EVEROLIMUS

5 WARNINGS AND PRECAUTIONS Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. ( 2.9 , 5.1 ) Infections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. ( 2.9 , 5.2 ) Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. ( 5.3 ) Angioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. ( 5.4 , 7.2 ) Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. ( 5.5 , 6.1 ) Renal Failure: Monitor renal function prior to treatment and periodically thereafter. ( 5.6 ) Risk of Impaired Wound Healing: Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established. ( 5.7 ) Geriatric Patients: Monitor and adjust dose for adverse reactions. ( 5.8 ) Metabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity ( 2.9 , 5.9 ) Myelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.10 ) Risk of Infection or Reduced Immune Response with Vaccination: Avoid live vaccines and close contact with those who have received live vaccines. Complete recommended childhood vaccinations prior to starting treatment. ( 5.11 ) Radiation Sensitization and Radiation Recall: Severe radiation reactions may occur. ( 5.12 , 6.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 ) 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with everolimus in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1) ] . Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Continue everolimus without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue everolimus based on severity [see Dosage and Administration (2.9) ] . Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose. 5.2 Infections Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1) ] . Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4) ] . Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue everolimus based on severity of infection [see Dosage and Administration (2.9) ] . Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. 5.3 Severe Hypersensitivity Reactions Hypersensitivity reactions to everolimus have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4) ] . The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue everolimus for the development of clinically significant hypersensitivity. 5.4 Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with everolimus may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus tablets with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue everolimus for angioedema. 5.5 Stomatitis Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions (6.1) ] . Stomatitis most often occurs within the first 8 weeks of treatment. When starting everolimus, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1) ] . If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed. 5.6 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking everolimus tablets. Elevations of serum creatinine and proteinuria have been reported in patients taking everolimus [see Adverse Reactions (6.1) ] . The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting everolimus and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure. 5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, everolimus have the potential to adversely affect wound healing. Withhold everolimus for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established. 5.8 Geriatric Patients In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), 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. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.9) , Use in Specific Populations (8.5) ] . 5.9 Metabolic Disorders Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking everolimus at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1) ] . In non-diabetic patients, monitor fasting serum glucose prior to starting everolimus and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting everolimus and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting everolimus. For Grade 3 to 4 metabolic events, withhold or permanently discontinue everolimus based on severity [see Dosage and Administration (2.9) ] . 5.10 Myelosuppression Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking everolimus. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1) ] . Monitor complete blood count (CBC) prior to starting everolimus every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue everolimus based on severity [see Dosage and Administration (2.9) ] . 5.11 Risk of Infection or Reduced Immune Response with Vaccination The safety of immunization with live vaccines during everolimus therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with everolimus. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. 5.12 Radiation Sensitization and Radiation Recall Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to everolimus treatment [ see Adverse Reactions (6.2) ]. Monitor patients closely when everolimus is administered during or sequentially with radiation treatment. 5.13 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action, everolimus can cause fetal harm when administered to a pregnant woman. 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 clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with everolimus and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with everolimus and for 4 weeks after the last dose [see Use in Specific Populations ( 8.1 , 8.3)] .

5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, everolimus have the potential to adversely affect wound healing. Withhold everolimus for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established.

5.12 Radiation Sensitization and Radiation Recall Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to everolimus treatment [ see Adverse Reactions (6.2) ]. Monitor patients closely when everolimus is administered during or sequentially with radiation treatment.

