Everolimus (everolimus .5 mg) Dailymed

• • Angioedema [increased risk with concomitant angiotensin converting enzyme (ACE inhibitors)]: Monitor for symptoms and treat promptly. (5.8)
• • Delayed Wound Healing/Fluid Accumulation: Monitor symptoms; treat promptly to minimize complications. (5.9)
• • Interstitial Lung Disease (ILD)/Non-Infectious Pneumonitis: Monitor for symptoms or radiologic changes; manage by dose reduction or discontinuation until symptoms resolve; consider use of corticosteroids. (5.10)
• • Hyperlipidemia (elevations of serum cholesterol and triglycerides): Monitor and consider anti-lipid therapy. (5.11)
• • Proteinuria (increased risk with higher trough concentrations): Monitor urine protein. (5.12)
• • Polyoma Virus Infections (activation of latent viral infections; BK virus associated nephropathy): Consider reducing immunosuppression. (5.13)
• • TMA/TTP/HUS (concomitant use with cyclosporine may increase risk): Monitor for hematologic changes or symptoms. (5.15)
• • New Onset Diabetes After Transplantation: Monitor serum glucose (5.16).
• • Male Infertility: Azoospermia or oligospermia may occur. (5.18, 13.1)
• • Immunizations: Avoid live vaccines. (5.19)
• • Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with everolimus and for 8 weeks after final dose (5.17, 8.1, 8.3)

5.1 Management of Immunosuppression

Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe everolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. In limited data with the complete elimination of calcineurin inhibition (CNI), there was an increased risk of acute rejection.

5.2 Lymphomas and Other Malignancies

Patients receiving immunosuppressants, including everolimus, are at increased 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.

As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

5.3 Serious Infections

Patients receiving immunosuppressants, including everolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.13), Adverse Reactions (6.1, 6.2)]. These infections may lead to serious, including fatal, outcomes. Because of the danger of over-immunosuppression, which can cause increased susceptibility to infection, combination immunosuppressant therapy should be used with caution.

Antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and prophylaxis for cytomegalovirus (CMV) is recommended in transplant recipients.

5.4 Kidney Graft Thrombosis

An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the first 30 days posttransplantation [see Boxed Warning].

5.5 Hepatic Artery Thrombosis

Mammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis (HAT). Reported cases mostly have occurred within the first 30 days posttransplant and most also lead to graft loss or death. Therefore, everolimus should not be administered earlier than 30 days after liver transplant.

5.6 Everolimus and Calcineurin Inhibitor-Induced Nephrotoxicity

In kidney transplant recipients, everolimus with standard dose cyclosporine increases the risk of nephrotoxicity resulting in a lower glomerular filtration rate. Reduced doses of cyclosporine are required for use in combination with everolimus in order to reduce renal dysfunction [see Boxed Warning, Indications and Usage (1.1), Clinical Pharmacology (12.8)].

In liver transplant recipients, everolimus has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with everolimus in order to minimize the potential risk of nephrotoxicity [see Indications and Usage (1.2), Clinical Pharmacology (12.9)].

Renal function should be monitored during the administration of everolimus. Consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related. Caution should be exercised when using other drugs which are known to impair renal function.

5.7 Heart Transplantation

In a clinical trial of de novo heart transplant patients, everolimus in an immunosuppressive regimen, with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months posttransplantation compared to the control regimen. Use of everolimus in heart transplantation is not recommended.

5.8 Angioedema

Everolimus has been associated with the development of angioedema. The concomitant use of everolimus with other drugs known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors may increase the risk of developing angioedema.

5.9 Wound Healing and Fluid Accumulation

Everolimus increases the risk of delayed wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele and seroma. These wound-related complications may require more surgical intervention. Generalized fluid accumulation, including peripheral edema (e.g., lymphoedema) and other types of localized fluid collection, such as pericardial and pleural effusions and ascites have also been reported.

5.10 Interstitial Lung Disease (ILD)/Non-Infectious Pneumonitis

A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out through appropriate investigations. Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some reported with pulmonary hypertension [including pulmonary arterial hypertension (PAH)] as a secondary event, have occurred in patients receiving rapamycins and their derivatives, including everolimus. Most cases generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.

5.11 Hyperlipidemia

Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur following initiation of everolimus and the risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations [see Adverse Reactions (6.2)]. Use of anti-lipid therapy may not normalize lipid levels in patients receiving everolimus.

Any patient who is administered everolimus should be monitored for hyperlipidemia. If detected, interventions, such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen containing everolimus. Similarly, the risk/benefit of continued everolimus therapy should be reevaluated in patients with severe refractory hyperlipidemia. Everolimus has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL.

Due to an interaction with cyclosporine, clinical trials of everolimus and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During everolimus therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents [see Drug Interactions (7.7)].

5.12 Proteinuria

The use of everolimus in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher everolimus whole blood trough concentrations. Patients receiving everolimus should be monitored for proteinuria [see Adverse Reactions (6.2)].

5.13 Polyoma Virus Infections

Patients receiving immunosuppressants, including everolimus, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus associated progressive multiple leukoencephalopathy (PML). PVAN has been observed in patients receiving immunosuppressants, including everolimus. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.2)]. Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

5.14 Interaction with Strong Inhibitors and Inducers of CYP3A4

Coadministration of everolimus with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) or strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations [see Drug Interactions (7)].

5.15 Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome

The concomitant use of everolimus with cyclosporine may increase the risk of thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Monitor hematologic parameters [see Adverse Reactions (6.2)].

