Data from FDA (Food and Drug Administration, USA) - Curated by Toby Galbraith - Last updated 13 September 2017

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 (advanced HR+ BC) 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. 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: Pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. (1.5) 1.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC) AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 1.2 Advanced 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 neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. AFINITOR® is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)]. 1.3 Advanced Renal Cell Carcinoma (RCC) AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. 1.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC) AFINITOR® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. 1.5 Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC) AFINITOR® Tablets and AFINITOR® DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

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contraindications
4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label [see Warnings and Precautions (5)]: Non-infectious pneumonitis [see Warnings and Precautions (5.1)]. Infections [see Warnings and Precautions (5.2)]. Angioedema with concomitant use of ACE inhibitors [see Warnings and Precautions (5.3)]. Oral ulceration [see Warnings and Precautions (5.4)]. Renal failure [see Warnings and Precautions (5.5)]. Impaired wound healing [see Warnings and Precautions (5.6)]. 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. Advanced HR+ BC, advanced NET, advanced 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, 6.2, 6.3) Renal angiomyolipoma with TSC: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.4) SEGA with TSC: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. (6.5) 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 Study Experience in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of 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, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥10% of Patients with Advanced HR+ BC* Grading according to CTCAE Version 3.0 * 160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo AFINITOR (10 mg/day) + exemestanea N=482 Placebo + exemestanea N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders Stomatitisb 67 8 0 11 0.8 0 Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations Infectionsc 50 4 1 25 2 0 Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 Pneumonitisd 19 4 0.2 0.4 0 0 Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median duration of treatmente 23.9 weeks 13.4 weeks Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥10% of Patients with Advanced HR+ BC Grading according to CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. Laboratory parameter AFINITOR (10 mg/day) + exemestanea N=482 Placebo + exemestanea N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 6.2 Clinical Study Experience in Advanced Neuroendocrine Tumors Advanced Pancreatic Neuroendocrine Tumors (PNET) In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 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 decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on AFINITOR and one patient on placebo. 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. There was one death due to pulmonary embolism on the placebo arm. 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 rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm. Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 4: Adverse Reactions Reported ≥10% of Patients with Advanced PNET Grading according to 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. AFINITOR N=204 Placebo N=203 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 49 13 98 32 8 Gastrointestinal disorders Stomatitisa 70 7 0 20 0 0 Diarrheab 50 5 0.5 25 3 0 Abdominal pain 36 4 0 32 6 1 Nausea 32 2 0 33 2 0 Vomiting 29 1 0 21 2 0 Constipation 14 0 0 13 0.5 0 Dry mouth 11 0 0 4 0 0 General disorders and administration site conditions Fatigue/malaise 45 3 0.5 27 2 0.5 Edema (general and peripheral) 39 1 0.5 12 1 0 Fever 31 0.5 0.5 13 0.5 0 Asthenia 19 3 0 20 3 0 Infections and infestations Nasopharyngitis/rhinitis/URI 25 0 0 13 0 0 Urinary tract infection 16 0 0 6 0.5 0 Investigations Weight decreased 28 0.5 0 11 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 18 1 0 Diabetes mellitus 10 2 0 0.5 0 0 Musculoskeletal and connective tissue disorders Arthralgia 15 1 0.5 7 0.5 0 Back pain 15 1 0 11 1 0 Pain in extremity 14 0.5 0 6 1 0 Muscle spasms 10 0 0 4 0 0 Nervous system disorders Headache/migraine 30 0.5 0 15 1 0 Dysgeusia 19 0 0 5 0 0 Dizziness 12 0.5 0 7 0 0 Psychiatric disorders Insomnia 14 0 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough/productive cough 25 0.5 0 13 0 0 Epistaxis 22 0 0 1 0 0 Dyspnea/dyspnea exertional 20 2 0.5 7 0.5 0 Pneumonitisc 17 3 0.5 0 0 0 Oropharyngeal pain 11 0 0 6 0 0 Skin and subcutaneous disorders Rash 59 0.5 0 19 0 0 Nail disorders 22 0.5 0 2 0 0 Pruritus/pruritus generalized 21 0 0 13 0 0 Dry skin/xeroderma 13 0 0 6 0 0 Vascular disorders Hypertension 13 1 0 6 1 0 Median duration of treatment (wks) 37 16 