Afinitor Disperz Drug Information

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 AFINITOR (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 AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm.

Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR 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.

AFINITOR 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

Diarrhea 33 2 18 0.8 Nausea 29 0.4 28 1 Vomiting 17

1 12

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 AFINITOR 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

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 AFINITOR (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 AFINITOR 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR (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 AFINITOR 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 AFINITOR. Causes of death on the AFINITOR 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 AFINITOR, 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 AFINITOR group.

Dose delay or reduction was necessary in 61% of AFINITOR patients. Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received AFINITOR was 37 weeks. In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females.

Table 8: Adverse Reactions Reported in ≥ 10% of Patients With PNET in RADIANT-3 Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. b Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. c Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. d No Grade 4 adverse reactions were reported. AFINITOR N = 204 Placebo N = 203 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis a 70 7 d 20 0 Diarrhea b 50 6 25 3 d Abdominal pain 36 4 d 32 7 Nausea 32 2 d 33 2 d Vomiting 29 1 d 21 2 d Constipation 14 0 13 0.5 d Dry mouth 11 0 4 0 General Fatigue/malaise 45 4 27 3 Edema (general and peripheral) 39 2 12 1 d Fever 31 1 13 0.5 d Asthenia 19 3 d 20 3 d Infections Nasopharyngitis/rhinitis/URI 25 0 13 0 Urinary tract infection 16 0 6 0.5 d Investigations Weight loss 28 0.5 d 11 0 Metabolism and nutrition Decreased appetite 30 1 d 18 1 d Diabetes mellitus 10 2 d 0.5 0 Musculoskeletal and connective tissue Arthralgia 15 1 7 0.5 d Back pain 15 1 d 11 1 d Pain in extremity 14 0.5 d 6 1 d Muscle spasms 10 0 4 0 Nervous system Headache/migraine 30 0.5 d 15 1 d Dysgeusia 19 0 5 0 Dizziness 12 0.5 d 7 0 Psychiatric Insomnia 14 0 8 0 Respiratory, thoracic and mediastinal Cough/productive cough 25 0.5 d 13 0 Epistaxis 22 0 1 0 Dyspnea/dyspnea exertional 20 3 7 0.5 d Pneumonitis c 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 d Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With PNET in RADIANT-3 Grading according to NCI CTCAE Version 3.0. Laboratory parameter AFINITOR N = 204 Placebo N = 203 All Grades Grade 3-4 All Grades Grade 3-4 % % % % 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

Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin

In a randomized, controlled trial (RADIANT-4) of AFINITOR (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 AFINITOR was 9.3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months. AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients.

Serious adverse reactions occurred in 42% of AFINITOR-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 AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4 Grading according to NCI CTCAE Version 4.03. a Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation. b Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis. c Includes pneumonitis and interstitial lung disease. d No Grade 4 adverse reactions were reported. AFINITOR N = 202 Placebo N = 98 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis a 63 9 d 22 0 Diarrhea 41 9 31 2 d Nausea 26 3 17 1 d Vomiting 15 4 d 12 2 d General Peripheral edema 39 3 d 6 1 d Fatigue 37 5 36 1 d Asthenia 23 3 8 0 Pyrexia 23 2 8 0 Infections Infections b 58 11 29 2 Investigations Weight loss 22 2 d 11 1 d Metabolism and nutrition Decreased appetite 22 1 d 17 1 d Nervous system Dysgeusia 18 1 d 4 0 Respiratory, thoracic and mediastinal Cough 27 0 20 0 Dyspnea 20 3 d 11 2 Pneumonitis c 16 2 d 2 0 Epistaxis 13 1 d 3 0 Skin and subcutaneous Rash 30 1 d 9 0 Pruritus 17 1 d 9 0 Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4 Grading according to NCI CTCAE Version 4.03. a No Grade 4 laboratory abnormalities were reported. AFINITOR N = 202 Placebo N = 98 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Anemia 81 5 a 41 2 a Lymphopenia 66 16 32 2 a Leukopenia 49 2 a 17 0 Thrombocytopenia 33 2 11 0 Neutropenia 32 2 a 15 3 a Chemistry Hypercholesterolemia 71 0 37 0 Increased AST 57 2 34 2 a Hyperglycemia (fasting) 55 6 a 36 1 a Increased ALT 46 5 39 1 a Hypophosphatemia 43 4 a 15 2 a Hypertriglyceridemia 30 3 8 1 a Hypokalemia 27 6 12 3 a Hypoalbuminemia 18 0 8 0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to AFINITOR (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 AFINITOR. 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 AFINITOR arm.

