Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE AFINITOR 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) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Limitation of Use: AFINITOR 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) AFINITOR and AFINITOR DISPERZ 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) AFINITOR DISPERZ is a kinase inhibitor indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. (1.6) 1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer AFINITOR® is 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) AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)]. 1.3 Renal Cell Carcinoma (RCC) AFINITOR is 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 AFINITOR is 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) AFINITOR and AFINITOR DISPERZ® 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. 1.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

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contraindications
4 CONTRAINDICATIONS AFINITOR/AFINITOR DISPERZ is 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)
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)]. Breast cancer, NET, RCC: Most common adverse reactions (incidence ≥ 30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. (6.1) TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.1) TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. (6.1) TSC-Associated Partial-Onset Seizures: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were White. The median follow-up was approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR versus placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks. Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Grading according to NCI CTCAE Version 3.0 aIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration bIncludes all reported infections including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. cIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis dNo Grade 4 adverse reactions were reported. AFINITOR 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 0.2d 8 0 Respiratory, thoracic and mediastinal Cough 24 0.6d 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 Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Grading according to NCI CTCAE Version 3.0 aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. bNo Grade 4 laboratory abnormalities were reported. Laboratory Parameter AFINITOR with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematologya Anemia 68 6 40 1 Leukopenia 58 2b 28 6 Thrombocytopenia 54 3 5 0.4 Lymphopenia 54 12 37 6 Neutropenia 31 2b 11 2 Chemistry Hypercholesterolemia 70 1 38 2 Hyperglycemia 69 9 44 1 Increased aspartate transaminase (AST) 69 4 45 3 Increased alanine transaminase (ALT) 51 4 29 5b Hypertriglyceridemia 50 0.8b 26 0 Hypoalbuminemia 33 0.8b 16 0.8b Hypokalemia 29 4 7 1b Increased creatinine 24 2 13 0 Topical Prophylaxis for Stomatitis In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with AFINITOR and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial. Coadministration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. Pancreatic Neuroendocrine Tumors (PNET) In a randomized, controlled trial (RADIANT-3) of AFINITOR (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression. The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia. Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on AFINITOR. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the AFINITOR group. Dose delay or reduction was necessary in 61% of AFINITOR patients. Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm. Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received AFINITOR was 37 weeks. In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females. Table 8: Adverse Reactions Reported in ≥ 10% of Patients with PNET in RADIANT-3 Grading according to NCI CTCAE Version 3.0 aIncludes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. bIncludes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. cIncludes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. dNo Grade 4 adverse reactions were reported. AFINITOR N = 204 Placebo N = 203 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitisa 70 7d 20 0 Diarrheab 50 6 25 3d Abdominal pain 36 4d 32 7 Nausea 32 2d 33 2d Vomiting 29 1d 21 2d Constipation 14 0 13 0.5d Dry mouth 11 0 4 0 General Fatigue/malaise 45 4 27 3 Edema (general and peripheral) 39 2 12 1d Fever 31 1 13 0.5d Asthenia 19 3d 20 3d Infections Nasopharyngitis/rhinitis/URI 25 0 13 0 Urinary tract infection 16 0 6 0.5d Investigations Weight loss 28 0.5d 11 0 Metabolism and nutrition Decreased appetite 30 1d 18 1d Diabetes mellitus 10 2d 0.5 0 Musculoskeletal and connective tissue Arthralgia 15 1 7 0.5d Back pain 15 1d 11 1d Pain in extremity 14 0.5d 6 1d Muscle spasms 10 0 4 0 Nervous system Headache/migraine 30 0.5d 15 1d Dysgeusia 19 0 5 0 Dizziness 12 0.5d 7 0 Psychiatric Insomnia 14 0 8 0 Respiratory, thoracic and mediastinal Cough/productive cough 25 0.5d 13 0 Epistaxis 22 0 1 0 Dyspnea/dyspnea exertional 20 3 7 0.5d Pneumonitisc 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 1d Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with PNET in RADIANT-3 Grading according to NCI CTCAE Version 3.0 Laboratory parameter AFINITOR N = 204 Placebo N = 203 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Anemia 86 15 63 1 Lymphopenia 45 16 22 4 Thrombocytopenia 45 3 11 0 Leukopenia 43 2 13 0 Neutropenia 30 4 17 2 Chemistry Hyperglycemia (fasting) 75 17 53 6 Increased alkaline phosphatase 74 8 66 8 Hypercholesterolemia 66 0.5 22 0 Bicarbonate decreased 56 0 40 0 Increased AST 56 4 41 4 Increased ALT 48 2 35 2 Hypophosphatemia 40 10 14 3 Hypertriglyceridemia 39 0 10 0 Hypocalcemia 37 0.5 12 0 Hypokalemia 23 4 5 0 Increased creatinine 19 2 14 0 Hyponatremia 16 1 16 1 Hypoalbuminemia 13 1 8 0 