In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females and none of the 33 females in the placebo group. Key observed laboratory abnormalities are presented in Table 5. Table 5: Key Laboratory Abnormalities Reported in ≥10% of Patients with Advanced PNET Grading according to CTCAE Version 3.0 Laboratory parameter AFINITOR N=204 Placebo N=203 All grades Grade 3-4 All grades Grade 3-4 % % % % Hematology Hemoglobin decreased 86 15 63 1 Lymphocytes decreased 45 16 22 4 Platelets decreased 45 3 11 0 WBC decreased 43 2 13 0 Neutrophils decreased 30 4 17 2 Clinical chemistry Alkaline phosphatase increased 74 8 66 8 Glucose (fasting) increased 75 17 53 6 Cholesterol increased 66 0.5 22 0 Bicarbonate decreased 56 0 40 0 Aspartate transaminase (AST) increased 56 4 41 4 Alanine transaminase (ALT) increased 48 2 35 2 Phosphate decreased 40 10 14 3 Triglycerides increased 39 0 10 0 Calcium decreased 37 0.5 12 0 Potassium decreased 23 4 5 0 Creatinine increased 19 2 14 0 Sodium decreased 16 1 16 1 Albumin decreased 13 1 8 0 Bilirubin increased 10 1 14 2 Potassium increased 7 0 10 0.5 Unresectable, Locally Advanced or Metastatic, Well-Differentiated, Non-Functional Neuroendocrine Tumors of Gastrointestinal or Lung Origin In a randomized, controlled trial of AFINITOR (n=202 treated) versus placebo (n=98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (range 22-86), 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). Table 6 and Table 7 summarize the incidence of adverse reactions of AFINITOR 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). Table 6: Adverse Reactions in ≥10% of AFINITOR-Treated Patients with Non-Functional NET of Gastrointestinal or Lung Origin† † Grading according to NCI CTCAE Version 4.03 a Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration and mucosal inflammation. b Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis. c Includes pneumonitis and interstitial lung disease. AFINITOR N=202 Placebo N=98 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 99 57 12 89 21 7 Gastrointestinal disorders Stomatitisa 63 9 0 22 0 0 Diarrhea 41 8 1 31 2 0 Nausea 26 3 1 17 1 0 Vomiting 15 4 0 12 2 0 General disorders and administration site conditions Peripheral edema 39 3 0 6 1 0 Fatigue 37 4 1 36 1 0 Asthenia 23 2 1 8 0 0 Pyrexia 23 1 1 8 0 0 Infections Infectionsb 58 8 3 29 1 1 Investigations Decreased weight 22 1 0 17 1 0 Metabolism and nutrition disorders Decreased appetite 22 1 0 17 1 0 Nervous system disorders Dysgeusia 18 1 0 4 0 0 Respiratory, thoracic and mediastinal disorders Cough 27 0 0 20 0 0 Dyspnea 20 3 0 11 1 1 Pneumonitisc 16 2 0 2 0 0 Epistaxis 13 1 0 3 0 0 Skin and subcutaneous disorders Rash 30 1 0 9 0 0 Pruritus 17 1 0 9 0 0 Table 7: Laboratory Abnormalities in ≥10% of AFINITOR-Treated Patients with Non-Functional NET of Gastrointestinal or Lung Origin† † Grading according to NCI CTCAE Version 4.03 AFINITOR N=202 Placebo N=98 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematology Anemia 81 5 0 41 2 0 Lymphopenia 66 15 2 32 2 0 Leukopenia 49 2 0 17 0 0 Thrombocytopenia 33 2 1 11 0 0 Neutropenia 32 2 0 15 3 0 Clinical chemistry Hypercholesterolemia 71 0 0 37 0 0 Elevated Aspartate transaminase (AST) 57 1 1 34 2 0 Hyperglycemia(fasting) 55 6 0 36 1 0 Elevated Alanine transaminase (ALT) 46 5 1 39 1 0 Hypophosphatemia 43 4 0 15 2 0 Hypertriglyceridemia 30 3 1 8 1 0 Hypokalemia 27 4 2 12 3 0 Hypoalbuminemia 18 0 0 8 0 0 6.3 Clinical Study Experience in Advanced Renal Cell Carcinoma The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving AFINITOR and 60 days (range 21-295 days) for those receiving placebo. 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 but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) 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. Table 8 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 8: Adverse Reactions Reported in at Least 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm Grading according to CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. AFINITOR 10 mg/day N=274 Placebo N=137 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any a dverse r eaction 97 52 13 93 23 5 Gastrointestinal d isorders Stomatitisa 44 4 <1 8 0 0 Diarrhea 30 1 0 7 0 0 Nausea 26 1 0 19 0 0 Vomiting 20 2 0 12 0 0 Infections and i nfestations b 37 7 3 18 1 0 General d isorders and a dministration s ite c onditions Asthenia 33 3 <1 23 4 0 Fatigue 31 5 0 27 3 <1 Edema peripheral 25 <1 0 8 <1 0 Pyrexia 20 <1 0 9 0 0 Mucosal inflammation 19 1 0 1 0 0 Respiratory, t horacic and m ediastinal d isorders Cough 30 <1 0 16 0 0 Dyspnea 24 6 1 15 3 0 Epistaxis 18 0 0 0 0 0 Pneumonitisc 14 4 0 0 0 0 Skin and s ubcutaneous t issue d isorders Rash 29 1 0 7 0 0 Pruritus 14 <1 0 7 0 0 Dry skin 13 <1 0 5 0 0 Metabolism and n utrition d isorders Anorexia 25 1 0 14 <1 0 Nervous s ystem d isorders Headache 19 <1 <1 9 <1 0 Dysgeusia 10 0 0 2 0 0 Musculoskeletal and c onnective t issue d isorders Pain in extremity 10 1 0 7 0 0 Medi an d uration of t reatment (d) 141 60 Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: 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 disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%) Vascular disorders: Hypertension (4%), deep vein thrombosis (< 1%) Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key