Afinitor (Page 4 of 12)

5.13 Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. 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 clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

  • Non-Infectious Pneumonitis [see Warnings and Precautions (5.1)]
  • Infections [see Warnings and Precautions (5.2)]
  • Severe Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
  • Angioedema with Concomitant Use of ACE inhibitors [see Warnings and Precautions (5.4)]
  • Stomatitis [see Warnings and Precautions (5.5)]
  • Renal Failure [see Warnings and Precautions (5.6)]
  • Impaired Wound Healing [see Warnings and Precautions (5.7)]
  • Metabolic Disorders [see Warnings and Precautions (5.9)]
  • Myelosuppression [see Warnings and Precautions (5.10)]
  • Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.12)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Hormone Receptor-Positive, HER2-Negative Breast Cancer

The safety of AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were White. The median follow-up was approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks.

Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2
Grading according to NCI CTCAE Version 3.0.a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration.b Includes all reported infections, including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections.c Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. d No Grade 4 adverse reactions were reported.
AFINITOR with Exemestane N = 482 Placebo with Exemestane N = 238
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 67 8d 11 0.8
Diarrhea 33 2 18 0.8
Nausea 29 0.4 28 1
Vomiting 17 1 12 0.8
Constipation 14 0.4d 13 0.4
Dry mouth 11 0 7 0
General
Fatigue 36 4 27 1d
Edema peripheral 19 1d 6 0.4d
Pyrexia 15 0.2d 7 0.4d
Asthenia 13 2 4 0
Infections
Infectionsb 50 6 25 2d
Investigations
Weight loss 25 1d 6 0
Metabolism and nutrition
Decreased appetite 30 1d 12 0.4d
Hyperglycemia 14 5 2 0.4d
Musculoskeletal and connective tissue
Arthralgia 20 0.8d 17 0
Back pain 14 0.2d 10 0.8d
Pain in extremity 9 0.4d 11 2d
Nervous system
Dysgeusia 22 0.2d 6 0
Headache 21 0.4d 14 0
Psychiatric
Insomnia 13 0.2d 8 0
Respiratory, thoracic and mediastinal
Cough 24 0.6d 12 0
Dyspnea 21 4 11 1
Epistaxis 17 0 1 0
Pneumonitisc 19 4 0.4 0
Skin and subcutaneous tissue
Rash 39 1d 6 0
Pruritus 13 0.2d 5 0
Alopecia 10 0 5 0
Vascular
Hot flush 6 0 14 0
Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2
Grading according to NCI CTCAE Version 3.0.a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.b No Grade 4 laboratory abnormalities were reported.
Laboratory Parameter AFINITOR with Exemestane N = 482 Placebo with Exemestane N = 238
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematologya
Anemia 68 6 40 1
Leukopenia 58 2b 28 6
Thrombocytopenia 54 3 5 0.4
Lymphopenia 54 12 37 6
Neutropenia 31 2b 11 2
Chemistry
Hypercholesterolemia 70 1 38 2
Hyperglycemia 69 9 44 1
Increased AST 69 4 45 3
Increased ALT 51 4 29 5b
Hypertriglyceridemia 50 0.8b 26 0
Hypoalbuminemia 33 0.8b 16 0.8b
Hypokalemia 29 4 7 1b
Increased creatinine 24 2 13 0

Topical Prophylaxis for Stomatitis

In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5 mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with AFINITOR and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.

Coadministration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

Pancreatic Neuroendocrine Tumors (PNET)

In a randomized, controlled trial (RADIANT-3) of AFINITOR (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia.

Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on AFINITOR. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the AFINITOR group. Dose delay or reduction was necessary in 61% of AFINITOR patients. Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received AFINITOR was 37 weeks.

In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females.

