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FDA Drug information

Everolimus

Read time: 7 mins
Marketing start date: 21 Jul 2024

Summary of product characteristics


Adverse Reactions

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, PNET, RCC: Most common adverse reactions (incidence ≥30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. ( 6.1 ) · TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) · TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceuticalat 1-800-828-9393 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) versus 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 (range 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. 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 versus 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 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 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 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 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 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 Tablets and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. Pancreatic Neuroendocrine Tumors (PNET) In a randomized, controlled trial (RADIANT-3) of Everolimus Tablets (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male. Patients on the placebo arm could cross over to open-label Everolimus Tablets upon disease progression. The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia. Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on Everolimus Tablets. Causes of death on the Everolimus Tablets arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label Everolimus Tablets, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the Everolimus Tablets group. Dose delay or reduction was necessary in 61% of Everolimus Tablets patients. Grade 3-4 renal failure occurred in six patients in the Everolimus Tablets arm. Thrombotic events included five patients with pulmonary embolus in the Everolimus Tablets arm as well as three patients with thrombosis in the Everolimus Tablets arm. Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus Tablets vs. placebo. Laboratory abnormalities are summarized in Table 9 . The median duration of treatment in patients who received Everolimus Tablets was 37 weeks. In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) Everolimus Tablets -treated females. Table 8: Adverse Reactions Reported in ≥ 10% of Patients with PNET in RADIANT-3 Everolimus Tablets N = 204 Placebo N = 203 All Grades % Grade 3-4 % All Grades % Grade 3-4 % 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 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. Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with PNET in RADIANT-3 Laboratory parameter Everolimus Tablets N=204 Placebo N=203 All grades Grade 3-4 All grades Grade 3-4 % % % % Hematology Anemia 86 15 63 1 Lymphopenia 45 16 22 4 Thrombocytopenia 45 3 11 0 Leukopenia 43 2 13 0 Neutropenia 30 4 17 2 Chemistry Hyperglycemia (fasting) 75 17 53 6 Increased alkaline phosphatase 74 8 66 8 Hypercholesterolemia 66 0.5 22 0 Bicarbonate decreased 56 0 40 0 Increased AST 56 4 41 4 Increased ALT 48 2 35 2 Hypophosphatemia 40 10 14 3 Hypertriglyceridemia 39 0 10 0 Hypocalcemia 37 0.5 12 0 Hypokalemia 23 4 5 0 Increased creatinine 19 2 14 0 Hyponatremia 16 1 16 1 Hypoalbuminemia 13 1 8 0 Hyperbilirubinemia 10 1 14 2 Hyperkalemia 7 0 10 0.5 Grading according to NCI CTCAE Version 3.0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to Everolimus Tablets (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving Everolimus Tablets. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Everolimus Tablets arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the Everolimus Tablets group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during Everolimus Tablets treatment were for infections, anemia, and stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus Tablets versus 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 Everolimus Tablets Arm than in the Placebo Arm in RECORD-1 Everolimus Tablets N = 274 Placebo N = 137 All Grades % Grade 3-4 % All Grades % Grade 3-4 % 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 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. Other notable adverse reactions occurring more frequently with Everolimus Tablets than with placebo, but with an incidence of < 10% include: Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%) Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (< 1%) Metabolism and nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%) Psychiatric: Insomnia (9%) Nervous system: Dizziness (7%), paresthesia (5%) Ocular: Eyelid edema (4%), conjunctivitis (2%) Vascular: Hypertension (4%), deep vein thrombosis (< 1%) Renal and urinary: Renal failure (3%) Cardiac: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue: Jaw pain (3%) Hematologic: Hemorrhage (3%) Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Everolimus Arm Than the Placebo Arm in RECORD-1 Laboratory parameter Everolimus Tablets N = 274 Placebo N = 137 All Grades % Grade 3-4 % All Grades % Grade3-4 % 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 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. 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-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-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-Treated Patients with TSC- Associated Renal Angiomyolipoma in EXIST-2 Everolimus Tablets N = 79 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade3-4 % 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 Tablets N = 79 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade3-4 % 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-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-Treated Patients with TSC-Associated SEGA in EXIST-1 Everolimus Tablets N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade3-4 % 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 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 Tablets N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade3-4 % 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 Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: Blood and lymphatic disorders: Thrombotic microangiopathy Cardiac: cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event Gastrointestinal: Acute pancreatitis Hepatobiliary: Cholecystitis and cholelithiasis Infections: Sepsis and septic shock Nervous System: Reflex sympathetic dystrophy Vascular: Arterial thrombotic events, lymphedema Injury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall

