Everolimus

6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Non-Infectious Pneumonitis [see Warnings and Precautions (5.1) ] . Infections [see Warnings and Precautions (5.2) ]. Severe Hypersensitivity Reactions [see Warnings and Precautions (5.3) ]. Angioedema with Concomitant Use of ACE inhibitors [see Warnings and Precautions (5.4) ] . Stomatitis [see Warnings and Precautions (5.5) ] . Renal Failure [see Warnings and Precautions (5.6) ] . Impaired Wound Healing [see Warnings and Precautions (5.7) ]. Metabolic Disorders [see Warnings and Precautions (5.9) ]. Myelosuppression [see Warnings and Precautions (5.10) ]. Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.12) ]. Breast cancer, NET, RCC: Most common adverse reactions (incidence ≥ 30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. ( 6.1 ) TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Hormone Receptor-Positive, HER2-Negative Breast Cancer The safety of everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were White. The median follow-up was approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received everolimus tablets. The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus tablets arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with everolimus tablets was 23.9 weeks; 33% were exposed to everolimus tablets for a period of ≥ 32 weeks. Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Everolimus Tablets with Exemestane Placebo with Exemestane N = 482 N = 238 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0. Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. 67 8 No Grade 4 adverse reactions were reported. 11 0.8 Diarrhea 33 2 18 0.8 Nausea 29 0.4 28 1 Vomiting 17 1 12 0.8 Constipation 14 0.4 13 0.4 Dry mouth 11 0 7 0 General Fatigue 36 4 27 1 Edema peripheral 19 1 6 0.4 Pyrexia 15 0.2 7 0.4 Asthenia 13 2 4 0 Infections Infections Includes all reported infections, including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. 50 6 25 2 Investigations Weight loss 25 1 6 0 Metabolism and nutrition Decreased appetite 30 1 12 0.4 Hyperglycemia 14 5 2 0.4 Musculoskeletal and connective tissue Arthralgia 20 0.8 17 0 Back pain 14 0.2 10 0.8 Pain in extremity 9 0.4 11 2 Nervous system Dysgeusia 22 0.2 6 0 Headache 21 0.4 14 0 Psychiatric Insomnia 13 0.2 8 0 Respiratory, thoracic and mediastinal Cough 24 0.6 12 0 Dyspnea 21 4 11 1 Epistaxis 17 0 1 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. 19 4 0.4 0 Skin and subcutaneous tissue Rash 39 1 6 0 Pruritus 13 0.2 5 0 Alopecia 10 0 5 0 Vascular Hot flush 6 0 14 0 Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Laboratory Parameter Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0. Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. Anemia 68 6 40 1 Leukopenia 58 2 No Grade 4 laboratory abnormalities were reported. 28 6 Thrombocytopenia 54 3 5 0.4 Lymphopenia 54 12 37 6 Neutropenia 31 2 11 2 Chemistry Hypercholesterolemia 70 1 38 2 Hyperglycemia 69 9 44 1 Increased AST 69 4 45 3 Increased ALT 51 4 29 5 Hypertriglyceridemia 50 0.8 26 0 Hypoalbuminemia 33 0.8 16 0.8 Hypokalemia 29 4 7 1 Increased creatinine 24 2 13 0 Topical Prophylaxis for Stomatitis In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5 mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with everolimus tablets and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial. Coadministration of everolimus tablets and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. Pancreatic Neuroendocrine Tumors (PNET) In a randomized, controlled trial (RADIANT-3) of everolimus tablets (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male. Patients on the placebo arm could cross over to open-label everolimus tablets upon disease progression. The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia. Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on everolimus tablets. Causes of death on the everolimus tablets arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label everolimus tablets, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the everolimus tablets group. Dose delay or reduction was necessary in 61% of everolimus tablets patients. Grade 3-4 renal failure occurred in six patients in the everolimus tablets arm. Thrombotic events included five patients with pulmonary embolus in the everolimus tablets arm as well as three patients with thrombosis in the everolimus tablets arm. Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received everolimus tablets was 37 weeks. In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) everolimus tablets-treated females. Table 8: Adverse Reactions Reported in ≥ 10% of Patients with PNET in RADIANT-3 Everolimus Tablets N = 204 Placebo N = 203 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0. Gastrointestinal Stomatitis Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 70 7 No Grade 4 adverse reactions were reported. 20 0 Diarrhea Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 50 6 25 3 Abdominal pain 36 4 32 7 Nausea 32 2 33 2 Vomiting 29 1 21 2 Constipation 14 0 13 0.5 Dry mouth 11 0 4 0 General Fatigue/malaise 45 4 27 3 Edema (general and peripheral) 39 2 12 1 Fever 31 1 13 0.5 Asthenia 19 3 20 3 Infections Nasopharyngitis/rhinitis/URI 25 0 13 0 Urinary tract infection 16 0 6 0.5 Investigations Weight loss 28 0.5 11 0 Metabolism and nutrition Decreased appetite 30 1 18 1 Diabetes mellitus 10 2 0.5 0 Musculoskeletal and connective tissue Arthralgia 15 1 7 0.5 Back pain 15 1 11 1 Pain in extremity 14 0.5 6 1 Muscle spasms 10 0 4 0 Nervous system Headache/migraine 30 0.5 15 1 Dysgeusia 19 0 5 0 Dizziness 12 0.5 7 0 Psychiatric Insomnia 14 0 8 0 Respiratory, thoracic and mediastinal Cough/productive cough 25 0.5 13 0 Epistaxis 22 0 1 0 Dyspnea/dyspnea exertional 20 3 7 0.5 Pneumonitis Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. 