laboratory abnormalities are presented in Table 9. Table 9: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm Grading according to 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. Laboratory p arameter AFINITOR 10 mg/day N=274 Placebo N=137 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematology a Hemoglobin decreased 92 12 1 79 5 <1 Lymphocytes decreased 51 16 2 28 5 0 Platelets decreased 23 1 0 2 0 <1 Neutrophils decreased 14 0 <1 4 0 0 Clinical c hemistry Cholesterol increased 77 4 0 35 0 0 Triglycerides increased 73 <1 0 34 0 0 Glucose increased 57 15 <1 25 1 0 Creatinine increased 50 1 0 34 0 0 Phosphate decreased 37 6 0 8 0 0 Aspartate transaminase (AST) increased 25 <1 <1 7 0 0 Alanine transaminase (ALT) increased 21 1 0 4 0 0 Bilirubin increased 3 <1 <1 2 0 0 6.4 Clinical Study Experience in Renal Angiomyolipoma with Tuberous Sclerosis Complex The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial 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 (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving AFINITOR and 45 weeks (range 9 to 115 weeks) for those receiving placebo. 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. Table 10 compares the incidence of adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 11. Table 10: Adverse Reactions Reported in ≥10% of AFINITOR-treated Patients with Renal Angiomyolipoma Grading according to CTCAE Version 3.0 a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. AFINITOR N=79 Placebo N=39 All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % Any adverse reaction 100 25 5 97 8 5 Gastrointestinal disorders Stomatitisa 78 6 0 23 0 0 Vomiting 15 0 0 5 0 0 Diarrhea 14 0 0 5 0 0 General disorders and administration site conditions Peripheral edema 13 0 0 8 0 0 Infections and infestations Upper respiratory tract infection 11 0 0 5 0 0 Musculoskeletal and connective tissue disorders Arthralgia 13 0 0 5 0 0 Respiratory, thoracic and mediastinal disorders Cough 20 0 0 13 0 0 Skin and subcutaneous tissue disorders Acne 22 0 0 5 0 0 Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. 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 11: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with Renal Angiomyolipoma Grading according to CTCAE Version 3.0 AFINITOR N=79 Placebo N=39 All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % Hematology Anemia 61 0 0 49 0 0 Leucopenia 37 0 0 21 0 0 Neutropenia 25 0 1 26 0 0 Lymphopenia 20 1 0 8 0 0 Thrombocytopenia 19 0 0 3 0 0 Clinical chemistry Hypercholesterolemia 85 1 0 46 0 0 Hypertriglyceridemia 52 0 0 10 0 0 Hypophosphatemia 49 5 0 15 0 0 Alkaline phosphatase increased 32 1 0 10 0 0 Elevated aspartate transaminase (AST) 23 1 0 8 0 0 Elevated alanine transaminase (ALT) 20 1 0 15 0 0 Fasting hyperglycemia 14 0 0 8 0 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 key 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%). 6.5 Clinical Study Experience in Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (Study 1) of AFINITOR in 117 patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The median age of patients was 9.5 years (range 0.8 to 26 years), 93% were Caucasian, and 57% were male. The median duration of blinded study treatment was 52 weeks (range 24 to 89 weeks) for patients receiving AFINITOR and 47 weeks (range 14 to 88 weeks) for those receiving placebo. 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 key 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. Table 12 compares the incidence of adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 13. Table 12: Adverse Reactions Reported in ≥10% of AFINITOR-treated Patients with SEGA in Study 1 Grading according to 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 AFINITOR N=78 Placebo N=39 All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % Any adverse reaction 97 36 3 92 23 3 Gastrointestinal disorders Stomatitisa 62 9 0 26 3 0 Vomiting 22 1 0 13 0 0 Diarrhea 17 0 0 5 0 0 Constipation 10 0 0 3 0 0 Infections and infestations Respiratory tract infectionb 31 1 1 23 0 0 Gastroenteritisc 10 4 1 3 0 0 Pharyngitis streptococcal 10 0 0 3 0 0 General disorders and administration site conditions Pyrexia 23 6 0 18 3 0 Fatigue 14 0 0 3 0 0 Psychiatric disorders Anxiety, aggression or other behavioral disturbanced 21 5 0 3 0 0 Skin and subcutaneous tissue disorders Rashe 21 0 0 8 0 0 Acne 10 0 0 5 0 0 Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. 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 13: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with SEGA in Study 1 Grading according to CTCAE Version 3.0 AFINITOR N=78 Placebo N=39 All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % Hematology Elevated partial thromboplastin time 72 3 0 44 5 0 Neutropenia 46 9 0 41 3 0 Anemia 41 0 0 21 0 0 Clinical chemistry Hypercholesterolemia 81 0 0 39 0 0 Elevated aspartate transaminase (AST) 33 0 0 0 0 0 Hypertriglyceridemia 27 0 0 15 0 0 Elevated alanine transaminase (ALT) 18 0 0 3 0 0 Hypophosphatemia 9 1 0 3 0 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 key 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 azospermia (1%). 6.6 Postmarketing Experience The following adverse reactions have been identified during post approval use of AFINITOR. 