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. aIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. bIncludes all reported infections, including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. cIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. dNo Grade 4 adverse reactions were reported.
	AFINITOR with Exemestane N = 482		Placebo with Exemestane N = 238
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Gastrointestinal
Stomatitisa	67	8d	11	0.8
Diarrhea	33	2	18	0.8
Nausea	29	0.4	28	1
Vomiting	17	1	12	0.8
Constipation	14	0.4d	13	0.4
Dry mouth	11	0	7	0
General
Fatigue	36	4	27	1d
Edema peripheral	19	1d	6	0.4d
Pyrexia	15	0.2d	7	0.4d
Asthenia	13	2	4	0
Infections
Infectionsb	50	6	25	2d
Investigations
Weight loss	25	1d	6	0
Metabolism and nutrition
Decreased appetite	30	1d	12	0.4d
Hyperglycemia	14	5	2	0.4d
Musculoskeletal and connective tissue
Arthralgia	20	0.8d	17	0
Back pain	14	0.2d	10	0.8d
Pain in extremity	9	0.4d	11	2d
Nervous system
Dysgeusia	22	0.2d	6	0
Headache	21	0.4d	14	0
Psychiatric
Insomnia	13	0.2d	8	0
Respiratory, thoracic and mediastinal
Cough	24	0.6d	12	0
Dyspnea	21	4	11	1
Epistaxis	17	0	1	0
Pneumonitisc	19	4	0.4	0
Skin and subcutaneous tissue
Rash	39	1d	6	0
Pruritus	13	0.2d	5	0
Alopecia	10	0	5	0
Vascular
Hot flush	6	0	14	0

Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2
Grading according to NCI CTCAE Version 3.0. aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. bNo Grade 4 laboratory abnormalities were reported.
Laboratory Parameter	AFINITOR with Exemestane N = 482		Placebo with Exemestane N = 238
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematologya
Anemia	68	6	40	1
Leukopenia	58	2b	28	6
Thrombocytopenia	54	3	5	0.4
Lymphopenia	54	12	37	6
Neutropenia	31	2b	11	2
Chemistry
Hypercholesterolemia	70	1	38	2
Hyperglycemia	69	9	44	1
Increased 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. aIncludes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. bIncludes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. cIncludes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. dNo Grade 4 adverse reactions were reported.
	AFINITOR N = 204		Placebo N = 203
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Gastrointestinal
Stomatitisa	70	7d	20	0
Diarrheab	50	6	25	3d
Abdominal pain	36	4d	32	7
Nausea	32	2d	33	2d
Vomiting	29	1d	21	2d
Constipation	14	0	13	0.5d
Dry mouth	11	0	4	0
General
Fatigue/malaise	45	4	27	3
Edema (general and peripheral)	39	2	12	1d
Fever	31	1	13	0.5d
Asthenia	19	3d	20	3d
Infections
Nasopharyngitis/rhinitis/URI	25	0	13	0
Urinary tract infection	16	0	6	0.5d
Investigations
Weight loss	28	0.5d	11	0
Metabolism and nutrition
Decreased appetite	30	1d	18	1d
Diabetes mellitus	10	2d	0.5	0
Musculoskeletal and connective tissue
Arthralgia	15	1	7	0.5d
Back pain	15	1d	11	1d
Pain in extremity	14	0.5d	6	1d
Muscle spasms	10	0	4	0
Nervous system
Headache/migraine	30	0.5d	15	1d
Dysgeusia	19	0	5	0
Dizziness	12	0.5d	7	0
Psychiatric
Insomnia	14	0	8	0
Respiratory, thoracic and mediastinal
Cough/productive cough	25	0.5d	13	0
Epistaxis	22	0	1	0
Dyspnea/dyspnea exertional	20	3	7	0.5d
Pneumonitisc	17	4	0	0
Oropharyngeal pain	11	0	6	0
Skin and subcutaneous
Rash	59	0.5	19	0
Nail disorders	22	0.5	2	0
Pruritus/pruritus generalized	21	0	13	0
Dry skin/xeroderma	13	0	6	0
Vascular
Hypertension	13	1	6	1d

Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With PNET in RADIANT-3
Grading according to NCI CTCAE Version 3.0.
Laboratory parameter	AFINITOR N = 204		Placebo N = 203
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematology
Anemia	86	15	63	1
Lymphopenia	45	16	22	4
Thrombocytopenia	45	3	11	0
Leukopenia	43	2	13	0
Neutropenia	30	4	17	2
Chemistry
Hyperglycemia (fasting)	75	17	53	6
Increased alkaline phosphatase	74	8	66	8
Hypercholesterolemia	66	0.5	22	0
Bicarbonate decreased	56	0	40	0
Increased AST	56	4	41	4
Increased ALT	48	2	35	2
Hypophosphatemia	40	10	14	3
Hypertriglyceridemia	39	0	10	0
Hypocalcemia	37	0.5	12	0
Hypokalemia	23	4	5	0
Increased creatinine	19	2	14	0
Hyponatremia	16	1	16	1
Hypoalbuminemia	13	1	8	0
Hyperbilirubinemia	10	1	14	2
Hyperkalemia	7	0	10	0.5

