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Afinitor

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Afinitor

Side Effects
Interactions

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in another section of the label [see WARNINGS AND PRECAUTIONS]:

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.

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*

  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 Gastrointestinal disorders 100 41 9 90 22 5
  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 treatment® 23.9 weeks 13.4 weeks
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

Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC

  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
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.

Clinical Study Experience In Advanced Pancreatic Neuroendocrine Tumors

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 Caucasian, 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

  AFINITOR
N=204
Placebo
N=203
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Any adverse reaction Gastrointestinal disorders 100 49 13 98 32 8
  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
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.

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

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
Grading according to CTCAE Version 3.0

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 6 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 6: 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

  AFINITOR 10 mg/day
N=274
Placebo
N=137
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Any adverse reaction 97 52 13 93 23 5
Gastrointestinal disorders
  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 infestationsb 37 7 3 18 1 0
General disorders and administration site conditions
  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, thoracic and mediastinal disorders
  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 subcutaneous tissue disorders
  Rash 29 1 0 7 0 0
  Pruritus 14 < 1 0 7 0 0
  Dry skin 13 < 1 0 5 0 0
Metabolism and nutrition disorders
  Anorexia 25 1 0 14 < 1 0
Nervous system disorders
  Headache 19 < 1 < 1 9 < 1 0
  Dysgeusia 10 0 0 2 0 0
Musculoskeletal and connective tissue disorders
  Pain in extremity 10 1 0 7 0 0
  Median duration of treatment (d) 141 60
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.

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%)

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 7.

Table 7: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm

Laboratory parameter AFINITOR 10 mg/day
N=274
Placebo
N=137
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Hematologya
  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 chemistry
  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
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.

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 8 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 9.

Table 8: Adverse Reactions Reported in ≥ 10% of AFINITOR-treated Patients with Renal Angiomyolipoma

  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
Grading according to CTCAE Version 3.0
a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.

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%), and pneumonitis (1%).

Table 9: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with Renal Angiomyolipoma

  AFINITOI
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
Grading according to CTCAE Version 3.0

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 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 SEGA in Study 1

  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
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

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 11: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with SEGA in Study 1

  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
Grading according to CTCAE Version 3.0

Longer-term follow-up of 34.2 months (range 4.7 to 47.1 months) from a non-randomized, open-label, 28-patient trial resulted in the following additional notable adverse reactions and key laboratory abnormalities: cellulitis (29%), hyperglycemia (25%), and elevated creatinine (14%).

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 and reflex sympathetic dystrophy.

Read the Afinitor (everolimus tablets) Side Effects Center for a complete guide to possible side effects

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.

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 and WARNINGS AND PRECAUTIONS].

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 and WARNINGS AND PRECAUTIONS].

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].

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).

Coadministration 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.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

Read the Afinitor Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 7/14/2014
This monograph has been modified to include the generic and brand name in many instances.

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