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: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events, reflex sympathetic dystrophy, and cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION AFINITOR is available in two dosage forms: tablets (AFINITOR Tablets) and tablets for oral suspension (AFINITOR DISPERZ). AFINITOR Tablets may be used for all approved indications. AFINITOR DISPERZ is approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). Advanced HR+ BC, advanced NET, advanced RCC, or renal angiomyolipoma with TSC: 10 mg once daily with or without food. (2.1) For patients with hepatic impairment, reduce the AFINITOR dose. (2.2) If moderate inhibitors of CYP3A4/P-glycoprotein (PgP) are required, reduce the AFINITOR dose to 2.5 mg once daily; if tolerated, consider increasing to 5 mg once daily. (2.2) If strong inducers of CYP3A4 are required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. (2.2) SEGA with TSC: 4.5 mg/m2 once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. (2.3) Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. (2.3, 2.4) For patients with severe hepatic impairment reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5) If concomitant use of moderate inhibitors of CYP3A4/PgP is required, reduce the dose of AFINITOR Tablets or AFINITOR DISPERZ by 50%. (2.3, 2.5) If concomitant use of strong inducers of CYP3A4/PgP is required, double the dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5) 2.1 Recommended Dose in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced NET, Advanced RCC, and Renal Angiomyolipoma with TSC The recommended dose of AFINITOR Tablets is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)]. AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets. Continue treatment until disease progression or unacceptable toxicity occurs. 2.2 Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced NET, Advanced RCC, and Renal Angiomyolipoma with TSC Adverse Reactions Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of AFINITOR therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered [see Warnings and Precautions (5)]. Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of AFINITOR in the management of adverse reactions. General management recommendations are also provided as applicable. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. Table 1: AFINITOR Dose Adjustment and Management Recommendation for Adverse Reactions a Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms. b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered. c Activities of daily living (ADL) d Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they may worsen mouth ulcers. Adverse Reaction Severitya AFINITOR Dose Adjustmentb and Management Recommendations Non-infectious pneumonitis Grade 1 Asymptomatic, radiographic findings only No dose adjustment required. Initiate appropriate monitoring. Grade 2 Symptomatic, not interfering with ADLc Consider interruption of therapy, rule out infection and consider treatment with corticosteroids until symptoms improve to ≤ Grade 1. Re-initiate AFINITOR at a lower dose. Discontinue treatment if failure to recover within 4 weeks. Grade 3 Symptomatic, interfering with ADLc; O2 indicated Interrupt AFINITOR until symptoms resolve to ≤ Grade 1. Rule out infection, and consider treatment with corticosteroids. Consider re-initiating AFINITOR at a lower dose. If toxicity recurs at Grade 3, consider discontinuation. Grade 4 Life-threatening, ventilatory support indicated Discontinue AFINITOR, rule out infection, and consider treatment with corticosteroids. Stomatitis Grade 1 Minimal symptoms, normal diet No dose adjustment required. Manage with non-alcoholic or salt water (0.9%) mouthwash several times a day. Grade 2 Symptomatic but can eat and swallow modified diet Temporary dose interruption until recovery to Grade ≤1. Re-initiate AFINITOR at the same dose. If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate AFINITOR at a lower dose. Manage with topical analgesic mouth treatments (e.g., benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e., triamcinolone oral paste).d Grade 3 Symptomatic and unable to adequately aliment or hydrate orally Temporary dose interruption until recovery to Grade ≤1. Re-initiate AFINITOR at a lower dose. Manage with topical analgesic mouth treatments (i.e., benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e., triamcinolone oral paste).d Grade 4 Symptoms associated with life-threatening consequences Discontinue AFINITOR and treat with appropriate medical therapy. Other non-hematologic toxicities (excluding metabolic events) Grade 1 If toxicity is tolerable, no dose adjustment required. Initiate appropriate medical therapy and monitor. Grade 2 If toxicity is tolerable, no dose adjustment required. Initiate appropriate medical therapy and monitor. If toxicity becomes intolerable, temporary dose interruption until recovery to Grade ≤1. Reinitiate AFINITOR at the same dose. If toxicity recurs at Grade 2, interrupt AFINITOR until recovery to Grade ≤1. Reinitiate AFINITOR at a lower dose. Grade 3 Temporary dose interruption until recovery to Grade ≤1. Initiate appropriate medical therapy and monitor. Consider reinitiating AFINITOR at a lower dose. If toxicity recurs at Grade 3, consider discontinuation. Grade 4 Discontinue AFINITOR and treat with appropriate medical therapy. Metabolic events (e.g. hyperglycemia, dyslipidemia) Grade 1 No dose adjustment required. Initiate appropriate medical therapy and monitor. Grade 2 No dose adjustment required. Manage with appropriate medical therapy and monitor. Grade 3 Temporary dose interruption. Reinitiate AFINITOR at a lower dose. Manage with appropriate medical therapy and monitor. Grade 4 Discontinue AFINITOR and treat with appropriate medical therapy. Hepatic Impairment Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.8)]. Dose adjustments are recommended: Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated. Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated. Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded. Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment. CYP3A4/P-glycoprotein (PgP) Inhibitors Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see Warnings and Precautions (5.9) and Drug Interactions (7.1)]. Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/PgP inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor. Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. Strong CYP3A4/PgP Inducers Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. This dose of AFINITOR is predicted, based on pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4/PgP inducers. If the strong inducer is discontinued, consider a washout period of 3 to 5 days, before the AFINITOR dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer [see Warnings and Precautions (5.9) and Drug Interactions (7.2)]. St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided. 2.3 Recommended Dose in SEGA with TSC The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily [see Dosage and Administration (2.5)]. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily [see Dosage and Administration (2.5)]. Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ. Do not combine AFINITOR Tablets and AFINITOR DISPERZ to achieve the desired total dose. Use therapeutic drug monitoring to guide subsequent dosing [see Dosage and Administration (2.4)]. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL [see Dosage and Administration (2.4, 2.5)]. Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown. 2.4 Therapeutic Drug Monitoring in SEGA with TSC Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment. Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. Once a stable dose is attained, monitor trough concentrations every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body surface area for the duration of treatment. Titrate the dose to attain trough concentrations of 5 to 15 ng/mL. For trough concentrations less than 5 ng/mL, increase the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ). For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ). If dose reduction is required for patients receiving the lowest available strength, administer every other day. 2.5 Dose Modifications in SEGA with TSC Adverse Reactions Temporarily interrupt or permanently discontinue AFINITOR Tablets or AFINITOR DISPERZ for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50% [see Dosage and Administration (2.2) and Warnings and Precautions (5)]. If dose reduction is required for patients receiving the lowest available strength, administer every other day. Hepatic Impairment Reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% in patients with SEGA who have severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.3)]. Adjustment to the starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment may not be needed. Subsequent dosing should be based on therapeutic drug monitoring. Assess everolimus trough concentrations approximately 2 weeks after commencing treatment, a change in dose, or any change in hepatic function [see Dosage and Administration (2.3, 2.4)]. CYP3A4/P-glycoprotein (PgP) Inhibitors Avoid the use of concomitant strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving AFINITOR Tablets or AFINITOR DISPERZ [see Warnings and Precautions (5.9) and Drug Interactions (7.1)]. For patients who require treatment with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem): Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL [see Dosage and Administration (2.3, 2.4)]. Assess everolimus trough concentrations approximately 2 weeks after dose reduction [see Dosage and Administration (2.3, 2.4)]. Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later [see Dosage and Administration (2.3, 2.4)]. Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice) that are known to inhibit cytochrome P450 or PgP activity. Strong CYP3A4/PgP Inducers Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available [see Warnings and Precautions (5.9) and Drug Interactions (7.2)]. For patients who require treatment with a strong CYP3A4/PgP inducer: Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability [see Dosage and Administration (2.3)]. Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL [see Dosage and Administration (2.3, 2.4)]. Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later [see Dosage and Administration (2.3, 2.4)]. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. 2.6 Administration of AFINITOR Tablets in SEGA with TSC Do not combine the 2 dosage forms (AFINITOR Tablets and AFINITOR DISPERZ) to achieve the desired total dose. Use one dosage form or the other. Administer AFINITOR Tablets orally once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)]. AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets. 2.7 Administration and Preparation of AFINITOR DISPERZ in SEGA with TSC Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person. Do not combine the 2 dosage forms (AFINITOR Tablets and AFINITOR DISPERZ) to achieve the desired total dose. Use one dosage form or the other. Administer AFINITOR DISPERZ (everolimus tablets for oral suspension) as a suspension only. Administer AFINITOR DISPERZ orally once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)]. Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation. Prepare suspension in water only. Using an oral syringe: Place the prescribed dose of AFINITOR DISPERZ 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 AFINITOR DISPERZ 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: Place the prescribed dose of AFINITOR DISPERZ into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg of AFINITOR DISPERZ 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 Lactation: Breast feeding not recommended. (8.2) Females and Males of Reproductive Potential: May impair fertility. (8.3) Hepatic impairment: For advanced HR+ BC, advanced NET, advanced RCC, or renal angiomyolipoma with TSC patients with hepatic impairment, reduce AFINITOR dose. For SEGA patients with severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.2, 2.3, 2.5, 5.10, 8.8) 8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], AFINITOR 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 clinical dose of 10 mg daily [see Data]. Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2-4% and 15-20% 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 exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. 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 in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and/or 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 lactating women not to breastfeed during treatment with AFINITOR and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential AFINITOR can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to seek counseling on fertility and family planning options prior to starting treatment with AFINITOR. Contraception Females Advise female patients of reproductive potential to use effective contraception while using AFINITOR and for 8 weeks after ending treatment with AFINITOR [see Use in Specific Populations (8.1)]. Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology (13.1)]. Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5)]. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were <3 years of age, 54 patients were 3 to <12 years of age, 27 patients were 12 to <18 years of age, and 16 patients were ≥18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients <3 years of age. A total of 6 of 13 patients (46%) <3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5)]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to <12 years, 6 patients were 12 to <18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5)]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. 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 Study 1 and Study 2, 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. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3)]. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4)]. 8.5 Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 years and over. 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 [see Warnings and Precautions (5.7)]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥65 years of age, while 7% were 75 years and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3)]. For advanced HR+ BC, advanced NET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2)]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [ see Dosage and Administration (2.4, 2.5)].

Interactions

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Strong CYP3A4/PgP inhibitors: Avoid concomitant use. (2.2, 2.5, 5.9, 7.1) Moderate CYP3A4/PgP inhibitors: If combination is required, use caution and reduce dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.1) Strong CYP3A4/PgP inducers: Avoid concomitant use. If combination cannot be avoided, increase dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.2) 7.1 Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) and Warnings and Precautions (5.9)]. Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) and Warnings and Precautions (5.9)]. 7.2 Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5)]. 7.3 Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Co-administration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Co-administration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

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 14-06-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 998189
Marketing authorisation holder Novartis Pharmaceuticals Corporation