17 4 0 0 Oropharyngeal pain 11 0 6 0 Skin and subcutaneous Rash 59 0.5 19 0 Nail disorders 22 0.5 2 0 Pruritus/pruritus generalized 21 0 13 0 Dry skin/xeroderma 13 0 6 0 Vascular Hypertension 13 1 6 1 Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with PNET in RADIANT-3 Laboratory Parameter Everolimus Tablets N = 204 Placebo N = 203 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0. Hematology Anemia 86 15 63 1 Lymphopenia 45 16 22 4 Thrombocytopenia 45 3 11 0 Leukopenia 43 2 13 0 Neutropenia 30 4 17 2 Chemistry Hyperglycemia (fasting) 75 17 53 6 Increased alkaline phosphatase 74 8 66 8 Hypercholesterolemia 66 0.5 22 0 Bicarbonate decreased 56 0 40 0 Increased AST 56 4 41 4 Increased ALT 48 2 35 2 Hypophosphatemia 40 10 14 3 Hypertriglyceridemia 39 0 10 0 Hypocalcemia 37 0.5 12 0 Hypokalemia 23 4 5 0 Increased creatinine 19 2 14 0 Hyponatremia 16 1 16 1 Hypoalbuminemia 13 1 8 0 Hyperbilirubinemia 10 1 14 2 Hyperkalemia 7 0 10 0.5 Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin In a randomized, controlled trial (RADIANT-4) of everolimus tablets (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were White, and 53% were female. The median duration of exposure to everolimus tablets was 9.3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months. Everolimus tablets was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of everolimus tablets-treated patients. Serious adverse reactions occurred in 42% of everolimus tablets-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Adverse reactions occurring at an incidence of ≥ 10% and at ≥ 5% absolute incidence over placebo (all Grades) or ≥ 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11. Table 10: Adverse Reactions in ≥ 10% of Everolimus Tablets-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4 Everolimus Tablets N = 202 Placebo N = 98 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 4.03. Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation. 63 9 No Grade 4 adverse reactions were reported. 22 0 Diarrhea 41 9 31 2 Nausea 26 3 17 1 Vomiting 15 4 12 2 General Peripheral edema 39 3 6 1 Fatigue 37 5 36 1 Asthenia 23 3 8 0 Pyrexia 23 2 8 0 Infections Infections Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis. 58 11 29 2 Investigations Weight loss 22 2 11 1 Metabolism and nutrition Decreased appetite 22 1 17 1 Nervous system Dysgeusia 18 1 4 0 Respiratory, thoracic and mediastinal Cough 27 0 20 0 Dyspnea 20 3 11 2 Pneumonitis Includes pneumonitis and interstitial lung disease. 16 2 2 0 Epistaxis 13 1 3 0 Skin and subcutaneous Rash 30 1 9 0 Pruritus 17 1 9 0 Table 11: Selected Laboratory Abnormalities in ≥ 10% of Everolimus Tablets-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4 Everolimus Tablets N = 202 Placebo N = 98 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 4.03. Hematology Anemia 81 5 No Grade 4 laboratory abnormalities were reported. 41 2 Lymphopenia 66 16 32 2 Leukopenia 49 2 17 0 Thrombocytopenia 33 2 11 0 Neutropenia 32 2 15 3 Chemistry Hypercholesterolemia 71 0 37 0 Increased AST 57 2 34 2 Hyperglycemia (fasting) 55 6 36 1 Increased ALT 46 5 39 1 Hypophosphatemia 43 4 15 2 Hypertriglyceridemia 30 3 8 1 Hypokalemia 27 6 12 3 Hypoalbuminemia 18 0 8 0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to everolimus tablets (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving everolimus tablets. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the everolimus tablets arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the everolimus tablets group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during everolimus tablets treatment were for infections, anemia, and stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13. Table 12: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the Everolimus Tablets Arm than in the Placebo Arm in RECORD-1 Everolimus Tablets N = 274 Placebo N = 137 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0 Gastrointestinal Stomatitis Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. 44 4 8 0 Diarrhea 30 2 No Grade 4 adverse reactions were reported. 7 0 Nausea 26 2 19 0 Vomiting 20 2 12 0 Infections Includes all reported infections, including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. 37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6 27 4 Edema peripheral 25 < 1 8 < 1 Pyrexia 20 < 1 9 0 Mucosal inflammation 19 2 1 0 Respiratory, thoracic and mediastinal Cough 30 < 1 16 0 Dyspnea 24 8 15 3 Epistaxis 18 0 0 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. 14 4 0 0 Skin and subcutaneous tissue Rash 29 1 7 0 Pruritus 14 < 1 7 0 Dry skin 13 < 1 5 0 Metabolism and nutrition Anorexia 25 2 14 < 1 Nervous system Headache 19 1 9 < 1 Dysgeusia 10 0 2 0 Musculoskeletal and connective tissue Pain in extremity 10 1 7 0 Other notable adverse reactions occurring more frequently with everolimus tablets than with placebo, but with an incidence of < 10% include: Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%) Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (< 1%) Metabolism and nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%) Psychiatric: Insomnia (9%) Nervous system: Dizziness (7%), paresthesia (5%) Ocular: Eyelid edema (4%), conjunctivitis (2%) Vascular: Hypertension (4%), deep vein thrombosis (< 1%) Renal and urinary: Renal failure (3%) Cardiac: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue: Jaw pain (3%) Hematologic: Hemorrhage (3%) Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Everolimus Tablets Arm than the Placebo Arm in RECORD-1 Laboratory parameter Everolimus Tablets N = 274 Placebo N = 137 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0 Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. Anemia 92 13 79 6 Lymphopenia 51 18 28 5 No Grade 4 laboratory abnormalities were reported. Thrombocytopenia 23 1 2 < 1 Neutropenia 14 < 1 4 0 Chemistry Hypercholesterolemia 77 4 35 0 Hypertriglyceridemia 73 < 1 34 0 Hyperglycemia 57 16 25 2 Increased creatinine 50 2 34 0 Hypophosphatemia 37 6 8 0 Increased AST 25 1 7 0 Increased ALT 21 1 4 0 Hyperbilirubinemia 3 1 2 0 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of everolimus tablets in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were White, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving everolimus tablets. The most common adverse reaction reported for everolimus tablets (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the everolimus tablets-treated patients. Adverse reactions leading to permanent discontinuation in the everolimus tablets arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of everolimus tablets-treated patients. The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets and occurring more frequently with everolimus tablets than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15. Table 14: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus tablets N = 79 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0 Gastrointestinal Stomatitis Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. 78 6 No Grade 4 adverse reactions were reported. 23 0 Vomiting 15 0 5 0 Diarrhea 14 0 5 0 General Peripheral edema 13 0 8 0 Infections Upper respiratory tract infection 11 0 5 0 Musculoskeletal and connective tissue Arthralgia 13 0 5 0 Respiratory, thoracic and mediastinal Cough 20 0 13 0 Skin and subcutaneous tissue Acne 22 0 5 0 Amenorrhea occurred in 15% of everolimus tablets-treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The following additional adverse reactions occurred in less than 10% of everolimus tablets-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%). Table 15: Selected Laboratory Abnormalities Reported in Everolimus Tablets-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus tablets N = 79 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0 Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1 No Grade 4 laboratory abnormalities were reported. 8 0 Thrombocytopenia 19 0 3 0 Chemistry Hypercholesterolemia 85 1 46 0 Hypertriglyceridemia 52 0 10 0 Hypophosphatemia 49 5 15 0 Increased alkaline phosphatase 32 1 10 0 Increased AST 23 1 8 0 Increased ALT 20 1 15 0 Hyperglycemia (fasting) 14 0 8 0 Updated safety information from 112 patients treated with everolimus tablets for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%). TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA) The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of everolimus tablets in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were White, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving everolimus tablets. The most common adverse reactions reported for everolimus tablets (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia. There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of everolimus tablets-treated patients. The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets and occurring more frequently with everolimus tablets than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17. Table 16: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets -Treated Patients with TSC-Associated SEGA in EXIST-1 Everolimus Tablets N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0. Gastrointestinal Stomatitis Includes mouth ulceration, stomatitis, and lip ulceration. 62 9 No Grade 4 adverse reactions were reported. 26 3 Vomiting 22 1 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. 31 3 23 0 Gastroenteritis Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 18 3 Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. 21 5 3 0 Skin and subcutaneous tissue Rash Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. 21 0 8 0 Acne 10 0 5 0 Amenorrhea occurred in 17% of everolimus tablets-treated females aged 10 to 55 years (3 of 18). For this same group of everolimus tablets-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%). The following additional adverse reactions occurred in less than 10% of everolimus tablets-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%), and pneumonitis (1%). Table 17: Selected Laboratory Abnormalities Reported in Everolimus Tablets-Treated Patients with TSC-Associated SEGA in EXIST-1 Everolimus Tablets N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0 Hematology Elevated partial thromboplastin time 72 3 No Grade 4 laboratory abnormalities were reported. 44 5 Neutropenia 46 9 41 3 Anemia 41 0 21 0 Chemistry Hypercholesterolemia 81 0 39 0 Elevated AST 33 0 0 0 Hypertriglyceridemia 27 0 15 0 Elevated ALT 18 0 3 0 Hypophosphatemia 9 1 3 0 Updated safety information from 111 patients treated with everolimus tablets for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of everolimus tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: Blood and lymphatic disorders: Thrombotic microangiopathy Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event Gastrointestinal: Acute pancreatitis Hepatobiliary: Cholecystitis and cholelithiasis Infections: Sepsis and septic shock Nervous System: Reflex sympathetic dystrophy Vascular: Arterial thrombotic events, lymphedema Injury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall

4. CONTRAINDICATIONS Everolimus tablets are contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3) ]. Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. ( 4 )

11. DESCRIPTION Everolimus tablets are kinase inhibitors. The chemical name of everolimus is (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[30.3.1.0 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 958.2 g/mol. The structural formula is: Everolimus tablets for oral administration contain 2.5 mg, 5 mg, 7.5 mg or 10 mg of everolimus. The tablets also contain anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, and magnesium stearate as inactive ingredients. Chemical Structure

2. DOSAGE AND ADMINISTRATION Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total daily dose. ( 2.1 ) Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. ( 2.1 ) Breast Cancer: 10 mg orally once daily. ( 2.2 ) NET: 10 mg orally once daily. ( 2.3 ) RCC: 10 mg orally once daily. ( 2.4 ) TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. ( 2.5 ) TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.6 , 2.8 ) 2.1 Important Dosage Information Everolimus tablets and everolimus tablets for oral suspension are two different dosage forms. Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total dose. Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10 , 2.11 , 2.12) ]. 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8) ]. 2.8 Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Monitor everolimus whole blood trough concentrations at time points recommended in Table 1. Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. Adjust the dose using the following equation: New dose The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration. = current dose × (target concentration divided by current concentration) When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Abbreviation: P-gp, P-glycoprotein. Initiation of everolimus tablets 1 to 2 weeks Modification of everolimus tablets dose 1 to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 to 6 months Stable dose with stable BSA Every 6 to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis [see Warnings and Precautions (5.1) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Stomatitis [see Warnings and Precautions (5.5) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose. If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Thrombocytopenia [see Warnings and Precautions (5.10) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. Grade 3 OR Grade 4 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Neutropenia [see Warnings and Precautions (5.10) ] Grade 3 Withhold until improvement to Grade 0, 1 or 2. Resume at same dose. Grade 4 Withhold until improvement to Grade 0, 1 or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Febrile neutropenia [see Warnings and Precautions (5.10) ] Grade 3 Withhold until improvement to Grade 0, 1 or 2 and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. 2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of everolimus tablets for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6) ]: Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Indication Dose Modification for Everolimus Tablets Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex. Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated. Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated. Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. TSC-Associated SEGA Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8) ]. 2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1) ]. Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking everolimus tablets with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Reduce dose to 2.5 mg once daily. May increase dose to 5 mg once daily if tolerated. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. TSC-Associated SEGA Reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8) ]. 2.12 Dosage Modifications for P-gp and CYP3A4 Inducers Avoid concomitant use of St. John's Wort ( Hypericum perforatum ). Increase the dose for patients taking everolimus tablets with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist. If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days. TSC-Associated SEGA Double the daily dose using increments of 5 mg or less. Multiple increments may be required. Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8) ]. Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. 2.13 Administration and Preparation Administer everolimus tablets at the same time each day. Administer everolimus tablets consistently either with or without food [see Clinical Pharmacology (12.3) ]. If a dose of everolimus tablets is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, everolimus tablets should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. Everolimus Tablets Everolimus Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

1. INDICATIONS AND USAGE Everolimus tablets are a kinase inhibitor indicated for the treatment of: Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. ( 1.1 ) Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Limitations of Use: Everolimus tablets are not indicated for the treatment of patients with functional carcinoid tumors. ( 1.2 ) Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. ( 1.3 ) Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. ( 1.4 ) Everolimus tablets are kinase inhibitors indicated for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. ( 1.5 ) 1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer Everolimus tablets are indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. 1.2 Neuroendocrine Tumors (NET) Everolimus tablets are indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Everolimus tablets are indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. Limitations of Use: Everolimus tablets are not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2) ]. 1.3 Renal Cell Carcinoma (RCC) Everolimus tablets are indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib. 1.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma Everolimus tablets are indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery. 1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Everolimus tablets are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

7. DRUG INTERACTIONS P-gp and strong CYP3A4 inhibitors: Avoid concomitant use. ( 2.11 , 7.1 ) P-gp and moderate CYP3A4 inhibitors: Reduce the dose as recommended. ( 2.11 , 7.1 ) P-gp and strong CYP3A4 inducers: Increase the dose as recommended. ( 2.12 , 7.1 ) 7.1 Effect of Other Drugs on Everolimus Tablets Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.11) , Clinical Pharmacology (12.3) ] . Reduce the dose for patients taking everolimus tablets with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration (2.11) , Clinical Pharmacology (12.3) ] . Inducers Increase the dose for patients taking everolimus tablets with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration (2.12) , Clinical Pharmacology (12.3) ] . 7.2 Effects of Combination Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with everolimus tablets may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with everolimus tablets [see Warnings and Precautions (5.4) ].

12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 ( TSC1, TSC2 ). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death. 12.2 Pharmacodynamics Exposure-Response Relationship In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration. Cardiac Electrophysiology In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of everolimus tablets (20 mg and 50 mg) and placebo. Everolimus tablets at single doses up to 50 mg did not prolong the QT/QTc interval. 12.3 Pharmacokinetics Absorption After administration of everolimus tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, C max is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in C max is less than dose-proportional; however, AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. In patients with TSC-associated SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m 2 to 14.4 mg/m 2 . Effect of Food: In healthy subjects, a high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to everolimus tablets 10 mg (as measured by AUC) by 22% and the peak blood concentration C max by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and C max by 42%. Relative Bioavailability: The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and everolimus tablets; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of everolimus tablets. The predicted trough concentrations at steady-state were similar after daily administration. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given everolimus tablets 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Elimination The mean elimination half-life of everolimus is approximately 30 hours. Metabolism: Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. Specific Populations No relationship was apparent between oral clearance and age or sex in patients with cancer. Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus. Patients with Hepatic Impairment: Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10) , Use in Specific Populations (8.6) ]. Pediatric Patients: In patients with TSC-associated SEGA, the mean C min values normalized to mg/m 2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to BSA was higher in pediatric patients as compared to adults. Race or Ethnicity: Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in Black patients than in White patients. Drug Interaction Studies Effect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when everolimus tablets were coadministered with: ketoconazole (a P-gp and strong CYP3A4 inhibitor) - C max and AUC increased by 3.9- and 15-fold, respectively. erythromycin (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2- and 4.4-fold, respectively. verapamil (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2.3- and 3.5-fold, respectively. Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of everolimus tablets with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and C max by 58% compared to everolimus tablets alone [see Dosage and Administration (2.12) ]. Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between everolimus tablets and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate). The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus tablets resulted in a 25% increase in midazolam C max and a 30% increase in midazolam AUC 0-inf . The coadministration of everolimus tablets with exemestane increased exemestane C min by 45% and C 2h by 64%; however, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse reactions related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. The coadministration of everolimus tablets with long-acting octreotide increased octreotide C min by approximately 50%. Effect of Everolimus on Antiepileptic Drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam's metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

12.1 Mechanism of Action Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 ( TSC1, TSC2 ). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

12.2 Pharmacodynamics Exposure-Response Relationship In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration. Cardiac Electrophysiology In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of everolimus tablets (20 mg and 50 mg) and placebo. Everolimus tablets at single doses up to 50 mg did not prolong the QT/QTc interval.

