively). Infections and infestations were reported as serious adverse reactions with the highest incidence followed by gastrointestinal disorders and hepatobiliary disorders. During the first 12 months of study, 13 deaths were reported in the everolimus group (one patient never took everolimus). In the same 12-month period, 7 deaths were reported in the tacrolimus control group. Deaths occurred in both groups for a variety of reasons and were mostly associated with liver-related issues, infections and sepsis. In the following 12 months of study, four additional deaths were reported in each treatment group. The most common adverse reactions (reported for greater or equal to 10% patients in any group) in the everolimus group were: diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, and leukopenia ( see Table 3 ). Infections The overall incidence of infections reported as adverse reactions was 50% for everolimus and 44% in the control group and similar at 24 months (56% and 52%, respectively). The types of infections were reported as follows: bacterial 16% vs 12%, viral 17% vs 13%; and fungal infections 2% vs 5% for everolimus and control, respectively [ see Warnings and Precautions (5.3)] . Wound Healing and Fluid Collections Wound healing complications were reported as adverse reactions for 11% of patients in the everolimus group compared to 8% of patients in the control group up to 24 months. Pleural effusions were reported in 5% in both groups, and ascites in 4% of patients in the everolimus group and 3% in the control arm. Neoplasms Malignant and benign neoplasms were reported as adverse reactions in 4% of patients in the everolimus group and 7% in the control group at 12 months. In the everolimus group, 3 malignant tumors were reported compared to 9 cases in the control group. For the everolimus group this included lymphoma, lymphoproliferative disorder and a hepatocellular carcinoma, and for the control group included Kaposi’s sarcoma (2), metastatic colorectal cancer, glioblastoma, malignant hepatic neoplasm, pancreatic neuroendocrine tumor, hemophagocytic histiocytosis, and squamous cell carcinomas. At 24 months, the rates of malignancies were similar (10% and 11%, respectively) [ s ee Boxed Warning, Warnings and Precautions (5.2) ]. Lipid Abnormalities Hyperlipidemia adverse reactions (including the preferred terms: hyperlipidemia, hypercholesterolemia, blood cholesterol increased, blood triglycerides increased, hypertriglyceridemia lipids increased, total cholesterol/HDL ratio increased, and dyslipidemia) were reported for 24% everolimus patients, and 10% control patients at 12 months. Results were similar at 24 months (28% and 12%, respectively). New Onset of Diabetes after Transplant (NODAT) Of the patients without diabetes mellitus at randomization, NODAT was reported in 32% in the everolimus group compared to 29% in the control group at 12 months and similar at 24 months. Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of greater than or equal to 10% for patients receiving everolimus with reduced exposure tacrolimus or standard dose tacrolimus from randomization to 24 months. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 3. Incidence Rates of Most Frequent (Greater Than or Equal to 10% in Any Treatment Group) Adverse Reactions at 12 Months and 24 Months After Liver Transplantation (Safety population*) * The safety analysis population is defined as all randomized liver transplant patients who received at least one dose of treatment and had at least one post-baseline safety assessment. Primary system organ classes are presented alphabetically. **No de novo hepatitis C cases were reported. Adverse reactions 12 months 24 months Everolimus with reduced exposure tacrolimus N = 245 n (%) Tacrolimus standard exposure N = 241 n (%) Everolimus with reduced exposure tacrolimus N = 245 n (%) Tacrolimus standard exposure N = 242 n (%) Any adverse reaction/infection 232 (95) 229 (95) 236 (96) 237 (98) Blood & lymphatic system disorders 66 (27) 47 (20) 79 (32) 58 (24) -Leukopenia 29 (12) 12 (5) 31 (13) 12 (5) G as t r o i n t e s t i nal d i s ord e rs 136 (56) 121 (50) 148 (60) 138 (57) -Diarrhea 47 (19) 50 (21) 59 (24) 61 (25) -Nausea 33 (14) 28 (12) 36 (15) 33 (14) -Abdominal pain 32 (13) 22 (9) 37 (15) 31 (13) G eneral d i s o rde r s and a d mi n i s t ra t i on s i t e con d i t i o ns 94 (38) 85 (35) 113 (46) 98 (41) -Peripheral edema 43 (18) 26 (11) 49 (20) 31 (13) -Pyrexia 32 (13) 25 (10) 43 (18) 28 (12) -Fatigue 22 (9) 26 (11) 27 (11) 28 (12) I n f e c t i ons and i n f es t a t i o n s 123 (50) 105 (44) 135 (56) 125 (52) -Hepatitis C** 28 (11) 19 (8) 33 (14) 24 (10) Inve s ti g a t i ons 81 (33) 78 (32) 92 (38) 98 (41) -Liver function test abnormal 16 (7) 24 (10) 19 (8) 25 (10) Metabolism and nutrition disorders 111 (45) 92 (38) 134 (55) 106 (44) -Hypercholesterolemia 23 (9) 6 (3) 27 (11) 9 (4) N ervous s ys t em d i s orde r s 89 (36) 85 (35) 99 (40) 101 (42) -Headache 47 (19) 46 (19) 53 (22) 54 (22) -Tremor 23 (9) 29 (12) 25 (10) 37 (15) -Insomnia 14 (6) 19 (8) 17 (7) 24 (10) Renal and urinary disorders 49 (20) 53 (22) 67 (27) 73 (30) -Renal failure 13 (5) 17 (7) 24 (10) 37 (15) V ascu l a r d i sord