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

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

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

Table 10: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4
Grading according to NCI CTCAE Version 4.03. aIncludes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation. bUrinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis. cIncludes pneumonitis and interstitial lung disease. dNo Grade 4 adverse reactions were reported.
	AFINITOR N = 202		Placebo N = 98
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Gastrointestinal
Stomatitisa	63	9d	22	0
Diarrhea	41	9	31	2d
Nausea	26	3	17	1d
Vomiting	15	4d	12	2d
General
Peripheral edema	39	3d	6	1d
Fatigue	37	5	36	1d
Asthenia	23	3	8	0
Pyrexia	23	2	8	0
Infections
Infectionsb	58	11	29	2
Investigations
Weight loss	22	2d	11	1d
Metabolism and nutrition
Decreased appetite	22	1d	17	1d
Nervous system
Dysgeusia	18	1d	4	0
Respiratory, thoracic and mediastinal
Cough	27	0	20	0
Dyspnea	20	3d	11	2
Pneumonitisc	16	2d	2	0
Epistaxis	13	1d	3	0
Skin and subcutaneous
Rash	30	1d	9	0
Pruritus	17	1d	9	0

Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4
Grading according to NCI CTCAE Version 4.03. aNo Grade 4 laboratory abnormalities were reported.
	AFINITOR N = 202		Placebo N = 98
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematology
Anemia	81	5a	41	2a
Lymphopenia	66	16	32	2a
Leukopenia	49	2a	17	0
Thrombocytopenia	33	2	11	0
Neutropenia	32	2a	15	3a
Chemistry
Hypercholesterolemia	71	0	37	0
Increased AST	57	2	34	2a
Hyperglycemia (fasting)	55	6a	36	1a
Increased ALT	46	5	39	1a
Hypophosphatemia	43	4a	15	2a
Hypertriglyceridemia	30	3	8	1a
Hypokalemia	27	6	12	3a
Hypoalbuminemia	18	0	8	0

Renal Cell Carcinoma (RCC)

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

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

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

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 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. aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration. bIncludes all reported infections, including but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. dNo Grade 4 adverse reactions were reported.
	AFINITOR N = 274		Placebo N = 137
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Gastrointestinal
Stomatitisa	44	4	8	0
Diarrhea	30	2d	7	0
Nausea	26	2d	19	0
Vomiting	20	2d	12	0
Infectionsb	37	10	18	2
General
Asthenia	33	4	23	4
Fatigue	31	6d	27	4
Edema peripheral	25	< 1d	8	< 1d
Pyrexia	20	< 1d	9	0
Mucosal inflammation	19	2d	1	0
Respiratory, thoracic and mediastinal
Cough	30	< 1d	16	0
Dyspnea	24	8	15	3d
Epistaxis	18	0	0	0
Pneumonitisc	14	4d	0	0
Skin and subcutaneous tissue
Rash	29	1d	7	0
Pruritus	14	< 1d	7	0
Dry skin	13	< 1d	5	0
Metabolism and nutrition
Anorexia	25	2d	14	< 1d
Nervous system
Headache	19	1	9	< 1d
Dysgeusia	10	0	2	0
Musculoskeletal and connective tissue
Pain in extremity	10	1d	7	0

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

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

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

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

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

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

Psychiatric: Insomnia (9%)

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

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

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

Renal and urinary: Renal failure (3%)

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

Musculoskeletal and connective tissue: Jaw pain (3%)

Hematologic: Hemorrhage (3%)

Table 13: Selected Laboratory Abnormalities Reported in Patients With RCC at a Higher Rate in the AFINITOR Arm Than the Placebo Arm in RECORD-1
Grading according to NCI CTCAE Version 3.0. aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. bNo Grade 4 laboratory abnormalities were reported.
Laboratory parameter	AFINITOR N = 274		Placebo N = 137
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematologya
Anemia	92	13	79	6
Lymphopenia	51	18	28	5b
Thrombocytopenia	23	1b	2	< 1
Neutropenia	14	< 1	4	0
Chemistry
Hypercholesterolemia	77	4b	35	0
Hypertriglyceridemia	73	< 1b	34	0
Hyperglycemia	57	16	25	2b
Increased creatinine	50	2b	34	0
Hypophosphatemia	37	6b	8	0
Increased AST	25	1	7	0
Increased ALT	21	1b	4	0
Hyperbilirubinemia	3	1	2	0

Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma

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

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

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

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

Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2
Grading according to NCI CTCAE Version 3.0. aIncludes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. bNo Grade 4 adverse reactions were reported.
	AFINITOR N = 79		Placebo N = 39
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Gastrointestinal
Stomatitisa	78	6b	23	0
Vomiting	15	0	5	0
Diarrhea	14	0	5	0
General
Peripheral edema	13	0	8	0
Infections
Upper respiratory tract infection	11	0	5	0
Musculoskeletal and connective tissue
Arthralgia	13	0	5	0
Respiratory, thoracic and mediastinal
Cough	20	0	13	0
Skin and subcutaneous tissue
Acne	22	0	5	0

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

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

Table 15: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2
Grading according to NCI CTCAE Version 3.0. aNo Grade 4 laboratory abnormalities were reported.
	AFINITOR N = 79		Placebo N = 39
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematology
Anemia	61	0	49	0
Leukopenia	37	0	21	0
Neutropenia	25	1	26	0
Lymphopenia	20	1a	8	0
Thrombocytopenia	19	0	3	0
Chemistry
Hypercholesterolemia	85	1a	46	0
Hypertriglyceridemia	52	0	10	0
Hypophosphatemia	49	5a	15	0
Increased alkaline phosphatase	32	1a	10	0
Increased AST	23	1a	8	0
Increased ALT	20	1a	15	0
Hyperglycemia (fasting)	14	0	8	0

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

TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA)

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

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

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

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

Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1
Grading according to NCI CTCAE Version 3.0. aIncludes mouth ulceration, stomatitis, and lip ulceration. bIncludes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. cIncludes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. dIncludes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. eIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. fNo Grade 4 adverse reactions were reported.
	AFINITOR N = 78		Placebo N = 39
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Gastrointestinal
Stomatitisa	62	9f	26	3f
Vomiting	22	1f	13	0
Diarrhea	17	0	5	0
Constipation	10	0	3	0
Infections
Respiratory tract infectionb	31	3	23	0
Gastroenteritisc	10	5	3	0
Pharyngitis streptococcal	10	0	3	0
General
Pyrexia	23	6f	18	3f
Fatigue	14	0	3	0
Psychiatric
Anxiety, aggression or other behavioral disturbanced	21	5f	3	0
Skin and subcutaneous tissue
Rashe	21	0	8	0
Acne	10	0	5	0

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

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

Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1
Grading according to NCI CTCAE Version 3.0. aNo Grade 4 laboratory abnormalities were reported.
	AFINITOR N = 78		Placebo N = 39
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematology
Elevated partial thromboplastin time	72	3a	44	5a
Neutropenia	46	9a	41	3a
Anemia	41	0	21	0
Chemistry
Hypercholesterolemia	81	0	39	0
Elevated 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
Grading according to NCI CTCAE Version 4.03. aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. bNo Grade 4 adverse reactions were reported.
	AFINITOR DISPERZ				Placebo
	Target of 3-7 ng/mL N = 117		Target of 9-15 ng/mL N = 130		N = 119
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Gastrointestinal
Stomatitisa	55	3b	64	4b	9	0
Diarrhea	17	0	22	0	5	0
Vomiting	12	0	10	2b	9	0
Infections
Nasopharyngitis	14	0	16	0	16	0
Upper respiratory tract infection	13	0	15	0	13	0.8b
General
Pyrexia	20	0	14	0.8b	5	0
Respiratory, thoracic and mediastinal
Cough	11	0	10	0	3	0
Skin and subcutaneous tissue
Rash	6	0	10	0	3	0

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

Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients With TSC-Associated Partial-Onset Seizures
Grading according to NCI CTCAE version 4.03. aNo Grade 4 laboratory abnormalities were reported.
	AFINITOR DISPERZ				Placebo
	Target of 3-7 ng/mL N = 117		Target of 9-15 ng/mL N = 130		N = 119
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Hematology
Neutropenia	25	4a	37	6	23	7a
Anemia	27	0.9a	30	0	21	0.8a
Thrombocytopenia	12	0	15	0	6	0
Chemistry
Hypercholesterolemia	86	0	85	0.8a	58	0
Hypertriglyceridemia	43	2a	39	2	22	0
Increased ALT	17	0	22	0	6	0
Increased AST	13	0	19	0	4	0
Hyperglycemia	19	0	18	0	17	0
Increased alkaline phosphatase	24	0	16	0	29	0
Hypophosphatemia	9	0.9a	16	2	3	0

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

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AFINITOR/AFINITOR DISPERZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure:

Blood and lymphatic disorders: Thrombotic microangiopathy
Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event
Gastrointestinal: Acute pancreatitis
Hepatobiliary: Cholecystitis and cholelithiasis
Infections: Sepsis and septic shock
Nervous system: Reflex sympathetic dystrophy
Vascular: Arterial thrombotic events, lymphedema
Injury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall