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, 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 renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

( 1.4 ) Everolimus tablets are a kinase inhibitor 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, 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) ].

1.4 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.

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: 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 Novugen Pharma (USA) LLC at 1-888-966-8843 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 (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 years 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 to Grade 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 to Grade 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.

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

Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus vs.

placebo are presented in Table 6.

Laboratory abnormalities are presented in Table 7.

The median duration of treatment with everolimus was 23.9 weeks; 33% were exposed to everolimus 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 with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 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.

Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Laboratory Parameter Everolimus with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 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.

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 (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 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 Grade 4 stomatitis within 8 weeks.

The incidence of Grade 2 to Grade 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 Grade 4 stomatitis were reported.

Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.

Co-administration of everolimus and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin In a randomized, controlled trial (RADIANT-4) of everolimus (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 years to 86 years), 76% were white, and 53% were female.

The median duration of exposure to everolimus was 9.3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months.

Everolimus was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of everolimus-treated patients.

Serious adverse reactions occurred in 42% of everolimus-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-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4 Everolimus N = 202 Placebo N = 98 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 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.

Table 11: Selected Laboratory Abnormalities in ≥ 10% of Everolimus-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4 Everolimus N = 202 Placebo N = 98 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 Grading according to NCI CTCAE Version 4.03.

a No Grade 4 laboratory abnormalities were reported.

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 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 years to 61 years), 89% were white, and 34% were male.

The median duration of blinded study treatment was 48 weeks (2 weeks to 115 weeks) for patients receiving everolimus.

The most common adverse reaction reported for everolimus (incidence ≥ 30%) was stomatitis.

The most common Grade 3 to Grade 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 to Grade 4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia.

The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the everolimus-treated patients.

Adverse reactions leading to permanent discontinuation in the everolimus arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia.

Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of everolimus-treated patients.

The most common adverse reaction leading to everolimus dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus and occurring more frequently with everolimus than with placebo are presented in Table 14.

Laboratory abnormalities are presented in Table 15.

Table 14: Adverse Reactions Reported in ≥ 10% of Everolimus-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus N = 79 Placebo N = 39 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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-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-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-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus N = 79 Placebo N = 39 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 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 in 117 patients with SEGA and TSC.

The median age of patients was 9.5 years (0.8 years to 26 years), 93% were white, and 57% were male.

The median duration of blinded study treatment was 52 weeks (24 weeks to 89 weeks) for patients receiving everolimus.

The most common adverse reactions reported for everolimus (incidence ≥ 30%) were stomatitis and respiratory tract infection.

The most common Grade 3 to Grade 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 to Grade 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-treated patients.

The most common adverse reaction leading to everolimus dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus and occurring more frequently with everolimus than with placebo are reported in Table 16.

Laboratory abnormalities are presented in Table 17.

Table 16: Adverse Reactions Reported in ≥ 10% of Everolimus-Treated Patients With TSC-Associated SEGA in EXIST-1 Everolimus N = 78 Placebo N = 39 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 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.

Amenorrhea occurred in 17% of everolimus-treated females aged 10 years to 55 years (3 of 18).

For this same group of everolimus-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-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-Treated Patients With TSC-Associated SEGA in EXIST-1 Everolimus N = 78 Placebo N = 39 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 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 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 postapproval 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