e rs 56 (23) 57 (24) 72 (29) 68 (28) -Hypertension 42 (17) 38 (16) 52 (21) 44 (18) Less Common Adverse Reactions Less common adverse reactions, occurring overall in greater than or equal to 1% to less than 10% of either kidney or liver transplant patients treated with everolimus include: Blood and Lymphatic System Disorders : anemia, leukocytosis, lymphadenopathy, neutropenia, pancytopenia, thrombocythemia, thrombocytopenia Cardiac and Vascular Disorders: angina pectoris, atrial fibrillation, cardiac failure congestive, palpitations, tachycardia, hypertension, including hypertensive crisis, hypotension, deep-vein thrombosis Endocrine Disorders: Cushingoid, hyperparathyroidism, hypothyroidism Eye Disorders: cataract, conjunctivitis, vision blurred Gastrointestinal Disorders : abdominal distention, abdominal hernia, ascites, constipation, dyspepsia, dysphagia, epigastric discomfort, flatulence, gastritis, gastroesophageal reflux disease, gingival hypertrophy, hematemesis, hemorrhoids, ileus, mouth ulceration, peritonitis, stomatitis General Disorders and Administrative Site Conditions: chest discomfort, chest pain, chills, fatigue, incisional hernia, inguinal hernia, malaise, edema, including generalized edema, pain Hepatobiliary Disorders: hepatic enzyme increased, bile duct stenosis, bilirubin increased, cholangitis, cholestasis, hepatitis (non-infectious) Infections and Infestations: BK virus infection [see Warnings and Precautions (5.13)] , bacteremia, bronchitis, candidiasis, cellulitis, CMV, folliculitis, gastroenteritis, herpes infections, influenza, lower respiratory tract, nasopharyngitis, onychomycosis, oral candidiasis, oral herpes, osteomyelitis, pneumonia, pyelonephritis, sepsis, sinusitis, tinea pedis, upper respiratory tract infection, urethritis, urinary tract infection, wound infection [see Boxed Warning, Warnings and Precautions (5.3)] Injury Poisoning and Procedural Complications: incision site complications, including infections, perinephric collection, seroma, wound dehiscence, incisional hernia, perinephric hematoma, localized intra-abdominal fluid collection, impaired healing, lymophocele, lymphorrhea Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood glucose increased, hemoglobin decreased, white blood cell count decreased, transaminases increased Metabolism and Nutrition Disorders: blood urea increased, acidosis, anorexia, dehydration, diabetes mellitus [see Warnings and Precautions (5.16)] , decreased appetite, fluid retention, gout, hypercalcemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypokalemia, hypoglycemia, hypomagnesemia, hyponatremia, iron deficiency, new onset diabetes mellitus, vitamin B12 deficiency Musculoskeletal and Connective Tissues Disorders : arthralgia, joint swelling, muscle spasms, muscular weakness, musculoskeletal pain, myalgia, osteoarthritis, osteonecrosis, osteopenia, osteoporosis, spondylitis Nervous System Disorders: dizziness, hemiparesis, hypoesthesia, lethargy, migraine, neuralgia, paresthesia, somnolence, syncope, tremor Psychiatric Disorders: agitation, anxiety, depression, hallucination Renal and Urinary Disorders: bladder spasm, hydronephrosis, micturation urgency, nephritis interstitial, nocturia, pollakiuria, polyuria, proteinuria [see Warnings and Precautions (5.12)] , pyuria, renal artery thrombosis [see Boxed Warning, Warnings and Precautions (5.4)] , acute renal failure, renal impairment [see Warnings and Precautions (5.6)] , renal tubular necrosis, urinary retention Reproductive System and Breast Disorders: amenorrhea , benign prostatic hyperplasia, erectile dysfunction, ovarian cyst, scrotal edema Respiratory, Thoracic, Mediastinal Disorders: atelectasis, bronchitis, dyspnea, cough, epistaxis, lower respiratory tract infection, nasal congestion, oropharyngeal pain, pleural effusions, pulmonary edema, rhinorrhea, sinus congestion, wheezing Skin and Subcutaneous Tissue Disorders: acne, alopecia, dermatitis acneiform, ecchymosis, hirsutism, hyperhidrosis, hypertrichosis, night sweats, pruritus, rash Vascular Disorders: venous thromboembolism (including deep vein thrombosis), phlebitis, pulmonary embolism Less common, serious adverse reactions occurring overall in less than 1% of either kidney or liver transplant patients treated with everolimus include: Angioedema [ s ee Warnings and Precautions ( 5.8 )] Interstitial Lung Disease/Non-Infectious Pneumonitis [ s ee Warnings and Precautions (5.10), Adverse Reactions (6.1)] Pericardial Effusions [see Warnings and Precautions (5.9)] Pancreatitis Thrombotic Microangiopathy (TMA), Thrombotic Thrombocytopenic Purpura (TTP), and Hemolytic Uremic Syndrome (HUS) [ s ee Warnings and Precautions (5.1 5 ) ] 6.3 Postmarketing Experience Adverse reactions identified from the postmarketing use of the combination regimen of everolimus and cyclosporine that are not specific to any one transplant indication include angioedema [ s ee Warnings and Precautions (5. 8 ) ] , erythroderma, leukocytoclastic vasculitis, pancreatitis, pulmonary alveolar proteinosis, and pulmonary embolism. There have also been reports of male infertility with mTOR inhibitors, including everolimus [ s ee Warnings and Precautions ( 5.1 8 ) ] .