The rate of adverse reactions resulting in permanent discontinuation was 14% for the AFINITOR 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 AFINITOR treatment were for infections, anemia, and stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 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 AFINITOR Arm than in the Placebo Arm in RECORD-1 Grading according to NCI CTCAE Version 3.0. a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all reported infections, including but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. d No Grade 4 adverse reactions were reported. AFINITOR N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis a 44 4 8 0 Diarrhea 30 2 d 7 0 Nausea 26 2 d 19 0 Vomiting 20 2 d 12 0 Infections b 37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6 d 27 4 Edema peripheral 25 < 1 d 8 < 1 d Pyrexia 20 < 1 d 9 0 Mucosal inflammation 19 2 d 1 0 Respiratory, thoracic and mediastinal Cough 30 < 1 d 16 0 Dyspnea 24 8 15 3 d Epistaxis 18 0 0 0 Pneumonitis c 14 4 d 0 0 Skin and subcutaneous tissue Rash 29 1 d 7 0 Pruritus 14 < 1 d 7 0 Dry skin 13 < 1 d 5 0 Metabolism and nutrition Anorexia 25 2 d 14 < 1 d Nervous system Headache 19 1 9 < 1 d Dysgeusia 10 0 2 0 Musculoskeletal and connective tissue Pain in extremity 10 1 d 7 0 Other notable adverse reactions occurring more frequently with AFINITOR 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 AFINITOR Arm Than the Placebo Arm in RECORD-1 Grading according to NCI CTCAE Version 3.0. a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. b No Grade 4 laboratory abnormalities were reported.

Laboratory parameter AFINITOR N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology a Anemia 92 13 79 6 Lymphopenia 51 18 28 5 b Thrombocytopenia 23 1 b 2 < 1 Neutropenia 14 < 1 4 0 Chemistry Hypercholesterolemia 77 4 b 35 0 Hypertriglyceridemia 73 < 1 b 34 0 Hyperglycemia 57 16 25 2 b Increased creatinine 50 2 b 34 0 Hypophosphatemia 37 6 b 8 0 Increased AST 25 1 7 0 Increased ALT 21 1 b 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 AFINITOR 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 AFINITOR. The most common adverse reaction reported for AFINITOR (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 AFINITOR-treated patients.

Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15. Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 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. AFINITOR 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 Amenorrhea occurred in 15% of AFINITOR-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 AFINITOR-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 AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported. AFINITOR 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 Updated safety information from 112 patients treated with AFINITOR 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 AFINITOR 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 AFINITOR. The most common adverse reactions reported for AFINITOR (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 AFINITOR-treated patients.

The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17. Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 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 urticaria. f No Grade 4 adverse reactions were reported. AFINITOR N = 78 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis a 62 9 f 26 3 f 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 f Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance d 21 5 f 3 0 Skin and subcutaneous tissue Rash e 21 0 8 0 Acne 10 0 5 0 Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-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 AFINITOR-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 AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported.

AFINITOR 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 Updated safety information from 111 patients treated with AFINITOR 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%). TSC-Associated Partial-Onset Seizures The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to AFINITOR DISPERZ low trough (LT) (n = 117), AFINITOR DISPERZ high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were white, and 52% were male. Patients received between one and three concomitant antiepileptic drugs.

The most common adverse reaction reported for AFINITOR DISPERZ in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia.

The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia. Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis.

Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 18. Laboratory abnormalities are presented in Table 19. Table 18: Adverse Reactions Reported in ≥ 10% of AFINITOR DISPERZ-Treated Patients With TSC-Associated Partial-Onset Seizures in EXIST-3 Grading according to NCI CTCAE Version 4.03. a Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. b No Grade 4 adverse reactions were reported.

AFINITOR DISPERZ Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N = 119 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Stomatitis a 55 3 b 64 4 b 9 0 Diarrhea 17 0 22 0 5 0 Vomiting 12 0 10 2 b 9 0 Infections Nasopharyngitis 14 0 16 0 16 0 Upper respiratory tract infection 13 0 15 0 13 0.8 b General Pyrexia 20 0 14 0.8 b 5 0 Respiratory, thoracic and mediastinal Cough 11 0 10 0 3 0 Skin and subcutaneous tissue Rash 6 0 10 0 3 0 The following additional adverse reactions occurred in < 10% of AFINITOR DISPERZ treated patients (% AFINITOR DISPERZ LT, % AFINITOR DISPERZ HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%). Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients With TSC-Associated Partial-Onset Seizures Grading according to NCI CTCAE version 4.03. a No Grade 4 laboratory abnormalities were reported. AFINITOR DISPERZ Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N = 119 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hematology Neutropenia 25 4 a 37 6 23 7 a Anemia 27 0.9 a 30 0 21 0.8 a Thrombocytopenia 12 0 15 0 6 0 Chemistry Hypercholesterolemia 86 0 85 0.8 a 58 0 Hypertriglyceridemia 43 2 a 39 2 22 0 Increased ALT 17 0 22 0 6 0 Increased AST 13 0 19 0 4 0 Hyperglycemia 19 0 18 0 17 0 Increased alkaline phosphatase 24 0 16 0 29 0 Hypophosphatemia 9 0.9 a 16 2 3 0 Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AFINITOR/AFINITOR DISPERZ. 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

Effect of Other Drugs on

AFINITOR/AFINITOR DISPERZ Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors . Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended . Inducers Increase the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended .

Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors Patients taking

concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ .

Pregnancy Risk Summary Based on animal studies and the mechanism of action , AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR 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 AFINITOR 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 AFINITOR 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 AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures 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.

Pediatric Use TSC-Associated SEGA The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 . The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years.

Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-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, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years. TSC-Associated Partial-Onset Seizures The safety and effectiveness of AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

Use of AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients . The safety and effectiveness of AFINITOR DISPERZ and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures. The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 AFINITOR DISPERZ-treated patients < 6 years had at least one infection, compared to 53% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years.

Sixteen percent of 70 AFINITOR DISPERZ-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients. Other Indications The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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

AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives . Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.