Contraindications

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

Description

11 DESCRIPTION Everolimus Tablets, are a kinase inhibitor. The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0 4,9 ]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C 53 H 83 NO 14 and the molecular weight is 958.2 g/mol. The structural formula is: Everolimus Tablets for oral administration contain 2.5 mg, 5 mg, 7.5 mg and 10 mg of everolimus and the following inactive ingredients: hypromellose, butylated hydroxytoluene, lactose anhydrous, crospovidone, colloidal silicon dioxide and magnesium stearate. structure

Dosage And Administration

2 DOSAGE AND ADMINISTRATION Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. ( 2.1 ) Breast Cancer: 10 mg orally once daily. ( 2.2 ) PNET: 10 mg orally once daily. ( 2.3 ) RCC: 10 mg orally once daily. ( 2.4 ) TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. ( 2.5 ) TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.6 , 2.8 ) 2.1 Important Dosage Information Everolimus Tablets are available in one dosage form: tablets (Everolimus Tablets) Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P­-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration ( 2.10 , 2.11 , 2.12 )] . 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of Everolimus Tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of Everolimus Tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of Everolimus Tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of Everolimus Tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of Everolimus Tablets is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration ( 2.8 )] . 2.8 Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Monitor everolimus whole blood trough concentrations at time points recommended in Table 1. Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. Adjust the dose using the following equation: New dose* = current dose x (target concentration divided by current concentration) *The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration. When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Initiation of Everolimus Tablets 1 to 2 weeks Modification of Everolimus Tablets dose 1 to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 to 6 months Stable dose with stable BSA Every 6 to 12 months Abbreviation: P-gp, P-glycoprotein 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of Everolimus Tablets for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis [see Warnings and Precautions ( 5.1 )] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Stomatitis [see Warnings and Precautions ( 5.5 )] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions ( 5.9 )] Grade 3 Withhold until improvement to Grade 0, 1 or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose. If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Thrombocytopenia [see Warnings and Precautions ( 5.10 )] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. Grade 3 OR Grade 4 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Neutropenia [see Warnings and Precautions ( 5.10 )] Grade 3 Withhold until improvement to Grade 0, 1 or 2. Resume at same dose. Grade 4 Withhold until improvement to Grade 0, 1 or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Febrile neutropenia [see Warnings and Precautions ( 5.10 )] Grade 3 Withhold until improvement to Grade 0, 1 or 2 and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. 2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of Everolimus Tablets for patients with hepatic impairment are described in Table 3 [ see Use in Specific Populations ( 8.6 )] : Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Indication Dose Modification for Everolimus Tablets Breast Cancer, PNET, RCC, and TSC-Associated Renal Angiomyolipoma Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orallyonce daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated. Moderatehepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated. Severe hepaticimpairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. TSC-Associated SEGA Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)] Abbreviations: PNET, Pancreatic Neuroendrocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex. 2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 )] . Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking Everolimus Tablets with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with a P­gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets Breast Cancer, PNET, RCC, and TSC-Associated Renal Angiomyolipoma Reduce dose to 2.5 mg once daily. May increase dose to 5 mg once daily if tolerated. Resume the dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. TSC-Associated SEGA Reduce the daily dose by 50% Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8)]. 2.12 Dosage Modifications for P-gp and CYP3A4 Inducers Avoid concomitant use of St. John’s Wort ( Hypericum perforatum ). Increase the dose for patients taking Everolimus Tablets with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [ see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets Breast Cancer, PNET, RCC, and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist. If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days. TSC-Associated SEGA Double the daily dose using increments of 5 mg or less. Multiple increments may be required. Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8)] Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. 2.13 Administration and Preparation Administer Everolimus Tablets at the same time each day. Administer Everolimus Tablets consistently either with or without food [see Clinical Pharmacology ( 12.3 )] . If a dose of Everolimus Tablets is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, Everolimus Tablets should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. Everolimus Tablets Everolimus Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

Indications And Usage

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

Adverse Reactions Table

Everolimus Tablets

with Exemestane N=482

Placebo

with Exemestane N=238

All grades

Grade 3-4

All grades

Grade 3-4

%

%

%

%

Gastrointestinal

Stomatitisa

67

8d

11

0.8

Diarrhea

33

2

18

0.8

Nausea

29

0.4

28

1

Vomiting

17

1

12

0.8

Constipation

14

0.4d

13

0.4

Dry mouth

11

0

7

0

General

Fatigue

36

4

27

1d

Edema peripheral

19

1d

6

0.4d

Pyrexia

15

0.2d

7

0.4d

Asthenia

13

2

4

0

Infections

Infectionsb

50

6

25

2d

Investigations

Weight loss

25

1d

6

0

Metabolism and nutrition

Decreased appetite

30

1d

12

0.4d

Hyperglycemia

14

5

2

0.4d

Musculoskeletal and connective tissue

Arthralgia

20

0.8d

17

0

Back pain

14

0.2d

10

0.8d

Pain in extremity

9

0.4d

11

2d

Nervous system

Dysgeusia

22

0.2d

6

0

Headache

21

0.4d

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

Pneumonitisc

19

4

0.4

0

Skin and subcutaneous tissue

Rash

39

1d

6

0

Pruritus

13

0.2d

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.

cIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.

dNo Grade 4 adverse reactions were reported.

Drug Interactions

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

Clinical Pharmacology

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

Mechanism Of Action

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

Pharmacodynamics

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

Pharmacokinetics

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

Effective Time

20210730

Version

18

Dosage And Administration Table

Event

When to Assess Trough Concentrations After Event

Initiation of Everolimus Tablets

1 to 2 weeks

Modification of Everolimus Tablets dose

1 to 2 weeks

Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor

2 weeks

Initiation or discontinuation of P-gp and strong CYP3A4 inducer

2 weeks

Change in hepatic function

2 weeks

Stable dose with changing body surface area (BSA)

Every 3 to 6 months

Stable dose with stable BSA

Every 6 to 12 months

Abbreviation: P-gp, P-glycoprotein

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHS Everolimus Tablets 2.5 mg tablet White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with "P" on one side and "119" on the other side. 5 mg tablet White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with "P" on one side and "125" on the other side. 7.5 mg tablet White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with "P" on one side and "127" on the other side. 10 mg tablet White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with "P" on one side and "128" on the other side. Everolimus Tablets: 2.5 mg, 5 mg, 7.5 mg and 10 mg tablets with no score ( 3 )

Spl Product Data Elements

Everolimus Everolimus EVEROLIMUS EVEROLIMUS HYPROMELLOSE 2910 (3 MPA.S) BUTYLATED HYDROXYTOLUENE ANHYDROUS LACTOSE CROSPOVIDONE SILICON DIOXIDE MAGNESIUM STEARATE to slightly yellow P;and;119 Everolimus Everolimus EVEROLIMUS EVEROLIMUS HYPROMELLOSE 2910 (3 MPA.S) BUTYLATED HYDROXYTOLUENE ANHYDROUS LACTOSE CROSPOVIDONE SILICON DIOXIDE MAGNESIUM STEARATE to slightly yellow P;and;125 Everolimus Everolimus EVEROLIMUS EVEROLIMUS HYPROMELLOSE 2910 (3 MPA.S) BUTYLATED HYDROXYTOLUENE ANHYDROUS LACTOSE CROSPOVIDONE SILICON DIOXIDE MAGNESIUM STEARATE to slightly yellow P;and;127 Everolimus Everolimus EVEROLIMUS EVEROLIMUS HYPROMELLOSE 2910 (3 MPA.S) BUTYLATED HYDROXYTOLUENE ANHYDROUS LACTOSE CROSPOVIDONE SILICON DIOXIDE MAGNESIUM STEARATE to slightly yellow P;and;128

Animal Pharmacology And Or Toxicology

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

Carcinogenesis And Mutagenesis And Impairment Of Fertility

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

Nonclinical Toxicology

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

Application Number

ANDA207934

Brand Name

Everolimus

Generic Name

Everolimus

Product Ndc

49884-127

Product Type

HUMAN PRESCRIPTION DRUG

Route

ORAL

Package Label Principal Display Panel

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL PRINCIPAL DISPLAY PANEL – 2.5 mg Blisters blister - 2.5 mg

Recent Major Changes

Warnings and Precautions, Radiation Sensitization and Radiation Recall (5.12) 04/2021

Information For Patients

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use) Non-infectious Pneumonitis Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions ( 5.1 )] . Infections Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions ( 5.2 )] . Hypersensitivity Reactions Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . Angioedema with Concomitant Use of ACE Inhibitors Advise patients to avoid ACE inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions ( 5.4 )] Stomatitis Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions ( 5.5 )] . Renal Impairment Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions ( 5.6 )] . Risk of Impaired Wound Healing Advise patients that Everolimus tablets may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure. [see Warnings and Precautions ( 5.7 )] . Geriatric Patients Inform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients ≥ 65 years compared to patients < 65 years [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.5 )] Metabolic Disorders Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions ( 5.9 )] . Myelosuppression Advise patients of the risk of myelosuppression and the need to monitor CBCs periodically during therapy [see Warnings and Precautions ( 5.10 )] . Risk of Infection or Reduced Immune Response with Vaccination Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions ( 5.11 )] . Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions ( 5.13 ) and Use in Specific Populations ( 8.1 , 8.3 )] . Radiation Sensitization and Radiation Recall Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to Everolimus Tablets treatment. Advise patients to inform their health care provider if they have had or are planning to receive radiation therapy [ see Warnings and Precautions ( 5.12 ) ]. Lactation Advise women not to breastfeed during treatment with Everolimus tablets and for 2 weeks after the last dose [see Use in Specific Populations ( 8.2 )] Infertility Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations ( 8.3 )] Manufactured by: Par Pharmaceutical Chestnut Ridge, NY 10977 R03/2022

