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boxed warning
WARNING: MALIGNANCIES and SERIOUS INFECTIONS; KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; and MORTALITY IN HEART TRANSPLANTATION Malignancies and Serious Infections Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe everolimus tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [ see Warnings and Precautions (5.1)] . Increased susceptibility to infection and the possible development of malignancies, such as lymphoma and skin cancer, may result from immunosuppression [see Warnings and Precautions (5.2, 5.3)]. Kidney Graft Thrombosis An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days posttransplantation [see Warnings and Precautions (5.4)]. Nephrotoxicity Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with everolimus tablets. Therefore, reduced doses of cyclosporine should be used in combination with everolimus tablets in order to reduce renal dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.6), Clinical Pharmacology (12.7, 12.8)]. Mortality in Heart Transplantation Increased mortality, often associated with serious infections, within the first three months posttransplantation was observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without induction therapy. Use in heart transplantation is not recommended [see Warnings and Precautions (5.7)]. WARNING : MALIGNANCIES and SERIOUS INFECTIONS; KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; and MORTALITY IN HEART TRANSPLANTATION See full prescribing information f or complete boxed warning . Only physicians experienced in immunosuppressive therapy and management of transplant patients should use everolimus tablets (5.1 ) Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression ( 5.2 , 5.3 ) Increased incidence of kidney graft thrombosis ( 5.4 ) Reduced doses of cyclosporine are ...
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • 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 tablets 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 tablets. 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...
warnings and cautions
5.22 Cannabidiol Drug Interactions 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), Drug Interactions (7.13)].
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adverse reactions
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 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 ...
adverse reactions table
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 reactionsEverolimus 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 disorders93 (34)111 (41) Anemia 70 (26)68 (25) Leukopenia 8 (3)33 (12)Gastrointestinal disorders196 (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 conditions181 (66)160 (59) Edema peripheral123 (45)108 (40) Pyrexia 51 (19)40 (15) Fatigue 25 (9)28 (10)Infections and infestations169 (62)185 (68) Urinary tract infection 60 (22)63 (23) Upper respiratory tract infection44 (16)49 (18)Injury, poisoning and procedural complications163 (60)163 (60) Incision-site pain 45 (16)47 (17) Procedural pain 40 (15)37 (14)Investigations137 (50)133 (49) Blood creatinine increased48 (18)59 (22)Metabolism and nutrition disorders222 (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 disorders112 (41)105 (39) Pain in extremity32 (12)29 (11) Back pain 30 (11)28 (10)Nervous system disorders92 (34)109 (40) Headache 49 (18)40 (15) Tremor 23 (8)38 (14)Psychiatric disorders90 (33)72 (26) Insomnia 47 (17)43 (16)Renal and urinary disorders112 (41)124 (45) Hematuria 33 (12) 33 (12) Dysuria 29 (11)28 (10)Respiratory, thoracic and mediastinal disorders86 (31)93 (34) Cough 20 (7)30 (11)Vascular disorders122 (45)124 (45) Hypertension 81 (30)82 (30)