Table 8: Adverse Reactions Reported in ≥ 10% of Patients with PNET in RADIANT-3
Grading according to NCI CTCAE Version 3.0.a Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation.b Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.c Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease.d No Grade 4 adverse reactions were reported.
AFINITOR N = 204 Placebo N = 203
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 70 7d 20 0
Diarrheab 50 6 25 3d
Abdominal pain 36 4d 32 7
Nausea 32 2d 33 2d
Vomiting 29 1d 21 2d
Constipation 14 0 13 0.5d
Dry mouth 11 0 4 0
General
Fatigue/malaise 45 4 27 3
Edema (general and peripheral) 39 2 12 1d
Fever 31 1 13 0.5d
Asthenia 19 3d 20 3d
Infections
Nasopharyngitis/rhinitis/URI 25 0 13 0
Urinary tract infection 16 0 6 0.5d
Investigations
Weight loss 28 0.5d 11 0
Metabolism and nutrition
Decreased appetite 30 1d 18 1d
Diabetes mellitus 10 2d 0.5 0
Musculoskeletal and connective tissue
Arthralgia 15 1 7 0.5d
Back pain 15 1d 11 1d
Pain in extremity 14 0.5d 6 1d
Muscle spasms 10 0 4 0
Nervous system
Headache/migraine 30 0.5d 15 1d
Dysgeusia 19 0 5 0
Dizziness 12 0.5d 7 0
Psychiatric
Insomnia 14 0 8 0
Respiratory, thoracic and mediastinal
Cough/productive cough 25 0.5d 13 0
Epistaxis 22 0 1 0
Dyspnea/dyspnea exertional 20 3 7 0.5d
Pneumonitisc 17 4 0 0
Oropharyngeal pain 11 0 6 0
Skin and subcutaneous
Rash 59 0.5 19 0
Nail disorders 22 0.5 2 0
Pruritus/pruritus generalized 21 0 13 0
Dry skin/xeroderma 13 0 6 0
Vascular
Hypertension 13 1 6 1d
Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with PNET in RADIANT-3
Grading according to NCI CTCAE Version 3.0.
Laboratory parameter AFINITOR N = 204 Placebo N = 203
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematology
Anemia 86 15 63 1
Lymphopenia 45 16 22 4
Thrombocytopenia 45 3 11 0
Leukopenia 43 2 13 0
Neutropenia 30 4 17 2
Chemistry
Hyperglycemia (fasting) 75 17 53 6
Increased alkaline phosphatase 74 8 66 8
Hypercholesterolemia 66 0.5 22 0
Bicarbonate decreased 56 0 40 0
Increased AST 56 4 41 4
Increased ALT 48 2 35 2
Hypophosphatemia 40 10 14 3
Hypertriglyceridemia 39 0 10 0
Hypocalcemia 37 0.5 12 0
Hypokalemia 23 4 5 0
Increased creatinine 19 2 14 0
Hyponatremia 16 1 16 1
Hypoalbuminemia 13 1 8 0
Hyperbilirubinemia 10 1 14 2
Hyperkalemia 7 0 10 0.5

Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin

In a randomized, controlled trial (RADIANT-4) of AFINITOR (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were White, and 53% were female. The median duration of exposure to AFINITOR was 9.3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months. AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients.

Serious adverse reactions occurred in 42% of AFINITOR-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Adverse reactions occurring at an incidence of ≥ 10% and at ≥ 5% absolute incidence over placebo (all Grades) or ≥ 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11.

Table 10: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4
Grading according to NCI CTCAE Version 4.03.a Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation.b Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis.c Includes pneumonitis and interstitial lung disease.d No Grade 4 adverse reactions were reported.
AFINITOR N = 202 Placebo N = 98
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 63 9d 22 0
Diarrhea 41 9 31 2d
Nausea 26 3 17 1d
Vomiting 15 4d 12 2d
General
Peripheral edema 39 3d 6 1d
Fatigue 37 5 36 1d
Asthenia 23 3 8 0
Pyrexia 23 2 8 0
Infections
Infectionsb 58 11 29 2
Investigations
Weight loss 22 2d 11 1d
Metabolism and nutrition
Decreased appetite 22 1d 17 1d
Nervous system
Dysgeusia 18 1d 4 0
Respiratory, thoracic and mediastinal
Cough 27 0 20 0
Dyspnea 20 3d 11 2
Pneumonitisc 16 2d 2 0
Epistaxis 13 1d 3 0
Skin and subcutaneous
Rash 30 1d 9 0
Pruritus 17 1d 9 0
Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4
Grading according to NCI CTCAE Version 4.03.a No Grade 4 laboratory abnormalities were reported.
AFINITOR N = 202 Placebo N = 98
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematology
Anemia 81 5a 41 2a
Lymphopenia 66 16 32 2a
Leukopenia 49 2a 17 0
Thrombocytopenia 33 2 11 0
Neutropenia 32 2a 15 3a
Chemistry
Hypercholesterolemia 71 0 37 0
Increased AST 57 2 34 2a
Hyperglycemia (fasting) 55 6a 36 1a
Increased ALT 46 5 39 1a
Hypophosphatemia 43 4a 15 2a
Hypertriglyceridemia 30 3 8 1a
Hypokalemia 27 6 12 3a
Hypoalbuminemia 18 0 8 0