Spl Patient Package Insert Table

PATIENT INFORMATION

Everolimus (E ver OH li mus) Tablets

Read this Patient Information leaflet that comes with Everolimus Tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Everolimus Tablets?

Everolimus Tablets can cause serious side effects, including:

1. You may develop lung or breathing problems. In some people lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you have any of these symptoms:

  • New or worsening cough
  • Shortness of breath
  • Chest pain
  • Difficulty breathing or wheezing
  • 2. You may be more likely to develop an infection, such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include active hepatitis B in people who have had hepatitis B in the past (reactivation). In some people (including adults and children) these infections may be severe and can lead to death. You may need to be treated as soon as possible.

    Tell your healthcare provider right away if you have a temperature of 100.5°F or above, chills, or do not feel well.

    Symptoms of hepatitis B or infection may include the following:

  • Fever
  • Chills
  • Skin rash
  • Joint pain and swelling
  • Tiredness
  • Loss of appetite
  • Nausea
  • Pale stools or dark urine
  • Yellowing of the skin
  • Pain in the upper right side of the stomach
  • 3. Severe allergic reactions. Call your healthcare provider or get medical help right away if you get signs and symptoms of a severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness.

    4. Possible increased risk for a type of allergic reaction called angioedema, in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with Everolimus Tablets. Talk with your healthcare provider before taking Everolimus Tablets if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with Everolimus Tablets.

    5. Mouth ulcers and sores. Mouth ulcers and sores are common during treatment with Everolimus Tablets but can also be severe. When you start treatment with Everolimus Tablets, your healthcare provider may tell you to also start a prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your healthcare provider’s instructions on how to use this prescription mouthwash. If you develop pain, discomfort, or open sores in your mouth, tell your healthcare provider. Your healthcare provider may tell you to re-start this mouthwash or to use a special mouthwash or mouth gel that does not contain alcohol, peroxide iodine or thyme.

    6. You may develop kidney failure. In some people this may be severe and can lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with Everolimus Tablets.

    If you have any of the serious side effects listed above, you may need to stop taking Everolimus Tablets for a while or use a lower dose. Follow your healthcare provider’s instructions.

    What are Everolimus Tablets?

    Everolimus Tablets are a prescription medicine used to treat:

  • advanced hormone receptor-positive, HER2-negative breast cancer, along with the medicine exemestane, in postmenopausal women who have already received certain other medicines for their cancer.
  • adults with a type of pancreatic cancer known as pancreatic neuroendocrine tumor (PNET), that has progressed and cannot be treated with surgery.
  • Everolimus Tablets are not for use in people with carcinoid tumors that actively produce hormones.

  • adults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked.
  • people with the following types of tumors that are seen with a genetic condition called tuberous sclerosis complex (TSC):
  • adults with a kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.
  • adults and children 1 year of age and older with a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.
  • It is not known if Everolimus Tablets are safe and effective in children to treat:

  • hormone receptor-positive, HER2-negative breast cancer
  • kidney cancer (renal cell carcinoma)
  • a kidney tumor called angiomyolipoma, that can happen in children with a genetic condition called tuberous sclerosis complex (TSC).
  • Do not take Everolimus Tablets if you have had a severe allergic reaction to everolimus.

    Talk to your healthcare provider before taking this medicine if you are allergic to:

  • a medicine that contains sirolimus
  • a medicine that contains temsirolimus
  • Ask your healthcare provider if you do not know.

    Before taking Everolimus Tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • Have or have had kidney problems
  • Have or have had liver problems
  • Have diabetes or high blood sugar
  • Have high blood cholesterol levels
  • Have any infections
  • Previously had hepatitis B
  • Are scheduled to receive any vaccinations. You should not receive a “live vaccine” or be around people who have recently received a “live vaccine” during your treatment with Everolimus Tablets. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. For children with TSC and SEGA or certain types of seizures, work with your healthcare provider to complete the recommended childhood series of vaccines before your child starts treatment with Everolimus Tablets.
  • Are pregnant, can become pregnant, or have a partner who can become pregnant. Everolimus Tablets can cause harm to your unborn baby.