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: 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 NorthStar Rx LLC at 1-800-206-7821 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 Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. b Includes all reported infections including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. c Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. d No Grade 4 adverse reactions were reported Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Stomatitis a 67 8 d 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 d 13 0.4 Dry mouth 11 0 7 0 General Fatigue 36 4 27 1 d Edema Peripheral 19 1 d 6 0.4 d Pyrexia 15 0.2 d 7 0.4 d Asthenia 13 2 4 0 Infections Infections b 50 6 25 2 d Investigations Weight loss 25 1 d 6 0 Metabolism and nutrition Decreased appetite 30 1 d 12 0.4 d Hyperglycemia 14 5 2 0.4 d Musculoskeletal and connective tissue Arthralgia 20 0.8 d 17 0 Back pain 14 0.2 d 10 0.8 d Pain in extremity 9 0.4 d 11 2 d Nervous system Dysgeusia 22 0.2 d 6 0 Headache 21 0.4 d 14 0 Psychiatric Insomnia 13 0.2 d 8 0 Respiratory, thoracic and mediastinal Cough 24 0.6 d 12 0 Dyspnea 21 4 11 1 Epistaxis 17 0 1 0 Pneumonitis c 19 4 0.4 0 Skin and subcutaneous tissue Rash 39 1 d 6 0 Pruritus 13 0.2 d 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 Grading according to NCI CTCAE Version 3.0. a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. b No Grade 4 laboratory abnormalities were reported. Laboratory Parameter Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hematology a Anemia 68 6 40 1 Leukopenia 58 2 b 28 6 Thrombocytopenia 54 3 5 0.4 Lymphopenia 54 12 37 6 Neutropenia 31 2 b 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 b Hypertriglyceridemia 50 0.8 b 26 0 Hypoalbuminemia 33 0.8 b 16 0.8 b Hypokalemia 29 4 7 1 b 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/5mL 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 and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. 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 % Gastrointestinal Stomatitis a 78 6 b 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 Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. b No Grade 4 adverse reactions were reported. 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 % Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1 a 8 0 Thrombocytopenia 19 0 3 0 Chemistry Hypercholesterolemia 85 1 a 46 0 Hypertriglyceridemia 52 0 10 0 Hypophosphatemia 49 5 a 15 0 Increased alkaline phosphatase 32 1 a 10 0 Increased AST 23 1 a 8 0 Increased ALT 20 1 a 15 0 Hyperglycemia (fasting) 14 0 8 0 Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported. 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 % Gastrointestinal Stomatitis a 62 9 f 26 3 Vomiting 22 1 f 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection b 31 3 23 0 Gastroenteritis c 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 f 18 3 Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioural disturbance d 21 5 f 3 0 Skin and subcutaneous tissue Rash e 21 0 8 0 Acne 10 0 5 0 Grading according to NCI CTCAE Version 3.0. Grading according to NCI CTCAE Version 3.0. a Includes mouth ulceration, stomatitis, and lip ulceration. b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticarial. f No Grade 4 adverse reactions were reported. 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 % Hematology Elevated partial thromboplastin time 72 3 a 44 5 a Neutropenia 46 9 a 41 3 a 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 a 3 0 Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported. 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. 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

