EVEROLIMUS (Page 3 of 8)

5.11 Risk of Infection or Reduced Immune Response With Vaccination

The safety of immunization with live vaccines during everolimus tablets therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with everolimus tablets. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

5.12 Radiation Sensitization and Radiation Recall

Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to everolimus treatment [see Adverse Reactions (6.2)]. Monitor patients closely when everolimus tablets are administered during or sequentially with radiation treatment.

5.13 Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action,everolimus 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 everolimus and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with everolimus and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

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)].

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 everolimus tablets (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 everolimus tablets. The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus tablets arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets versus placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with everolimus tablets was 23.9 weeks; 33% were exposed to everolimus tablets 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.
	Everolimus Tablets 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	Everolimus Tablets with Exemestane N = 482		Placebo with Exemestane N = 238
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Hematologya
Anemia	68	6	40	1
Leukopenia	58	2b	28	6
Thrombocytopenia	54	3	5	0.4
Lymphopenia	54	12	37	6
Neutropenia	31	2b	11	2
Chemistry
Hypercholesterolemia	70	1	38	2
Hyperglycemia	69	9	44	1
Increased aspartate transaminase (AST)	69	4	45	3
Increased alanine transaminase (ALT)	51	4	29	5b
Hypertriglyceridemia	50	0.8b	26	0
Hypoalbuminemia	33	0.8b	16	0.8b
Hypokalemia	29	4	7	1b
Increased creatinine	24	2	13	0

Topical Prophylaxis for Stomatitis

In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with everolimus tablets 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 everolimus and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

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 everolimus tablets in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) orsporadic 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 everolimus tablets.

The most common adverse reaction reported for everolimus tablets (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 everolimus tablets -treated patients. Adverse reactions leading to permanent discontinuation in the Everolimus tablets arm werehypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of everolimus tablets -treated patients. The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis.

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

Table 14: Adverse Reactions Reported in ≥ 10% of Everolimus tablets -Treated Patients With TSC Associated Renal Angiomyolipoma in EXIST-2

	Everolimus tablets 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 respiratorytract 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
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.

Amenorrhea occurred in 15% of Everolimus tablets -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 everolimus tablets -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 Everolimus tablets -Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2

	Everolimus tablets 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
Grading according to NCI CTCAE Version 3.0.a No Grade 4 laboratory abnormalities were reported.

Updated safety information from 112 patients treated with everolimus tablets 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 everolimus tablets 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 everolimus tablets.

The most common adverse reactions reported for everolimus tablets (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 everolimus tablets-treated patients. The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis.

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

Table 16: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets -Treated Patients With TSC Associated SEGA in EXIST-1

	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
* Includes mouth ulceration, stomatitis, and lip ulceration. † No Grade 4 adverse reactions were reported. ‡ Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. § Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. ¶ Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. # Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticarial.
	Everolimus Tablets N = 78		Placebo N = 39
Gastrointestinal
Stomatitis *	62	9†	26	3†
Vomiting	22	1†	13	0
Diarrhea	17	0	5	0
Constipation	10	0	3	0
Infections
Respiratory tract infection ‡	31	3	23	0
Gastroenteritis §	10	5	3	0
Pharyngitis streptococcal	10	0	3	0
General
Pyrexia	23	6†	18	3†
Fatigue	14	0	3	0
Psychiatric
Anxiety, aggression or other behavioural disturbance ¶	21	5†	3	0
Skin and subcutaneous tissue
Rash #	21	0	8	0
Acne	10	0	5	0
Grading according to NCI CTCAE Version 3.0.

Amenorrhea occurred in 17% of everolimus tablets -treated females aged 10 to 55 years (3 of 18). For this same group of everolimus tablets-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 everolimus tablets-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 Everolimus Tablets-Treated Patients With TSC-Associated SEGA in EXIST-1

* No Grade 4 laboratory abnormalities were reported.
	Everolimus Tablets N = 78		Placebo N = 39
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Hematology
Elevated partial thromboplastin time	72	3*	44	5*
Neutropenia	46	9*	41	3*
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	1*	3	0
Grading according to NCI CTCAE Version 3.0.

Updated safety information from 111 patients treated with everolimus tablets 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%).