Strong-moderate CYP3A4 inhibitors (e.g., cyclosporine, ketoconazole, erythromycin, verapamil) and CYP3A4 inducers (e.g., rifampin) may affect everolimus concentrations ( 7.1 ). Consider everolimus tablets dose adjustment ( 5.14 ) Therapeutic drug monitoring and dose reduction for everolimus tablets should be considered when everolimus tablets are coadministered with cannabidiol (5.22, 7.13) 7.1 Interactions With Strong Inhibitors or Inducers of CYP3A4 and P-glycoprotein Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-gp. Concurrent treatment with strong inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and inducers (e.g., rifampin, rifabutin) of CYP3A4 is not recommended. Inhibitors of P-gp (e.g., digoxin, cyclosporine) may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro , everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of medicinal products eliminated by these enzymes. Thus, caution should be exercised when coadministering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index [ s ee Dosage and Administration ( 2. 3 ) ] . All in vivo interaction studies were conducted without concomitant cyclosporine. Pharmacokinetic interactions between everolimus and concomitantly administered drugs are discussed below. Drug interaction studies have not been conducted with drugs other than those described below. 7.2 Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate) The steady-state C max and area under the curve (AUC) estimates of everolimus were significantly increased by coadministration of single dose cyclosporine [ s ee Clinical Pharmaco logy (12. 5 )] . Dose adjustment of everolimus might be needed if the cyclosporine dose is altered [ s ee Dosage and Administration ( 2. 3)] . Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral). 7.3 Ketoconazole and Other Strong CYP3A4 Inhibitors Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus C max , AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with everolimus [ s ee Warnings and Precautions ( 5. 1 4 ), Clinical Pharmaco logy (12. 5 )] . 7.4 Erythromycin (Moderate CYP3A4 Inhibitor) Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus C max , AUC, and half-life. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Clinical Pharmaco logy (12. 5 )] . 7.5 Verapamil (CYP3A4 and P-gp Substrate) Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus C max and AUC. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Clinical Pharmaco logy (12. 5 ) ] . 7.6 Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate) Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be monitored for the development of rhabdomyolysis and other adverse reactions as described in the respective labeling for these products. 7.7 Simvastatin and Lovastatin Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin [ s ee Warnings and Precautions ( 5.1 1 )] . 7.8 Rifampin (Strong CYP3A4/P-gp Inducers) Pretreatment of healthy subjects with multiple-dose rifampin followed by a single dose of everolimus increased everolimus clearance and decreased the everolimus C max and AUC estimates. Combination with rifampin is not recommended [ s ee Warnings and Precautions ( 5.1 4 ) , Clinical Pharmacology (12. 5 )] . 7.9 Midazolam (CYP3A4/5 Substrate) Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose everolimus indicated that everolimus is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when everolimus is coadministered with midazolam or other CYP3A4/5 substrates [ s ee Clinical Pharmacology (12. 5 )] . 7.10 Other Possible Interactions Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood concentrations (e.g., St. John’s Wort [ Hypericum perforatum ]; anticonvulsants: carbamazepine, phenobarbital, phenytoin; efavirenz, nevirapine). 7.11 Octreotide Coadministration of everolimus and depot octreotide increased octreotide C min by approximately 50%. 7.12 Tacrolimus There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and consequently, dose adjustment of everolimus is not necessary when everolimus is coadministered with tacrolimus. 7.13 Cannabidiol The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol [see Dosage and Administration (2.3), Warnings and Precautions (5.22)]. 7.13 Cannabidiol The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol [see Dosage and Administration (2.3), Warnings and Precautions (5.22)].