Renal Cell Carcinoma (RCC)

The data described below reflect exposure to AFINITOR (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving AFINITOR.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia.

Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the AFINITOR group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13.

Table 12: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm in RECORD-1
Grading according to NCI CTCAE Version 3.0.a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.b Includes all reported infections, including but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections.c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.d No Grade 4 adverse reactions were reported.
AFINITOR N = 274 Placebo N = 137
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 44 4 8 0
Diarrhea 30 2d 7 0
Nausea 26 2d 19 0
Vomiting 20 2d 12 0
Infectionsb 37 10 18 2
General
Asthenia 33 4 23 4
Fatigue 31 6d 27 4
Edema peripheral 25 < 1d 8 < 1d
Pyrexia 20 < 1d 9 0
Mucosal inflammation 19 2d 1 0
Respiratory, thoracic and mediastinal
Cough 30 < 1d 16 0
Dyspnea 24 8 15 3d
Epistaxis 18 0 0 0
Pneumonitisc 14 4d 0 0
Skin and subcutaneous tissue
Rash 29 1d 7 0
Pruritus 14 < 1d 7 0
Dry skin 13 < 1d 5 0
Metabolism and nutrition
Anorexia 25 2d 14 < 1d
Nervous system
Headache 19 1 9 < 1d
Dysgeusia 10 0 2 0
Musculoskeletal and connective tissue
Pain in extremity 10 1d 7 0

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:

Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)

General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%)

Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)

Skin and subcutaneous tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (< 1%)

Metabolism and nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%)

Psychiatric: Insomnia (9%)

Nervous system: Dizziness (7%), paresthesia (5%)

Ocular: Eyelid edema (4%), conjunctivitis (2%)

Vascular: Hypertension (4%), deep vein thrombosis (< 1%)

Renal and urinary: Renal failure (3%)

Cardiac: Tachycardia (3%), congestive cardiac failure (1%)

Musculoskeletal and connective tissue: Jaw pain (3%)

Hematologic: Hemorrhage (3%)

Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm Than the Placebo Arm in RECORD-1
Grading according to NCI CTCAE Version 3.0.a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.b No Grade 4 laboratory abnormalities were reported.
Laboratory parameter AFINITOR N = 274 Placebo N = 137
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematologya
Anemia 92 13 79 6
Lymphopenia 51 18 28 5b
Thrombocytopenia 23 1b 2 < 1
Neutropenia 14 < 1 4 0
Chemistry
Hypercholesterolemia 77 4b 35 0
Hypertriglyceridemia 73 < 1b 34 0
Hyperglycemia 57 16 25 2b
Increased creatinine 50 2b 34 0
Hypophosphatemia 37 6b 8 0
Increased AST 25 1 7 0
Increased ALT 21 1b 4 0
Hyperbilirubinemia 3 1 2 0

Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were White, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving AFINITOR.

The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia.

The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15.

Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2
Grading according to NCI CTCAE Version 3.0.a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.b No Grade 4 adverse reactions were reported.
AFINITOR N = 79 Placebo N = 39
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 78 6b 23 0
Vomiting 15 0 5 0
Diarrhea 14 0 5 0
General
Peripheral edema 13 0 8 0
Infections
Upper respiratory tract infection 11 0 5 0
Musculoskeletal and connective tissue
Arthralgia 13 0 5 0
Respiratory, thoracic and mediastinal
Cough 20 0 13 0
Skin and subcutaneous tissue
Acne 22 0 5 0

Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).

The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%).