12.3 Pharmacokinetics Absorption After administration of everolimus tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, C max is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in C max is less than dose-proportional; however, AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. In patients with TSC-associated SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m 2 to 14.4 mg/m 2 . Effect of Food: In healthy subjects, a high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to everolimus tablets 10 mg (as measured by AUC) by 22% and the peak blood concentration C max by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and C max by 42%. Relative Bioavailability: The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and everolimus tablets; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of everolimus tablets. The predicted trough concentrations at steady-state were similar after daily administration. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given everolimus tablets 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Elimination The mean elimination half-life of everolimus is approximately 30 hours. Metabolism: Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. Specific Populations No relationship was apparent between oral clearance and age or sex in patients with cancer. Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus. Patients with Hepatic Impairment: Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10) , Use in Specific Populations (8.6) ]. Pediatric Patients: In patients with TSC-associated SEGA, the mean C min values normalized to mg/m 2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to BSA was higher in pediatric patients as compared to adults. Race or Ethnicity: Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in Black patients than in White patients. Drug Interaction Studies Effect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when everolimus tablets were coadministered with: ketoconazole (a P-gp and strong CYP3A4 inhibitor) - C max and AUC increased by 3.9- and 15-fold, respectively. erythromycin (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2- and 4.4-fold, respectively. verapamil (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2.3- and 3.5-fold, respectively. Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of everolimus tablets with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and C max by 58% compared to everolimus tablets alone [see Dosage and Administration (2.12) ]. Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between everolimus tablets and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate). The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus tablets resulted in a 25% increase in midazolam C max and a 30% increase in midazolam AUC 0-inf . The coadministration of everolimus tablets with exemestane increased exemestane C min by 45% and C 2h by 64%; however, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse reactions related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. The coadministration of everolimus tablets with long-acting octreotide increased octreotide C min by approximately 50%. Effect of Everolimus on Antiepileptic Drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam's metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

20230601

12

3. DOSAGE FORMS AND STRENGTHS Everolimus Tablets: 2.5 mg, 5 mg, 7.5 mg and 10 mg tablets with no score ( 3 ) Everolimus Tablets 2.5 mg tablet White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '2.5' on the other side. 5 mg tablet White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '5' on the other side. 7.5 mg tablet White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '7.5' on the other side. 10 mg tablet White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and 'NAT' on the other side.

Everolimus Everolimus Everolimus Everolimus Acetone Anhydrous lactose Butylated hydroxytoluene Hypromellose 2910 (3 MPA.S) Crospovidone (120 .MU.M) Magnesium Stearate EVR;2;5 Everolimus Everolimus Everolimus Everolimus Acetone Anhydrous lactose Butylated hydroxytoluene Hypromellose 2910 (3 MPA.S) Crospovidone (120 .MU.M) Magnesium Stearate EVR;5 Everolimus Everolimus Everolimus Everolimus Acetone Anhydrous lactose Butylated hydroxytoluene Hypromellose 2910 (3 MPA.S) Crospovidone (120 .MU.M) Magnesium Stearate EVR;7;5 Everolimus Everolimus Everolimus Everolimus Acetone Anhydrous lactose Butylated hydroxytoluene Hypromellose 2910 (3 MPA.S) Crospovidone (120 .MU.M) Magnesium Stearate EVR;NAT

13.2 Animal Toxicology and/or Pharmacology In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of everolimus tablets 10 mg orally once daily. Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m 2 /day, approximately 255-fold the recommended dose of everolimus tablets 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA, based on the BSA), administered as 2 doses, 24 hours apart. Based on non-clinical findings, everolimus tablets may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng∙hr/mL and 414 ng∙hr/mL, respectively) were within the range of human exposure at the recommended dose of everolimus tablets 10 mg orally once daily (560 ng∙hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC 0-24h values 10% to 81% lower than human exposure at the recommended dose of everolimus tablets 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%. Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of everolimus tablets 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of everolimus tablets 10 mg orally once daily. Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m 2 /day, approximately 255-fold the recommended dose of everolimus tablets 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA, based on the BSA), administered as 2 doses, 24 hours apart. Based on non-clinical findings, everolimus tablets may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng∙hr/mL and 414 ng∙hr/mL, respectively) were within the range of human exposure at the recommended dose of everolimus tablets 10 mg orally once daily (560 ng∙hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC 0-24h values 10% to 81% lower than human exposure at the recommended dose of everolimus tablets 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%. Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of everolimus tablets 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility. 13.2 Animal Toxicology and/or Pharmacology In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

ANDA205426

Everolimus

Everolimus

51991-823

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label NDC 51991-821-33 Everolimus Tablets 2.5 mg Rx Only 30 Tablets breckenridge A Towa Company PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label

Manufactured by: Natco Pharma Limited Kothur – 509 228, India Distributed by: Breckenridge Pharmaceutical Inc. Berlin, CT 06037 xxxxxxxx