<table><caption>Table 6: Adverse Reactions Reported in &#x2265; 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2</caption><col width="100"/><col width="100"/><col width="100"/><col width="100"/><col width="100"/><tfoot><tr><td colspan="5" styleCode="Toprule">Grading according to NCI CTCAE Version 3.0. ^aIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. ^bIncludes all reported infections including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. ^cIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. ^dNo Grade 4 adverse reactions were reported</td></tr></tfoot><tbody><tr><td styleCode="Toprule"/><td align="center" colspan="2" styleCode="Toprule"><content styleCode="bold">Everolimus Tablets</content><content styleCode="bold"> with Exemestane</content> <content styleCode="bold">N = 482</content></td><td align="center" colspan="2" styleCode="Toprule"><content styleCode="bold">Placebo with Exemestane </content> <content styleCode="bold">N = 238</content></td></tr><tr><td/><td align="center"><content styleCode="bold">All Grades %</content></td><td align="center"><content styleCode="bold">Grade 3-4 %</content></td><td align="center"><content styleCode="bold">All Grades %</content></td><td align="center"><content styleCode="bold">Grade 3-4 %</content></td></tr><tr><td colspan="5" styleCode="Toprule"><content styleCode="bold">Gastrointestinal</content></td></tr><tr><td> Stomatitis^a</td><td align="center">67</td><td align="center">8^d</td><td align="center">11</td><td align="center">0.8</td></tr><tr><td> Diarrhea</td><td align="center">33</td><td align="center">2</td><td align="center">18</td><td align="center">0.8</td></tr><tr><td> Nausea</td><td align="center">29</td><td align="center">0.4</td><td align="center">28</td><td align="center">1</td></tr><tr><td> Vomiting</td><td align="center">17</td><td align="center">1</td><td align="center">12</td><td align="center">0.8</td></tr><tr><td> Constipation</td><td align="center">14</td><td align="center">0.4^d</td><td align="center">13</td><td align="center">0.4</td></tr><tr><td> Dry mouth</td><td align="center">11</td><td align="center">0</td><td align="center">7</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">General</content></td></tr><tr><td> Fatigue</td><td align="center">36</td><td align="center">4</td><td align="center">27</td><td align="center">1^d</td></tr><tr><td> Edema Peripheral</td><td align="center">19</td><td align="center">1^d</td><td align="center">6</td><td align="center">0.4^d</td></tr><tr><td> Pyrexia</td><td align="center">15</td><td align="center">0.2^d</td><td align="center">7</td><td align="center">0.4^d</td></tr><tr><td> Asthenia</td><td align="center">13</td><td align="center">2</td><td align="center">4</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Infections</content></td></tr><tr><td> Infections^b</td><td align="center">50</td><td align="center">6</td><td align="center">25</td><td align="center">2^d</td></tr><tr><td colspan="5"><content styleCode="bold">Investigations</content></td></tr><tr><td> Weight loss</td><td align="center">25</td><td align="center">1^d</td><td align="center">6</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Metabolism and nutrition</content></td></tr><tr><td> Decreased appetite</td><td align="center">30</td><td align="center">1^d</td><td align="center">12</td><td align="center">0.4^d</td></tr><tr><td> Hyperglycemia</td><td align="center">14</td><td align="center">5</td><td align="center">2</td><td align="center">0.4^d</td></tr><tr><td colspan="5"><content styleCode="bold">Musculoskeletal and connective tissue</content></td></tr><tr><td> Arthralgia</td><td align="center">20</td><td align="center">0.8^d</td><td align="center">17</td><td align="center">0</td></tr><tr><td> Back pain</td><td align="center">14</td><td align="center">0.2^d</td><td align="center">10</td><td align="center">0.8^d</td></tr><tr><td> Pain in extremity</td><td align="center">9</td><td align="center">0.4^d</td><td align="center">11</td><td align="center">2^d</td></tr><tr><td colspan="5"><content styleCode="bold">Nervous system</content></td></tr><tr><td> Dysgeusia</td><td align="center">22</td><td align="center">0.2^d</td><td align="center">6</td><td align="center">0</td></tr><tr><td> Headache</td><td align="center">21</td><td align="center">0.4^d</td><td align="center">14</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Psychiatric</content></td></tr><tr><td> Insomnia</td><td align="center">13</td><td align="center">0.2^d</td><td align="center">8</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Respiratory, thoracic and mediastinal</content></td></tr><tr><td> Cough</td><td align="center">24</td><td align="center">0.6^d</td><td align="center">12</td><td align="center">0</td></tr><tr><td> Dyspnea</td><td align="center">21</td><td align="center">4</td><td align="center">11</td><td align="center">1</td></tr><tr><td> Epistaxis</td><td align="center">17</td><td align="center">0</td><td align="center">1</td><td align="center">0</td></tr><tr><td> Pneumonitis^c</td><td align="center">19</td><td align="center">4</td><td align="center">0.4</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Skin and subcutaneous tissue</content></td></tr><tr><td> Rash</td><td align="center">39</td><td align="center">1^d</td><td align="center">6</td><td align="center">0</td></tr><tr><td> Pruritus</td><td align="center">13</td><td align="center">0.2^d</td><td align="center">5</td><td align="center">0</td></tr><tr><td> Alopecia</td><td align="center">10</td><td align="center">0</td><td align="center">5</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Vascular</content></td></tr><tr><td> Hot flush</td><td align="center">6</td><td align="center">0</td><td align="center">14</td><td align="center">0</td></tr></tbody></table>