    Females who are able to become pregnant:

  • Your healthcare provider will give you a pregnancy test before you start treatment with Everolimus Tablets.
  • You should use effective birth control during treatment and for 8 weeks after your last dose of Everolimus tablets.
  • Males with a female partner, you should use effective birth control during treatment and for 4 weeks after your last dose of Everolimus Tablets.

    Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away.

  • Are breastfeeding or plan to breastfeed. It is not known if Everolimus Tablets pass into your breast milk. Do not breastfeed during treatment and for 2 weeks after your last dose of Everolimus Tablets.
  • Are planning to have surgery, or if you have had a recent surgery. You should stop taking Everolimus Tablets at least 1 week before planned surgery. See “What are the possible side effects of Everolimus Tablets?”
  • Have received radiation therapy or are planning to receive radiation therapy in the future. See “What are the possible side effects of Everolimus Tablets?”
  • Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Everolimus Tablets may affect the way other medicines work, and other medicines can affect how Everolimus Tablets work. Taking Everolimus Tablets with other medicines can cause serious side effects.

    Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Especially tell your healthcare provider if you take:

  • St. John’s Wort (Hypericum perforatum)
  • Medicine for:
  • Fungal infections
  • Bacterial infections
  • Tuberculosis
  • Seizures
  • HIV-AIDS
  • Heart conditions or high blood pressure
  • Medicines that weaken your immune system (your body’s ability to fight infections and other problems)
  • Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those taken for the conditions listed above. If you are taking any medicines for the conditions listed above, your healthcare provider might need to prescribe a different medicine or your dose of Everolimus Tablets may need to be changed. You should also tell your healthcare provider before you start taking any new medicine.

    How should I take Everolimus Tablets?

  • Your healthcare provider will prescribe the dose of Everolimus Tablets that is right for you.
  • Take Everolimus Tablets exactly as your healthcare provider tells you to.
  • Your healthcare provider may change your dose of Everolimus Tablets or tell you to temporarily interrupt dosing, if needed.
  • Use scissors to open the blister pack.
  • Take Everolimus Tablets 1 time each day at about the same time.
  • Take Everolimus Tablets the same way each time, either with food or without food.
  • If you take too much Everolimus Tablets contact your healthcare provider or go to the nearest hospital emergency room right away. Take the pack of Everolimus Tablets with you.
  • If you miss a dose of Everolimus Tablets, you may still take it if it is less than 6 hours after the time you normally take it. If it is more than 6 hours after you normally take your Everolimus Tablets, skip the dose for that day. The next day, take Everolimus Tablets at your usual time. Do not take 2 doses to make up for a missed dose. If you are not sure about what to do, call your healthcare provider.
  • You should have blood tests before you start Everolimus Tablets and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels.
  • If you take Everolimus Tablets to treat SEGA, you will also need to have blood tests regularly to measure how much medicine is in your blood. This will help your healthcare provider decide how much Everolimus Tablets you need to take.

    Everolimus Tablets:

  • Swallow Everolimus Tablets whole with a glass of water. Do not take any tablet that is broken or crushed.
  • What should I avoid while taking Everolimus Tablets?

    You should not drink grapefruit juice or eat grapefruit during your treatment with Everolimus Tablets. It may make the amount of Everolimus Tablets in your blood increase to a harmful level.

    What are the possible side effects of Everolimus Tablets?

    Everolimus Tablets can cause serious side effects, including:

  • See “What is the most important information I should know about Everolimus Tablets?” for more information.
  • Risk of wound healing problems. Wounds may not heal properly during Everolimus Tablets treatment.Tell your healthcare provider if you plan to have any surgery before starting or during treatment with Everolimus Tablets.
  • You should stop taking Everolimus Tablets at least 1 week before planned surgery.
  • Your healthcare provider should tell you when you may start taking Everolimus Tablets again after surgery.
  • Increased blood sugar and fat (cholesterol and triglyceride) levels in the blood. Your healthcare provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in the blood before you start and during treatment with Everolimus Tablets.
  • Decreased blood cell counts. Everolimus Tablets can cause you to have decreased red blood cells, white blood cells, and platelets. Your healthcare provider should do blood tests to check your blood cell counts before you start and during treatment with Everolimus Tablets.
  • Worsening side effects from radiation treatment, that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy.
  • The most common side effects of Everolimus Tablets in people with advanced hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of the pancreas, stomach and intestine (gastrointestinal) or lung, and advanced kidney cancer include:

  • Infections
  • Stomach-area (abdominal) pain
  • Rash
  • Nausea
  • Feeling weak or tired
  • Fever
  • Diarrhea
  • Cough
  • Swelling of arms, hands, feet, ankles, face or other parts of the body
  • Headache
  • Decreased appetite
  • The most common side effects of Everolimus Tablets in people who have SEGA, renal angiomyolipoma, or certain types of seizures with TSC include respiratory tract infections.