17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Non-infectious Pneumonitis Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1) ]. Infections Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2) ]. Hypersensitivity Reactions Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction, including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4) , Warnings and Precautions (5.3) ]. Angioedema with Concomitant Use of ACE Inhibitors Advise patients to avoid ACE inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4) ]. Stomatitis Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5) ]. Renal Impairment Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6) ]. Risk of Impaired Wound Healing Advise patients that everolimus tablets may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7) ]. Geriatric Patients Inform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients ≥ 65 years compared to patients < 65 years [see Warnings and Precautions (5.8) , Use in Specific Populations (8.5) ]. Metabolic Disorders Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9) ]. Myelosuppression Advise patients of the risk of myelosuppression and the need to monitor CBCs periodically during therapy [see Warnings and Precautions (5.10) ]. Risk of Infection or Reduced Immune Response with Vaccination Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11) ]. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions (5.13) , Use in Specific Populations (8.1 , 8.3) ]. Radiation Sensitization and Radiation Recall Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to everolimus tablets treatment. Advise patients to inform their healthcare provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.12) ]. Lactation Advise women not to breastfeed during treatment with everolimus tablets and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ]. Infertility Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3) ].

14. CLINICAL STUDIES 14.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of everolimus tablets in combination with exemestane vs. placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease. The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. Other outcome measures included overall survival (OS) and objective response rate (ORR). Patients were randomized 2:1 to everolimus tablets 10 mg orally once daily in combination with exemestane 25 mg once daily (n = 485) or to placebo in combination with exemestane 25 mg orally once daily (n = 239). The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to everolimus tablets at the time of disease progression. The trial demonstrated a statistically significant improvement in PFS by investigator assessment (Table 20 and Figure 1). The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy. ORR was higher in the everolimus tablets in combination with exemestane arm vs. the placebo in combination with exemestane arm (Table 20). There were 3 complete responses (0.6%) and 58 partial responses (12%) in the everolimus tablets arm. There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm. After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the everolimus tablets in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)]. Table 20: Efficacy Results in Hormone-Receptor Positive, HER-2 Negative Breast Cancer in BOLERO-2 Analysis Everolimus Tablets with Exemestane N = 485 Placebo with Exemestane N = 239 Hazard Ratio p-value Median progression-free survival (months, 95% CI) Investigator radiological review 7.8 (6.9, 8.5) 3.2 (2.8, 4.1) 0.45 Hazard ratio is obtained from the stratified Cox proportional-hazards model by sensitivity to prior hormonal therapy and presence of visceral metastasis. (0.38, 0.54) < 0.0001 p-value is obtained from the one-sided log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis. Independent radiological review 11.0 (9.7, 15.0) 4.1 (2.9, 5.6) 0.38 (0.3, 0.5) < 0.0001 Best overall response (%, 95% CI) Objective response rate (ORR) Objective response rate = proportion of patients with CR or PR. 12.6% (9.8, 15.9) 1.7% (0.5, 4.2) n/a Not applicable. Figure 1: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in Hormone Receptor-Positive, HER-2 Negative Breast Cancer in BOLERO-2 Figure 1 14.2 Neuroendocrine Tumors (NET) Pancreatic Neuroendocrine Tumors (PNET) A randomized, double-blind, multi-center trial (RADIANT-3, NCT00510068) of everolimus tablets in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes vs. no) and WHO performance status (0 vs. 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The major efficacy outcome was PFS evaluated by RECIST. After documented radiological progression, patients randomized to placebo could receive open-label everolimus tablets. Other outcome measures included ORR, response duration, and OS. Patients were randomized 1:1 to receive either everolimus tablets 10 mg once daily (n = 207) or placebo (n = 203). Demographics were well balanced (median age 58 years, 55% male, 79% White). Of the 203 patients randomized to BSC, 172 patients (85%) received everolimus tablets following documented radiologic progression. The trial demonstrated a statistically significant improvement in PFS (Table 21 and Figure 2). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use. The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 21. Table 21: Progression-Free Survival Results in PNET in RADIANT-3 Analysis N Everolimus Tablets N = 207 Placebo N = 203 Hazard Ratio (95% CI) p-value 410 Median progression-free survival (months) (95% CI) Investigator radiological review 11.0 (8.4, 13.9) 4.6 (3.1, 5.4) 0.35 (0.27, 0.45) < 0.001 Central radiological review 13.7 (11.2, 18.8) 5.7 (5.4, 8.3) 0.38 (0.28, 0.51) < 0.001 Adjudicated radiological review Includes adjudication for discrepant assessments between investigator radiological review and central radiological review. 11.4 (10.8, 14.8) 5.4 (4.3, 5.6) 0.34 (0.26, 0.44) < 0.001 Figure 2: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in PNET in RADIANT-3 Investigator-determined response rate was 4.8% in the everolimus tablets arm and there were no complete responses. Overall Survival (OS) was not statistically significantly different between arms [HR = 0.94 (95% CI 0.73, 1.20); p = 0.30]. Figure 2 NET of Gastrointestinal (GI) or Lung Origin A randomized, double-blind, multicenter study (RADIANT-4, NCT01524783) of everolimus tablets in combination with BSC compared to placebo in combination with BSC was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional NET of GI (excluding pancreatic) or lung origin. The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization. Patients were randomized 2:1 to receive either everolimus tablets 10 mg once daily or placebo, and stratified by prior somatostatin analog use (yes vs. no), tumor origin and WHO performance status (0 vs. 1). The major efficacy outcome measure was PFS based on independent radiological assessment evaluated by RECIST. Additional efficacy outcome measures were OS and ORR. A total of 302 patients were randomized, 205 to the everolimus tablets arm and 97 to the placebo arm. The median age was 63 years (22 to 86 years); 47% were male; 76% were White; 74% had WHO performance status of 0 and 26% had WHO performance status of 1. The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%). The study demonstrated a statistically significant improvement in PFS per independent radiological review (Table 22 and Figure 3). The final OS analysis did not show a statistically significant difference between those patients who received everolimus tablets or placebo (HR = 0.90 [95% CI: 0.66, 1.24]). Table 22: Progression-Free Survival in Neuroendocrine Tumors of Gastrointestinal or Lung Origin in RADIANT-4 EVEROLIMUS TABLETS N = 205 Placebo N = 97 Progression-Free Survival Number of Events 113 (55%) 65 (67%) Progressive Disease 104 (51%) 60 (62%) Death 9 (4%) 5 (5%) Median PFS in months (95% CI) 11.0 (9.2, 13.3) 3.9 (3.6, 7.4) Hazard Ratio (95% CI) Hazard ratio is obtained from the stratified Cox model. 0.48 (0.35,0.67) p-value p-value is obtained from the stratified log-rank test. < 0.001 Overall Response Rate 2% 1% Figure 3: Kaplan-Meier Curves for Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4 Figure 3 Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors The safety and effectiveness of everolimus tablets in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multi-center trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, everolimus tablets in combination with long-acting octreotide (Sandostatin LAR ® ) was compared to placebo in combination with long-acting octreotide. After documented radiological progression, patients on the placebo arm could receive everolimus tablets; of those randomized to placebo, 67% received open-label everolimus tablets in combination with long-acting octreotide. The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm. 14.3 Renal Cell Carcinoma (RCC) An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing everolimus tablets 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy. The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review. After documented radiological progression, patients randomized to placebo could receive open-label everolimus tablets. Other outcome measures included OS. In total, 416 patients were randomized 2:1 to receive everolimus tablets (n = 277) or placebo (n = 139). Demographics were well balanced between the arms (median age 61 years; 77% male, 88% White, 74% received prior sunitinib or sorafenib, and 26% received both sequentially). Everolimus tablets were superior to placebo for PFS (Table 23 and Figure 4). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield a hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label everolimus tablets occurred in 80% of the 139 patients and may have confounded the OS benefit. Table 23: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1 Everolimus Tablets N = 277 Placebo N = 139 Hazard Ratio (95% CI) p-value Log-rank test stratified by prognostic score. Median Progression-free Survival (95% CI) 4.9 months (4.0, 5.5) 1.9 months (1.8, 1.9) 0.33 (0.25, 0.43) <0.0001 Objective Response Rate 2% 0% n/a Not applicable. n/a Figure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1 Figure 4 14.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of everolimus tablets was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received everolimus tablets 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no). Of the 118 patients enrolled, 79 were randomized to everolimus tablets and 39 to placebo. The median age was 31 years (18 to 61 years), 34% were male, and 89% were White. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm 3 (9 to 1612 cm 3 ) and 120 cm 3 (3 to 4520 cm 3 ) in the everolimus tablets and placebo arms, respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 mo nths) at the time of the primary analysis. The renal angiomyolipoma response rate was statistically significantly higher in everolimus tablets-treated patients (Table 24). The median response duration was 5.3+ months (2.3+ to 19.6+ months). There were 3 patients in the everolimus tablets arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the everolimus tablets arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001). Table 24: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus Tablets N = 79 Placebo N = 39 p-value Primary Analysis Angiomyolipoma response rate Per independent central radiology review - (%) 41.8 0 < 0.0001 95% CI (30.8, 53.4) (0.0, 9.0) Skin lesion response rates were assessed by local investigators for 77 patients in the everolimus tablets arm and 37 patients in the placebo arm who presented with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the everolimus tablets arm (26% vs. 0, p = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least 8 weeks (Physician's Global Assessment of Clinical Condition). Patients randomized to placebo were permitted to receive everolimus tablets at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with everolimus tablets underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 112 patients (79 randomized to everolimus tablets and 33 randomized to placebo) received at least one dose of everolimus tablets. The median duration of everolimus tablets treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years). During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months). Fourteen percent of the 112 patients treated with everolimus tablets had angiomyolipoma progression by the end of the follow-up period. No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with everolimus tablets. 14.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) EXIST-1 A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of everolimus tablets was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received everolimus tablets at a starting dose of 4.5 mg/m 2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. Everolimus tablets or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter. The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no). Of the 117 patients enrolled, 78 were randomized to everolimus tablets and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were White. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm 3 (0.18 to 25.15 cm 3 ) and 1.30 cm 3 (0.32 to 9.75 cm 3 ) in the everolimus tablets and placebo arms, respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis. The SEGA response rate was statistically significantly higher in everolimus tablets-treated patients (Table 25). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months). With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive everolimus tablets. No patient in either treatment arm required surgical intervention. Table 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1 Everolimus Tablets N = 78 Placebo N = 39 p-value Primary Analysis SEGA response rate Per independent central radiology review – (%) 35 0 < 0.0001 95% CI 24, 46 0, 9 Patients randomized to placebo were permitted to receive everolimus tablets at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with everolimus tablets underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to everolimus tablets and 33 patients randomized to placebo) received at least one dose of everolimus tablets. Median duration of everolimus tablets treatment and follow-up was 3.9 years (0.2 to 4.9 years). By four years after the last patient was enrolled, 58% of the 111 patients treated with everolimus tablets had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with everolimus tablets had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study. Study 2485 Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of everolimus tablets 3 mg/m 2 /orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study. A total of 28 patients received everolimus tablets for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on everolimus tablets for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% White. At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years). By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on everolimus tablets. Nine additional patients were identified as having a ≥50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating everolimus tablets, including 3 patients who had surgical resection with subsequent regrowth prior to receiving everolimus tablets.