<table><caption>Table 7: Selected Laboratory Abnormalities Reported in &#x2265; 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2</caption><col width="100"/><col width="100"/><col width="100"/><col width="100"/><col width="100"/><tfoot><tr><td colspan="5" styleCode="Toprule">Grading according to NCI CTCAE Version 3.0. ^aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. ^bNo Grade 4 laboratory abnormalities were reported.</td></tr></tfoot><tbody><tr><td styleCode="Toprule"><content styleCode="bold">Laboratory Parameter</content></td><td align="center" colspan="2" styleCode="Toprule"><content styleCode="bold">Everolimus Tablets</content><content styleCode="bold"> with Exemestane</content> <content styleCode="bold">N = 482</content></td><td align="center" colspan="2" styleCode="Toprule"><content styleCode="bold">Placebo with Exemestane </content> <content styleCode="bold">N = 238</content></td></tr><tr><td/><td align="center"><content styleCode="bold">All Grades %</content></td><td align="center"><content styleCode="bold">Grade 3-4 %</content></td><td align="center"><content styleCode="bold">All Grades %</content></td><td align="center"><content styleCode="bold">Grade 3-4 %</content></td></tr><tr><td colspan="5" styleCode="Toprule"><content styleCode="bold">Hematology^a</content></td></tr><tr><td> Anemia</td><td align="center">68</td><td align="center">6</td><td align="center">40</td><td align="center">1</td></tr><tr><td> Leukopenia</td><td align="center">58</td><td align="center">2^b</td><td align="center">28</td><td align="center">6</td></tr><tr><td> Thrombocytopenia</td><td align="center">54</td><td align="center">3</td><td align="center">5</td><td align="center">0.4</td></tr><tr><td> Lymphopenia</td><td align="center">54</td><td align="center">12</td><td align="center">37</td><td align="center">6</td></tr><tr><td> Neutropenia</td><td align="center">31</td><td align="center">2^b</td><td align="center">11</td><td align="center">2</td></tr><tr><td colspan="5"><content styleCode="bold">Chemistry</content></td></tr><tr><td> Hypercholesterolemia</td><td align="center">70</td><td align="center">1</td><td align="center">38</td><td align="center">2</td></tr><tr><td> Hyperglycemia</td><td align="center">69</td><td align="center">9</td><td align="center">44</td><td align="center">1</td></tr><tr><td> Increased AST</td><td align="center">69</td><td align="center">4</td><td align="center">45</td><td align="center">3</td></tr><tr><td> Increased ALT</td><td align="center">51</td><td align="center">4</td><td align="center">29</td><td align="center">5^b</td></tr><tr><td> Hypertriglyceridemia</td><td align="center">50</td><td align="center">0.8^b</td><td align="center">26</td><td align="center">0</td></tr><tr><td> Hypoalbuminemia</td><td align="center">33</td><td align="center">0.8^b</td><td align="center">16</td><td align="center">0.8^b</td></tr><tr><td> Hypokalemia</td><td align="center">29</td><td align="center">4</td><td align="center">7</td><td align="center">1^b</td></tr><tr><td> Increased creatinine </td><td align="center">24</td><td align="center">2</td><td align="center">13</td><td align="center">0</td></tr></tbody></table>

<table><col/><col/><col/><col/><col/><tbody><tr><td/><td colspan="2"><content styleCode="bold">Everolimus tablets N = 79</content></td><td colspan="2"><content styleCode="bold">Placebo N = 39</content></td></tr><tr><td/><td valign="middle"><content styleCode="bold">All Grades %</content></td><td valign="middle"><content styleCode="bold">Grade 3-4 %</content></td><td valign="middle"><content styleCode="bold">All Grades %</content></td><td valign="middle"><content styleCode="bold">Grade 3-4 %</content></td></tr><tr><td><content styleCode="bold">Gastrointestinal</content></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td> Stomatitis^a</td><td valign="middle">78</td><td valign="middle">6^b</td><td valign="middle">23</td><td valign="middle">0</td></tr><tr><td>Vomiting </td><td valign="middle">15</td><td valign="middle">0</td><td valign="middle">5</td><td valign="middle">0</td></tr><tr><td>Diarrhea</td><td valign="middle">14</td><td valign="middle">0</td><td valign="middle">5</td><td valign="middle">0</td></tr><tr><td><content styleCode="bold">General</content></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td>Peripheral Edema</td><td valign="middle">13</td><td valign="middle">0</td><td valign="middle">8</td><td valign="middle">0</td></tr><tr><td><content styleCode="bold">Infections</content></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td>Upper respiratory tract infection</td><td valign="middle">11</td><td valign="middle">0</td><td valign="middle">5</td><td valign="middle">0</td></tr><tr><td><content styleCode="bold">Musculoskeletal and connective tissue</content></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td>Arthralgia</td><td valign="middle">13</td><td valign="middle">0</td><td valign="middle">5</td><td valign="middle">0</td></tr><tr><td><content styleCode="bold">Respiratory, thoracic and mediastinal</content></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td>Cough</td><td valign="middle">20</td><td valign="middle">0</td><td valign="middle">13</td><td valign="middle">0</td></tr><tr><td><content styleCode="bold">Skin and subcutaneous tissue</content></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td>Acne</td><td valign="middle">22</td><td valign="middle">0</td><td valign="middle">5</td><td valign="middle">0</td></tr><tr><td colspan="5"><paragraph>Grading according to NCI CTCAE Version 3.0.</paragraph><paragraph>^aIncludes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.</paragraph><paragraph>^bNo Grade 4 adverse reactions were reported.</paragraph></td></tr></tbody></table>