Table 15: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2
Grading according to NCI CTCAE Version 3.0.a No Grade 4 laboratory abnormalities were reported.
AFINITOR N = 79 Placebo N = 39
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematology
Anemia 61 0 49 0
Leukopenia 37 0 21 0
Neutropenia 25 1 26 0
Lymphopenia 20 1a 8 0
Thrombocytopenia 19 0 3 0
Chemistry
Hypercholesterolemia 85 1a 46 0
Hypertriglyceridemia 52 0 10 0
Hypophosphatemia 49 5a 15 0
Increased alkaline phosphatase 32 1a 10 0
Increased AST 23 1a 8 0
Increased ALT 20 1a 15 0
Hyperglycemia (fasting) 14 0 8 0

Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%).

TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA)

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were White, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR.

The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia.

There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17.

Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1
Grading according to NCI CTCAE Version 3.0.a Includes mouth ulceration, stomatitis, and lip ulceration.b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral.c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection.d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder.e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria.f No Grade 4 adverse reactions were reported.
AFINITOR N = 78 Placebo N = 39
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 62 9f 26 3f
Vomiting 22 1f 13 0
Diarrhea 17 0 5 0
Constipation 10 0 3 0
Infections
Respiratory tract infectionb 31 3 23 0
Gastroenteritisc 10 5 3 0
Pharyngitis streptococcal 10 0 3 0
General
Pyrexia 23 6f 18 3f
Fatigue 14 0 3 0
Psychiatric
Anxiety, aggression or other behavioral disturbanced 21 5f 3 0
Skin and subcutaneous tissue
Rashe 21 0 8 0
Acne 10 0 5 0

Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).

The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%), and pneumonitis (1%).

Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1
Grading according to NCI CTCAE Version 3.0.a No Grade 4 laboratory abnormalities were reported.
AFINITOR N = 78 Placebo N = 39
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematology
Elevated partial thromboplastin time 72 3a 44 5a
Neutropenia 46 9a 41 3a
Anemia 41 0 21 0
Chemistry
Hypercholesterolemia 81 0 39 0
Elevated AST 33 0 0 0
Hypertriglyceridemia 27 0 15 0
Elevated ALT 18 0 3 0
Hypophosphatemia 9 1a 3 0

Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%).

TSC-Associated Partial-Onset Seizures

The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to AFINITOR DISPERZ low trough (LT) (n = 117), AFINITOR DISPERZ high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were White, and 52% were male. Patients received between one and three concomitant antiepileptic drugs.

The most common adverse reaction reported for AFINITOR DISPERZ in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia.

Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 18. Laboratory abnormalities are presented in Table 19.

Table 18: Adverse Reactions Reported in ≥ 10% of AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures in EXIST-3
a Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain.b No Grade 4 adverse reactions were reported.
AFINITOR DISPERZ Placebo
Target of3-7 ng/mLN = 117 Target of9-15 ng/mLN = 130 N=119
All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 55 3b 64 4b 9 0
Diarrhea 17 0 22 0 5 0
Vomiting 12 0 10 2b 9 0
Infections
Nasopharyngitis 14 0 16 0 16 0
Upper respiratory tract infection 13 0 15 0 13 0.8b
General
Pyrexia 20 0 14 0.8b 5 0
Respiratory, thoracic and mediastinal
Cough 11 0 10 0 3 0
Skin and subcutaneous tissue
Rash 6 0 10 0 3 0

The following additional adverse reactions occurred in < 10% of AFINITOR DISPERZ treated patients (% AFINITOR DISPERZ LT, % AFINITOR DISPERZ HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%).

Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures
Grading according to NCI CTCAE version 4.03.a No Grade 4 laboratory abnormalities were reported.
AFINITOR DISPERZ Placebo
Target of3-7 ng/mLN = 117 Target of9-15 ng/mLN = 130 N=119
All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Neutropenia 25 4a 37 6 23 7a
Anemia 27 0.9a 30 0 21 0.8a
Thrombocytopenia 12 0 15 0 6 0
Chemistry
Hypercholesterolemia 86 0 85 0.8a 58 0
Hypertriglyceridemia 43 2a 39 2 22 0
Increased ALT 17 0 22 0 6 0
Increased AST 13 0 19 0 4 0
Hyperglycemia 19 0 18 0 17 0
Increased alkaline phosphatase 24 0 16 0 29 0
Hypophosphatemia 9 0.9a 16 2 3 0

Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

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