15. REFERENCES OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

8.5 Geriatric Use In BOLERO-2, 40% of patients with breast cancer treated with everolimus tablets were ≥ 65 years of age, while 15% were ≥ 75 years of age. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last everolimus tablets dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. In RECORD-1, 41% of patients with renal cell carcinoma treated with everolimus tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with everolimus tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus tablets have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of everolimus tablets for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.5) ] . The safety and effectiveness of everolimus tablets have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 everolimus tablets-treated patients < 6 years had at least one infection compared to 67% of 55 everolimus tablets-treated patients ≥ 6 years. Thirty-five percent of 23 everolimus tablets-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 everolimus tablets-treated patients ≥ 6 years. Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, everolimus tablets did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with everolimus tablets for a median duration of 4.1 years. Other Indications The safety and effectiveness of everolimus tablets in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer Neuroendocrine tumors (NET) Renal cell carcinoma (RCC) TSC-associated renal angiomyolipoma

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , everolimus tablets can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus tablets use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of everolimus tablets 10 mg orally once daily (see Data ) . Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of everolimus tablets 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of everolimus tablets 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), based on BSA. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m 2 ), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

8. USE IN SPECIFIC POPULATIONS For breast cancer, NET, RCC, or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. ( 2.10 , 8.6 ) For patients with TSC-associated SEGA and severe hepatic impairment, reduce the starting dose and adjust dose to attain target trough concentrations. ( 2.8 , 2.10 , 8.6 ) 8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , everolimus tablets can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus tablets use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of everolimus tablets 10 mg orally once daily (see Data ) . Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of everolimus tablets 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of everolimus tablets 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), based on BSA. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m 2 ), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. 8.2 Lactation Risk Summary There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with everolimus tablets and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting everolimus tablets [see Use in Specific Populations(8.1) ]. Contraception Everolimus tablets can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ]. Females: Advise female patients of reproductive potential to use effective contraception during treatment with everolimus tablets and for 8 weeks after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with everolimus tablets and for 4 weeks after the last dose. Infertility Females: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking everolimus tablets. Based on these findings, everolimus tablets may impair fertility in female patients [see Adverse Reactions (6.1) , Nonclinical Toxicology (13.1) ]. Males: Cases of reversible azoospermia have been reported in male patients taking everolimus tablets. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of everolimus tablets 10 mg orally once daily. Based on these findings, everolimus tablets may impair fertility in male patients [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus tablets have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of everolimus tablets for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.5) ] . The safety and effectiveness of everolimus tablets have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 everolimus tablets-treated patients < 6 years had at least one infection compared to 67% of 55 everolimus tablets-treated patients ≥ 6 years. Thirty-five percent of 23 everolimus tablets-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 everolimus tablets-treated patients ≥ 6 years. Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, everolimus tablets did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with everolimus tablets for a median duration of 4.1 years. Other Indications The safety and effectiveness of everolimus tablets in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer Neuroendocrine tumors (NET) Renal cell carcinoma (RCC) TSC-associated renal angiomyolipoma 8.5 Geriatric Use In BOLERO-2, 40% of patients with breast cancer treated with everolimus tablets were ≥ 65 years of age, while 15% were ≥ 75 years of age. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last everolimus tablets dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. In RECORD-1, 41% of patients with renal cell carcinoma treated with everolimus tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with everolimus tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients. 8.6 Hepatic Impairment Everolimus tablets exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3) ]. For patients with breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the everolimus tablets dose as recommended [see Dosage and Administration (2.10) ]. For patients with TSC-associated SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of everolimus tablets as recommended and adjust the dose based on everolimus trough concentrations [see Dosage and Administration (2.8 , 2.10) ].

16. HOW SUPPLIED/STORAGE AND HANDLING Everolimus Tablets 2.5 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '2.5' on the other side; available in: Bottles of 30 tablets NDC 51991-821-33 Blisters of 28 tablets NDC 51991-821-28 (51991-821-99) Each carton contains 4 blister cards of 7 tablets each 5 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '5' on the other side; available in: Bottles of 30 tablets NDC 51991-822-33 Blisters of 28 tablets NDC 51991-822-28 (51991-822-99) Each carton contains 4 blister cards of 7 tablets each 7.5 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '7.5' on the other side; available in: Bottles of 30 tablets NDC 51991-823-33 Blisters of 28 tablets NDC 51991-823-28 (51991-823-99) Each carton contains 4 blister cards of 7 tablets each 10 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and 'NAT' on the other side; available in: Bottles of 30 tablets NDC 51991-824-33 Blisters of 28 tablets NDC 51991-824-28 (51991-824-99) Each carton contains 4 blister cards of 7 tablets each Store Everolimus Tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture. Follow special handling and disposal procedures for anti-cancer pharmaceuticals. 1

Store Everolimus Tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture. Follow special handling and disposal procedures for anti-cancer pharmaceuticals. 1