    Other side effects that may occur with Everolimus Tablets:

  • Absence of menstrual periods (menstruation). You may miss 1 or more menstrual periods. Tell your healthcare provider if this happens.
  • Everolimus tablets may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.
  • Everolimus tablets may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.
  • Tell your healthcare provider if you have any side effect that bothers you or does not go away.

    These are not all the possible side effects of Everolimus Tablets. For more information, ask your healthcare provider or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Everolimus Tablets?

  • Store Everolimus Tablets at room temperature, between 68°F to 77°F (20°C to 25°C).
  • Keep Everolimus Tablets in the pack it comes in.
  • Open the blister pack just before taking Everolimus Tablets.
  • Keep Everolimus Tablets dry and away from light.
  • Do not use Everolimus Tablets that is out of date or no longer needed.
  • Keep Everolimus Tablets and all medicines out of the reach of children.

    General information about the safe and effective use of Everolimus Tablets

    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Everolimus Tablets for a condition for which it was not prescribed. Do not give Everolimus Tablets to other people, even if they have the same problem you have. It may harm them.

    This leaflet summarizes the most important information about Everolimus Tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information written for healthcare professionals.

    For more information call1-800-828-9393 or go to www.parpharm.com.

    What are the ingredients in Everolimus Tablets?

    Active ingredient: everolimus.

    Inactive ingredients: hypromellose, butylated hydroxytoluene, lactose anhydrous, crospovidone, colloidal silicon dioxide and magnesium stearate.

    This Patient Information has been approved by the U.S. Food and Drug Administration.

    Manufactured by:

    Par Pharmaceutical

    Chestnut Ridge, NY 10977

    Revised: 03/2022

    Clinical Studies

    14 CLINICAL STUDIES 14.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of Everolimus tablets in combination with exemestane versus placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes versus no) and by the presence of visceral metastasis (yes versus no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. Patients were permitted to have received 0 to1 prior lines of chemotherapy for advanced disease. The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria In Solid Tumors), based on investigator (local radiology) assessment. Other outcome measures included overall survival (OS) and objective response rate (ORR). Patients were randomized 2:1 to Everolimus tablets 10 mg orally once daily in combination with exemestane 25 mg orally once daily (n = 485) or to placebo in combination with exemestane 25 mg once daily (n = 239). The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to Everolimus tablets at the time of disease progression. The trial demonstrated a statistically significant improvement in PFS by investigator assessment ( Table 20 and Figure 1 ). The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy. ORR was higher in the Everolimus Tablets in combination with exemestane arm versus the placebo in combination with exemestane arm ( Table 20 ). There were 3 complete responses (0.6%) and 58 partial responses (12%) in the Everolimus Tablets arm. There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm. After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the Everolimus tablets in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)]. Table 20: Efficacy Results in Hormone-Receptor Positive, HER2-Negative Breast Cancer in BOLERO-2 Analysis Everolimus Tablets with Exemestane N = 485 Placebo with Exemestane N = 239 Hazard ratio P-value Median progression-free survival (months, 95% CI) Investigator radiological review 7.8 (6.9, 8.5) 3.2 (2.8, 4.1) 0.45 a (0.38, 0.54) <0.0001 b Independent Radiological review 11.0 (9.7, 15.0) 4.1 (2.9, 5.6) 0.38 a (0.3, 0.5) <0.0001 b Best overall response (%, 95% CI) Objective response rate (ORR) c 12.6% (9.8, 15.9) 1.7% (0.5, 4.2) n/a d a Hazard ratio is obtained from the stratified Cox proportional-hazards model by sensitivity to prior hormonal therapy and presence of visceral metastasis. b p-value is obtained from the one-sided log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis. c Objective response rate = proportion of patients with CR or PR. d Not applicable. Figure 1: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in Hormone Receptor-Positive, HER2-Negative Breast Cancer in BOLERO-2 figure 1 14.2 Neuroendocrine Tumors (NET) Pancreatic Neuroendocrine Tumors (PNET) A randomized, double-blind, multi-center trial (RADIANT-3, NCT00510068) of Everolimus in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes versus no) and WHO performance status (0 versus 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The major efficacy outcome was PFS evaluated by RECIST. After documented radiological progression, patients randomized to placebo could receive open-label Everolimus. Other outcome measures included ORR, response duration, and OS. Patients were randomized 1:1 to receive either Everolimus 10 mg once daily (n = 207) or placebo (n = 203). Demographics were well balanced (median age 58 years, 55% male, 79% White). Of the 203 patients randomized to BSC, 172 patients (85%) received Everolimus following documented radiologic progression. The trial demonstrated a statistically significant improvement in PFS ( Table 21 and Figure 2 ). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use. The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 21 . Table 21: Progression-Free Survival Results in PNET in RADIANT-3 Analysis N Everolimus Tablets N = 207 Placebo N = 203 Hazard Ratio (95% CI) P-value 410 Median progression-free survival (months) (95% CI) Investigator radiological review 11.0 (8.4, 13.9) 4.6 (3.1, 5.4) 0.35 (0.27, 0.45) <0.001 Central radiological review 13.7 (11.2, 18.8) 5.7 (5.4, 8.3) 0.38 (0.28, 0.51) <0.001 Adjudicated radiological review a 11.4 (10.8, 14.8) 5.4 (4.3, 5.6) 0.34 (0.26, 0.44) <0.001 a Includes adjudication for discrepant assessments between investigator radiological review and central radiological review. Figure 2: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in PNET in RADIANT-3 Investigator-determined response rate was 4.8% in the Everolimus arm and there were no complete responses. Overall Survival (OS) was not statistically significantly different between arms [HR = 0.94 (95% CI 0.73, 1.20); p = 0.30]. Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors The safety and effectiveness of Everolimus tablets in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multi-center trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, Everolimus tablets in combination with long-acting octreotide (Sandostatin LAR ® ) was compared to placebo in combination with long-acting octreotide. After documented radiological progression, patients on the placebo arm could receive Everolimus tablets; of those randomized to placebo, 67% received open-label Everolimus tablets in combination with long-acting octreotide. The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm. figure 2 14.3 Renal Cell Carcinoma (RCC) An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing Everolimus 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy. The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review. After documented radiological progression, patients randomized to placebo could receive open-label Everolimus. Other outcome measures included OS. In total, 416 patients were randomized 2:1 to receive Everolimus (n = 277) or placebo (n = 139). Demographics were well balanced between the arms (median age 61 years; 77% male, 88% White, 74% received prior sunitinib or sorafenib, and 26% received both sequentially). Everolimus was superior to placebo for PFS ( Table 23 and Figure 4 ). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield a hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label Everolimus occurred in 80% of the 139 patients and may have confounded the OS benefit. Table 23: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1 Everolimus Tablets N = 277 Placebo N = 139 Hazard Ratio (95% CI) p-value a Median Progression-free Survival 4.9 months 1.9 months 0.33 < 0.0001 (95% CI) (4.0, 5.5) (1.8, 1.9) (0.25, 0.43) Objective Response Rate 2% 0% n/a b n/a b a Log-rank test stratified by prognostic score. b Not applicable. Figure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1 figure 4 14.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of Everolimus was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received Everolimus 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes versus no). Of the 118 patients enrolled, 79 were randomized to Everolimus and 39 to placebo. The median age was 31 years (18 to 61 years), 34% were male, and 89% were White. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm 3 (9 to 1612 cm 3 ) and 120 cm 3 (3 to 4520 cm 3 ) in the Everolimus Tablets and placebo arms, respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis. The renal angiomyolipoma response rate was statistically significantly higher in Everolimus-treated patients ( Table 24 ). The median response duration was 5.3+ months (2.3+ to 19.6+ months). There were 3 patients in the Everolimus arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the Everolimus arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001). Table 24: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus Tablets N=79 Placebo N=39 p-value Primary analysis Angiomyolipoma response rate a - % 41.8 0 < 0.0001 95% CI (30.8, 53.4) (0.0, 9.0) a Per independent central radiology review. Skin lesion response rates were assessed by local investigators for 77 patients in the Everolimus arm and 37 patients in the placebo arm who presented with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the Everolimus arm (26% vs. 0, p = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least 8 weeks (Physician's Global Assessment of Clinical Condition). Patients randomized to placebo were permitted to receive Everolimus at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with Everolimus underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 112 patients (79 randomized to Everolimus and 33 randomized to placebo) received at least one dose of Everolimus. The median duration of Everolimus treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years). During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months). Fourteen percent of the 112 patients treated with Everolimus had angiomyolipoma progression by the end of the follow-up period. No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with Everolimus. 14.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) EXIST-1 A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of Everolimus was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received Everolimus at a starting dose of 4.5 mg/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. Everolimus or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter. The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no). Of the 117 patients enrolled, 78 were randomized to Everolimus and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were White. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm 3 (0.18 to 25.15 cm 3 ) and 1.30 cm 3 (0.32 to 9.75 cm 3 ) in the Everolimus and placebo arms respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis. The SEGA response rate was statistically significantly higher in Everolimus -treated patients ( Table 25 ). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months). With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive Everolimus. No patient in either treatment arm required surgical intervention. Table 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1 Everolimus N = 78 Placebo N = 39 p-value Primary analysis SEGA response rate a - (%) 35 0 < 0.0001 95% CI 24, 46 0, 9 a Per independent central radiology review. Patients randomized to placebo were permitted to receive Everolimus at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with Everolimus Tablets underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to Everolimus and 33 patients randomized to placebo) received at least one dose of Everolimus Tablets. Median duration of Everolimus treatment and follow-up was 3.9 years (0.2 to 4.9 years). By four years after the last patient was enrolled, 58% of the 111 patients treated with Everolimus had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with Everolimus had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study. Study 2485 Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of Everolimus 3 mg/m 2 /orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study. A total of 28 patients received Everolimus for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on Everolimus for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% White. At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years). By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on Everolimus. Nine additional patients were identified as having a ≥ 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating Everolimus including 3 patients who had surgical resection with subsequent regrowth prior to receiving Everolimus.

