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.
The data described below reflect exposure to Zortress in an open-label, randomized trial of de novo kidney transplant patients of concentration-controlled everolimus at an initial Zortress 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 Zortress group, 47 years control group); a majority of recipients were male (64% in the Zortress group, 69% control group); and a majority of patients were Caucasian (70% in the Zortress 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 Zortress 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 Zortress 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 Zortress 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 Zortress 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 Zortress 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 Zortress group and 12% (32/273) in the control group] followed by renal and urinary disorders [10% (28/274) in the Zortress group and 13% (36/273) in the control group] and vascular disorders [10% (26/274) in the Zortress 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 Zortress 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 Zortress 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 Zortress 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 Zortress group were: peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia.
The overall incidence of bacterial, fungal and viral infections reported as adverse reactions was higher in the control group (68%) compared to the Zortress group (64%) and was primarily due to an increased number of viral infections (21% in the control group and 10% in the Zortress group). The incidence of CMV infections reported as adverse reactions was 8% in the control group compared to 1% in the Zortress group; and 3% of the serious CMV infections in the control group versus 0% in the Zortress group were considered serious [ see Warnings and Precautions (5.3) ] .
BK virus infections were lower in incidence in the Zortress group (2 patients, 1%) compared to the control group (11 patients, 4%). One of the two BK virus infections in the Zortress 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 Zortress 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 Zortress group compared to control.
Adverse reactions due to major fluid collections such as edema and other types of fluid collections was 45% in the Zortress group and 40% in the control group [ see Warnings and Precautions ( 5. 9 ) ] .
Adverse reactions due to malignant and benign neoplasms were reported in 3% of patients in the Zortress 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 Zortress group who underwent a melanoma excision prior to transplantation died due to metastatic melanoma [ see Boxed Warning, Warnings and Precautions (5.2) ] .
New O nset D iabetes M ellitus (NODM)
NODM reported based on adverse reactions and random serum glucose values, was 9% in the Zortress group compared to 7% in the control group.
Endocrine Effects in Males
In the Zortress group, serum testosterone levels significantly decreased while the FSH levels significantly increased without significant changes being observed in the control group. In both the Zortress and the control groups mean testosterone and FSH levels remained within the normal range with the mean FSH level in the Zortress group being at the upper limit of the normal range (11.1 U/L). More patients were reported with erectile dysfunction in the Zortress 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 Zortress 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.
|* 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.|
|Primary System Organ Class Preferred Term||Zortress (e verolimus ) 1.5 mg With R educed Exposure Cyclosporine N = 274 n (%)||M ycophenolic 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 Zortress 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 Zortress 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 Zortress group, the overall safety was worse and consequently higher doses of Zortress 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 Zortress when used at this higher dose were injury, poisoning and procedural complications (Zortress 1.5 mg: 5%, Zortress 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 Zortress 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 Zortress increases the cyclosporine-induced nephrotoxicity; and therefore, should only be used in a concentration-controlled regimen with reduced exposure cyclosporine [ see Boxed Warnings, Indications and Usage (1. 1 ) , Warnings and Precautions (5. 6 ) ] .
The data described below reflect exposure to Zortress 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 Zortress 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 Zortress group, 55 years in the tacrolimus control group); 74% were male in both Zortress and control groups, respectively, and a majority were Caucasian (86% Zortress 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 Zortress 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 Zortress group. At 24 months, the rate of discontinuation of study medication in liver transplant patients was greater for the Zortress group (42%) compared to tacrolimus control group (33%).
The overall incidences of serious adverse reactions were 50% (122/245) in the Zortress 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 Zortress group (one patient never took Zortress). 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 Zortress group were: diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, and leukopenia (see Table 3).
The overall incidence of infections reported as adverse reactions was 50% for Zortress 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 Zortress 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 Zortress 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 Zortress group and 3% in the control arm.
Malignant and benign neoplasms were reported as adverse reactions in 4% of patients in the Zortress group and 7% in the control group at 12 months. In the Zortress group, 3 malignant tumors were reported compared to 9 cases in the control group. For the Zortress 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 A bnormalities
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% Zortress 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 Zortress 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 Zortress 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.
|* 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.|
|Preferred System Organ Class Preferred Term||12 month||24 m onth|
|Zortress With Reduced Exposure Tacrolimus N = 245 n ( %)||Tacrolimus Standard Exposure N = 241 n ( %)||Zortress 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)|
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 Zortress 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 [ s ee Warnings and Precautions ( 5.1 3 ) ] , 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 [ s ee 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 [ s ee Warnings and Precautions ( 5.1 6 ) ] , 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 [s ee Warnings and Precautions ( 5.1 2 ) ], pyuria, renal artery thrombosis [ s ee Boxed Warning, Warnings and Precautions ( 5.4 ) ] , acute renal failure, renal impairment [ s ee 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 than1% of either kidney or liver transplant patients treated with Zortress 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 [ s ee Warnings and Precautions (5.9)]
- Thrombotic Microangiopathy (TMA), Thrombotic Thrombocytopenic Purpura (TTP), and Hemolytic Uremic Syndrome (HUS) [ s ee Warnings and Precautions (5.1 5 ) ]
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