Hyperbilirubinemia 10 1 14 2 Hyperkalemia 7 0 10 0.5 Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin In a randomized, controlled trial (RADIANT-4) of AFINITOR (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were White, and 53% were female. The median duration of exposure to AFINITOR was 9.3 months; 64% of patients were treated for > 6 months and 39% were treated for > 12 months. AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients. Serious adverse reactions occurred in 42% of AFINITOR-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Adverse reactions occurring at an incidence of ≥ 10% and at > 5% absolute incidence over placebo (all Grades) or > 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11. Table 10: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4 Grading according to NCI CTCAE Version 4.03 aIncludes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation. bUrinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis. cIncludes pneumonitis and interstitial lung disease. dNo Grade 4 adverse reactions were reported. AFINITOR N = 202 Placebo N = 98 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitisa 63 9d 22 0 Diarrhea 41 9 31 2d Nausea 26 3 17 1d Vomiting 15 4d 12 2d General Peripheral edema 39 3d 6 1d Fatigue 37 5 36 1d Asthenia 23 3 8 0 Pyrexia 23 2 8 0 Infections Infectionsb 58 11 29 2 Investigations Weight loss 22 2d 11 1d Metabolism and nutrition Decreased appetite 22 1d 17 1d Nervous system Dysgeusia 18 1d 4 0 Respiratory, thoracic and mediastinal Cough 27 0 20 0 Dyspnea 20 3d 11 2 Pneumonitisc 16 2d 2 0 Epistaxis 13 1d 3 0 Skin and subcutaneous Rash 30 1d 9 0 Pruritus 17 1d 9 0 Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4 Grading according to NCI CTCAE Version 4.03 aNo Grade 4 laboratory abnormalities were reported. AFINITOR N = 202 Placebo N = 98 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Anemia 81 5a 41 2a Lymphopenia 66 16 32 2a Leukopenia 49 2a 17 0 Thrombocytopenia 33 2 11 0 Neutropenia 32 2a 15 3a Chemistry Hypercholesterolemia 71 0 37 0 Increased AST 57 2 34 2a Hyperglycemia (fasting) 55 6a 36 1a Increased ALT 46 5 39 1a Hypophosphatemia 43 4a 15 2a Hypertriglyceridemia 30 3 8 1a Hypokalemia 27 6 12 3a Hypoalbuminemia 18 0 8 0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to AFINITOR (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving AFINITOR. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the AFINITOR group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 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 the AFINITOR Arm than in the Placebo Arm in RECORD-1 Grading according to NCI CTCAE Version 3.0 aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration. bIncludes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. dNo Grade 4 adverse reactions were reported. AFINITOR N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitisa 44 4 8 0 Diarrhea 30 2d 7 0 Nausea 26 2d 19 0 Vomiting 20 2d 12 0 Infectionsb 37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6d 27 4 Edema peripheral 25 < 1d 8 < 1d Pyrexia 20 < 1d 9 0 Mucosal inflammation 19 2d 1 0 Respiratory, thoracic and mediastinal Cough 30 < 1d 16 0 Dyspnea 24 8 15 3d Epistaxis 18 0 0 0 Pneumonitisc 14 4d 0 0 Skin and subcutaneous tissue Rash 29 1d 7 0 Pruritus 14 < 1d 7 0 Dry skin 13 < 1d 5 0 Metabolism and nutrition Anorexia 25 2d 14 < 1d Nervous system Headache 19 1 9 < 1d Dysgeusia 10 0 2 0 Musculoskeletal and connective tissue Pain in extremity 10 1d 7 0 Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include: Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%) Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (< 1%) Metabolism and nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%) Psychiatric: Insomnia (9%) Nervous system: Dizziness (7%), paresthesia (5%) Ocular: Eyelid edema (4%), conjunctivitis (2%) Vascular: Hypertension (4%), deep vein thrombosis (< 1%) Renal and urinary: Renal failure (3%) Cardiac: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue: Jaw pain (3%) Hematologic: Hemorrhage (3%) Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm in RECORD-1 Grading according to NCI CTCAE Version 3.0 aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. bNo Grade 4 laboratory abnormalities were reported. Laboratory parameter AFINITOR N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematologya Anemia 92 13 79 6 Lymphopenia 51 18 28 5b Thrombocytopenia 23 1b 2 < 1 Neutropenia 14 < 1 4 0 Chemistry Hypercholesterolemia 77 4b 35 0 Hypertriglyceridemia 73 < 1b 34 0 Hyperglycemia 57 16 25 2b Increased creatinine increased 50 2b 34 0 Hypophosphatemia 37 6b 8 0 Increased AST 25 1 7 0 Increased ALT 21 1b 4 0 Hyperbilirubinemia 3 1 2 0 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were White, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving AFINITOR. The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15. Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Grading according to NCI CTCAE Version 3.0 aIncludes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. bNo Grade 4 adverse reactions were reported. AFINITOR N = 79 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitisa 78 6b 23 0 Vomiting 15 0 5 0 Diarrhea 14 0 5 0 General Peripheral edema 13 0 8 0 Infections Upper respiratory tract infection 11 0 5 0 Musculoskeletal and connective tissue Arthralgia 13 0 5 0 Respiratory, thoracic and mediastinal Cough 20 0 13 0 Skin and subcutaneous tissue Acne 22 0 5 0 Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%). Table 15: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Grading according to NCI CTCAE Version 3.0 aNo Grade 4 laboratory abnormalities were reported. AFINITOR N = 79 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1a 8 0 Thrombocytopenia 19 0 3 0 Chemistry Hypercholesterolemia 85 1a 46 0 Hypertriglyceridemia 52 0 10 0 Hypophosphatemia 49 5a 15 0 Increased alkaline phosphatase 32 1a 10 0 Increased AST 23 1a 8 0 Increased ALT 20 1a 15 0 Hyperglycemia (fasting) 14 0 8 0 Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%). TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA) The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were White, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR. The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia. There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17. Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1 Grading according to NCI CTCAE Version 3.0 aIncludes mouth ulceration, stomatitis, and lip ulceration bIncludes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral cIncludes gastroenteritis, gastroenteritis viral, and gastrointestinal infection dIncludes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder eIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria fNo Grade 4 adverse reactions were reported. AFINITOR N = 78 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitisa 62 9f 26 3f Vomiting 22 1f 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infectionb 31 3 23 0 Gastroenteritisc 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6f 18 3f Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbanced 21 5f 3 0 Skin and subcutaneous tissue Rashe 21 0 8 0 Acne 10 0 5 0 Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%). The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%), and pneumonitis (1%). Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1 Grading according to NCI CTCAE Version 3.0 aNo Grade 4 laboratory abnormalities were reported. AFINITOR N = 78 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Elevated partial thromboplastin time 72 3a 44 5a Neutropenia 46 9a 41 3a Anemia 41 0 21 0 Chemistry Hypercholesterolemia 81 0 39 0 Elevated aspartate transaminase (AST) 33 0 0 0 Hypertriglyceridemia 27 0 15 0 Elevated alanine transaminase (ALT) 18 0 3 0 Hypophosphatemia 9 1a 3 0 Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%). TSC-Associated Partial-Onset Seizures The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to AFINITOR DISPERZ low trough (LT) (n = 117), AFINITOR DISPERZ high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were White, and 52% were male. Patients received between one and three concomitant antiepileptic drugs. The most common adverse reaction reported for AFINITOR DISPERZ in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia. Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 18. Laboratory abnormalities are presented in Table 19. Table 18: Adverse Reactions Reported in ≥ 10% of AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures in EXIST-3 aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain bNo Grade 4 adverse reactions were reported. AFINITOR DISPERZ Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N=119 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Stomatitisa 55 3b 64 4b 9 0 Diarrhea 17 0 22 0 5 0 Vomiting 12 0 10 2b 9 0 Infections Nasopharyngitis 14 0 16 0 16 0 Upper respiratory tract infection 13 0 15 0 13 0.8b General Pyrexia 20 0 14 0.8b 5 0 Respiratory, thoracic and mediastinal Cough 11 0 10 0 3 0 Skin and subcutaneous tissue Rash 6 0 10 0 3 0 The following additional adverse reactions occurred in < 10% of AFINITOR DISPERZ treated patients (% AFINITOR DISPERZ LT, % AFINITOR DISPERZ HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%). Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures Grading according to NCI CTCAE version 4.03 aNo Grade 4 laboratory abnormalities were reported. AFINITOR DISPERZ Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N=119 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hematology Neutropenia 25 4a 37 6 23 7a Anemia 27 0.9a 30 0 21 0.8a Thrombocytopenia 12 0 15 0 6 0 Chemistry Hypercholesterolemia 86 0 85 0.8a 58 0 Hypertriglyceridemia 43 2a 39 2 22 0 Increased ALT 17 0 22 0 6 0 Increased AST 13 0 19 0 4 0 Hyperglycemia 19 0 18 0 17 0 Increased alkaline phosphatase 24 0 16 0 29 0 Hypophosphatemia 9 0.9a 16 2 3 0 Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total daily dose. (2.1) Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. (2.1) Breast Cancer: 10 mg orally once daily. (2.2) NET: 10 mg orally once daily. (2.3) RCC: 10 mg orally once daily. (2.4) TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. (2.5) TSC-Associated SEGA: 4.5 mg/m2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. (2.6, 2.8) TSC-Associated Partial-Onset Seizures: 5 mg/m2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. (2.7, 2.8) 2.1 Important Dosage Information AFINITOR and AFINITOR DISPERZ are two different dosage forms. Select the recommended dosage form based on the indication [see Indications and Usage (1)]. Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total dose. Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10, 2.11, 2.12)]. 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of AFINITOR 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 AFINITOR 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 AFINITOR 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 AFINITOR/AFINITOR DISPERZ is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)]. 2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The recommended starting dosage of AFINITOR DISPERZ is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)]. 2.8 Therapeutic Drug Monitoring and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) and TSC-Associated Partial-Onset Seizures 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 therapeutic drug monitoring throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Initiation of AFINITOR/AFINITOR DISPERZ 1 to 2 weeks Modification of AFINITOR/AFINITOR DISPERZ dose 1 to 2 weeks Switch between AFINITOR and AFINITOR DISPERZ 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 Every 3 to 6 months Stable dose with stable body surface area Every 6 to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the management of adverse reactions. Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated. Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated. Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. TSC-Associated SEGA and TSC- Associated Partial-Onset Seizures Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)]. 2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ with a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for AFINITOR/AFINITOR DISPERZ Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Reduce dose to 2.5 mg once daily. May increase dose to 5 mg once daily if tolerated. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. TSC-Associated SEGA and TSC- Associated Partial-Onset Seizures 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for AFINITOR/AFINITOR DISPERZ Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist. If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days. TSC-Associated SEGA and TSC- Associated Partial-Onset Seizures 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 AFINITOR/AFINITOR DISPERZ at the same time each day. Administer AFINITOR/AFINITOR DISPERZ consistently either with or without food [see Clinical Pharmacology (12.3)]. If a dose of AFINITOR/AFINITOR DISPERZ 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, AFINITOR/AFINITOR DISPERZ should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. AFINITOR AFINITOR should be swallowed whole with a glass of water. Do not break or crush tablets. AFINITOR DISPERZ Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person. Administer as a suspension only. Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation. Prepare suspension in water only. Using an Oral Syringe to Prepare Oral Suspension: Place the prescribed dose into a 10-mL syringe. Do not exceed a total of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets. Draw approximately 5 mL of water and 4 mL of air into the syringe. Place the filled syringe into a container (tip up) for 3 minutes, until the tablets are in suspension. Gently invert the syringe 5 times immediately prior to administration. After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe. Using a Small Drinking Glass to Prepare Oral Suspension: Place the prescribed dose into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets. Allow 3 minutes for suspension to occur. Stir the contents gently with a spoon, immediately prior to drinking. After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles. Administer the entire contents of the glass.
Use in special populations
8 USE IN SPECIFIC POPULATIONS For breast cancer, NET, RCC, or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. (2.10, 8.6) For patients with TSC-associated SEGA or TSC-associated partial-onset seizures 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)], AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily (see Data). Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on body surface area. 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/m2), 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ [see Use in Specific Population (8.1)]. Contraception AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in female patients [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)]. Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in male patients [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of AFINITOR/AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.5)]. The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years. Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years. TSC-Associated Partial-Onset Seizures The safety and effectiveness of AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)]. The safety and effectiveness of AFINITOR DISPERZ and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures. The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 AFINITOR DISPERZ-treated patients < 6 years had at least one infection, compared to 53% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years. Sixteen percent of 70 AFINITOR DISPERZ-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients. Other Indications The safety and effectiveness of AFINITOR/AFINITOR DISPERZ in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer Neuroendocrine tumors (NET) Renal cell carcinoma (RCC) TSC-associated renal angiomyolipoma 8.5 Geriatric Use In BOLERO-2, 40% of patients with breast cancer treated with AFINITOR 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 AFINITOR 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 AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with AFINITOR 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 AFINITOR/AFINITOR DISPERZ exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. For patients with breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the AFINITOR dose as recommended [see Dosage and Administration (2.10)]. For patients with TSC-associated SEGA and TSC-associated partial-onset seizures who have severe hepatic impairment (Child-Pugh C), reduce the starting dose of AFINITOR/AFINITOR DISPERZ as recommended and adjust the dose based on everolimus trough concentrations [see Dosage and Administration (2.8, 2.10)].

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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ [see Warnings and Precautions (5.4)].

More information

Category Value
Authorisation number NDA022334
Agency product number 9HW64Q8G6G
Orphan designation No
Product NDC 0078-0594,0078-0566,0078-0567,0078-0628,0078-0620,0078-0627,0078-0626
Date Last Revised 06-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 998189
Marketing authorisation holder Novartis Pharmaceuticals Corporation