    Clinical Studies Table

    Analysis

    Everolimus Tablets

    with Exemestane

    N = 485

    Placebo

    with Exemestane

    N = 239

    Hazard ratio

    P-value

    Median progression-free survival (months, 95% CI)

    Investigator radiological review

    7.8

    (6.9, 8.5)

    3.2

    (2.8, 4.1)

    0.45a

    (0.38, 0.54)

    <0.0001b

    Independent

    Radiological review

    11.0

    (9.7, 15.0)

    4.1

    (2.9, 5.6)

    0.38a

    (0.3, 0.5)

    <0.0001b

    Best overall response (%, 95% CI)

    Objective response rate

    (ORR)c

    12.6%

    (9.8, 15.9)

    1.7%

    (0.5, 4.2)

    n/ad

    References

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

    Geriatric Use

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

    Labor And Delivery

    8.2 Lactation Risk Summary There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with Everolimus Tablets and for 2 weeks after the last dose.

    Nursing Mothers

    8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting Everolimus Tablets [see Use in Specific Populations ( 8.1 )]. Contraception Everolimus Tablets can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )]. Females: Advise female patients of reproductive potential to use effective contraception during treatment with Everolimus tablets and for 8 weeks after the last dose . Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Everolimus Tablets and for 4 weeks after the last dose. Infertility Females: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking Everolimus tablets. Based on these findings, Everolimus Tablets, may impair fertility in female patients [see Adverse Reactions ( 6.1 ) and Nonclinical Toxicology ( 13.1 )]. Males: Cases of reversible azoospermia have been reported in male patients taking Everolimus. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of Everolimus 10 mg orally once daily. Based on these findings, Everolimus Tablets may impair fertility in male patients [see Nonclinical Toxicology ( 13.1 )] .

    Pregnancy

    8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology ( 12.1 )], Everolimus tablets can cause fetal harm when administered to a pregnant woman. There are limited case reports of Everolimus tablets use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of Everolimus tablets 10 mg orally once daily (see Data). Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of Everolimus tablets 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of Everolimus tablets 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). 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.

    Use In Specific Populations

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

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Everolimus Tablets 2.5 mg tablets White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with “P” on one side and “119” on the other side; available in: Blisters of 28 tablets……………………………………………………………………NDC 49884-119-91 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with “P” on one side and “125” on the other side; available in: Blisters of 28 tablets……………………………………………………………………NDC 49884-125-91 Each carton contains 4 blister cards of 7 tablets each 7.5 mg tablets White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with “P” on one side and “127” on the other side; available in: Blisters of 28 tablets……………………………………………………………………NDC 49884-127-91 Each carton contains 4 blister cards of 7 tablets each 10 mg tablets White to slightly yellow, capsule shaped tablets with a beveled edge and no score, engraved with “P” on one side and “128” on the other side; available in: Blisters of 28 tablets……………………………………………………………………NDC 49884-128-91 Each carton contains 4 blister cards of 7 tablets each Store Everolimus Tablets at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Follow special handling and disposal procedures for anticancer pharmaceuticals. 1

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