5.16 New Onset Diabetes After Transplant

Everolimus has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients using everolimus.

5.17 Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], everolimus may cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception while using everolimus and for 8 weeks after ending treatment [see Use in Specific Populations (8.1, 8.3)].

5.18 Male Infertility

Azoospermia or oligospermia may be observed [see Adverse Reactions (6.2), Nonclinical Toxicology (13.1)]. Everolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

5.19 Immunizations

The use of live vaccines should be avoided during treatment with everolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.20 Interaction with Grapefruit Juice

Grapefruit and grapefruit juice inhibit cytochrome P450 3A4 and P-gp activity and should therefore be avoided with concomitant use of everolimus and cyclosporine or tacrolimus.

5.21 Patients with Hereditary Disorders/Other

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take everolimus as this may result in diarrhea and malabsorption.

5.22 Cannabidiol Drug Interactions

When cannabidiol and everolimus tablets 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 tablets are coadministered with cannabidiol [se e Dosage and Administration (2.3), Drug Interactions (7.13)].

6 Adverse Reactions

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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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 and 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 (5.12)]
• •Polyoma Virus Infections [see Warnings and Precautions (5.13)]
• •Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS) [see Warnings and Precautions (5.15)]
• •New Onset Diabetes After Transplant [see Warnings and Precautions (5.16)]
• •Male Infertility [see Warnings and Precautions (5.18)]

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%) [see 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^*)
AnemiaLeukopeniaConstipationNauseaDiarrheaVomitingAbdominal painDyspepsiaAbdominal pain upperEdema peripheral PyrexiaFatigueUrinary tract infection Upper respiratory tract infectionIncision-site painProcedural painBlood creatinine increasedPain in extremityBack painHeadacheTremorInsomniaHematuriaDysuriaCoughHypertension

Adverse reactions	Everolimus 1.5 mg with reduced exposure cyclosporine N=274n (%)	Mycophenolic acid1.44 g with standard exposure cyclosporine N=273n (%)
Any adverse reactions*	271 (99)	270 (99)
Blood lymphatic system disorders	93 (34)	111 (41)
70 (26)	68 (25)
8 (3)	33 (12)
Gastrointestinal disorders	196 (72)	207 (76)
105 (38)	117 (43)
79 (29)	85 (31)
51 (19)	54 (20)
40 (15)	60 (22)
36 (13)	42 (15)
12 (4)	31 (11)
9 (3)	30 (11)
General disorders and administration site conditions	181 (66)	160 (59)
123 (45)	108 (40)
51 (19)	40 (15)
25 (9)	28 (10)
Infections and infestations	169 (62)	185 (68)
60 (22)	63 (23)
44 (16)	49 (18)
Injury, poisoning and procedural complications	163 (60)	163 (60)
45 (16)	47 (17)
40 (15)	37 (14)
Investigations	137 (50)	133 (49)
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)
32 (12)	29 (11)
30 (11)	28 (10)
Nervous system disorders	92 (34)	109 (40)
49 (18)	40 (15)
23 (8)	38 (14)
Psychiatric disorders	90 (33)	72 (26)
47 (17)	43 (16)
Renal and urinary disorders	112 (41)	124 (45)
33 (12)	33 (12)
29 (11)	28 (10)
Respiratory, thoracic and mediastinal disorders	86 (31)	93 (34)
20 (7)	30 (11)
Vascular disorders	122 (45)	124 (45)
81 (30)	82 (30)
*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 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) [see 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.
LeukopeniaDiarrheaNauseaAbdominal painPeripheral edemaPyrexiaFatigue Hepatitis C^**Liver function test abnormal HypercholesterolemiaHeadacheTremorInsomniaRenal failureHypertension

Less Common Adverse Reactions
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*)
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)
29 (12)	12 (5)	31 (13)	12 (5)
Gastrointestinal disorders	136 (56)	121 (50)	148 (60)	138 (57)
47 (19)	50 (21)	59 (24)	61 (25)
33 (14)	28 (12)	36 (15)	33 (14)
32 (13)	22 (9)	37 (15)	31(13)
General disorders and administration site conditions	94 (38)	85 (35)	113 (46)	98 (41)
43 (18)	26 (11)	49 (20)	31 (13)
32 (13)	25 (10)	43 (18)	28 (12)
22 (9)	26 (11)	27 (11)	28 (12)
Infections and infestations	123 (50)	105 (44)	135 (56)	125 (52)
28 (11)	19 (8)	33 (14)	24 (10)
Investigations	81 (33)	78 (32)	92 (38)	98 (41)
16 (7)	24 (10)	19 (8)	25 (10)
Metabolism and nutrition disorders	111 (45)	92 (38)	134 (55)	106 (44)
23 (9)	6 (3)	27 (11)	9 (4)
Nervous system disorders	89 (36)	85 (35)	99 (40)	101 (42)
47 (19)	46 (19)	53 (22)	54 (22)
23 (9)	29 (12)	25 (10)	37 (15)
14 (6)	19 (8)	17 (7)	24 (10)
Renal and urinary disorder	49 (20)	53 (22)	67 (27)	73 (30)
13 (5)	17 (7)	24 (10)	37 (15)
Vascular disorders	56 (23)	57 (24)	72 (29)	68 (28)
42 (17)	38 (16)	52 (21)	44 (18)
*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.

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 [see Warnings and Precautions (5.8)]
• •Interstitial Lung Disease/Non-Infectious Pneumonitis [see 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) [see Warnings and Precautions (5.15)]

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 [see 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 [see Warnings and Precautions (5.18)].