6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

•: Risk of Bleeding [see Warnings and Precautions (5.1)]
•: Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions (5.2)]
•: Injection Site Reaction [see Warnings and Precautions (5.3)]
•: Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]

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.

Monotherapy

Comparison of FASLODEX 500 mg and FASLODEX 250 mg (CONFIRM)

The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month. The most frequently reported adverse reactions in the FASLODEX 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients), and bone pain (9.4% of patients); the most frequently reported adverse reactions in the FASLODEX 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients), and injection site pain (9.1% of patients).

Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from CONFIRM.

Table 1: Adverse Reactions in CONFIRM (≥5% in Either Treatment Group)
* Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.
Adverse Reactions	FASLODEX 500 mg N=361 %	FASLODEX 250 mg N=374 %
Body as a Whole
Injection Site Pain*	12	9
Headache	8	7
Back Pain	8	11
Fatigue	8	6
Pain in Extremity	7	7
Asthenia	6	6
Vascular System
Hot Flash	7	6
Digestive System
Nausea	10	14
Vomiting	6	6
Anorexia	6	4
Constipation	5	4
Musculoskeletal System
Bone Pain	9	8
Arthralgia	8	8
Musculoskeletal Pain	6	3
Respiratory System
Cough	5	5
Dyspnea	4	5

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 500 mg and Anastrozole 1 mg (FALCON)

The safety of FASLODEX 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data described below reflect exposure to FASLODEX in 228 out of 460 patients with HR-positive advanced breast cancer in postmenopausal women not previously treated with endocrine therapy who received at least one (1) dose of treatment in FALCON.

Permanent discontinuation associated with an adverse reaction occurred in 4 of 228 (1.8%) patients receiving FASLODEX and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions leading to discontinuation for those patients receiving FASLODEX included drug hypersensitivity (0.9%), injection site hypersensitivity (0.4%), and elevated liver enzymes (0.4%).

The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX arm were arthralgia, hot flash, fatigue, and nausea.

Adverse reactions reported in patients who received FASLODEX in FALCON at an incidence of ≥5% in either treatment arm are listed in Table 2, and laboratory abnormalities are listed in Table 3.

Table 2: Adverse Reactions in FALCON
Adverse Reactions	FASLODEX 500 mg N=228		Anastrozole 1 mg N=232
Adverse Reactions	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Vascular Disorders
Hot flash	11	0	10	0
Gastrointestinal Disorders
Nausea	11	0	10	<1
Diarrhea	6	0	6	<1
Musculoskeletal and Connective Tissue Disorders
Arthralgia	17	0	10	0
Myalgia	7	0	3	0
Pain in extremity	6	0	4	0
Back pain	9	<1	6	0
General Disorders and Administration Site Conditions
Fatigue	11	<1	7	<1

Table 3: Laboratory Abnormalities in FALCON*
* In FALCON, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >10% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1%-3% of patients.
Laboratory Parameters	FASLODEX 500 mg N=228		Anastrozole 1 mg N=232
Laboratory Parameters	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Alanine aminotransferase increased (ALT)	7	1	3	0
Aspartate aminotransferase increased (AST)	5	1	3	<1

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 0020 and 0021)

The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea, and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.

Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients given the single 5 mL injection (Study 0020) and in 27% of patients given the 2 x 2.5 mL injections (Study 0021) in the two clinical trials that compared FASLODEX 250 mg and anastrozole 1 mg.

Table 4 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 4: Adverse Reactions in Studies 0020 and 0021 (≥5% from Combined Data)
Adverse Reactions	FASLODEX 250 mg N=423 %	Anastrozole 1 mg N=423 %
* Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All patients on FASLODEX received injections, but only those anastrozole patients who were in Study 0021 received placebo injections.
Body as a Whole	68	68
Asthenia	23	27
Pain	19	20
Headache	15	17
Back Pain	14	13
Abdominal Pain	12	12
Injection Site Pain*	11	7
Pelvic Pain	10	9
Chest Pain	7	5
Flu Syndrome	7	6
Fever	6	6
Accidental Injury	5	6
Cardiovascular System	30	28
Vasodilatation	18	17
Digestive System	52	48
Nausea	26	25
Vomiting	13	12
Constipation	13	11
Diarrhea	12	13
Anorexia	9	11
Hemic and Lymphatic Systems	14	14
Anemia	5	5
Metabolic and Nutritional Disorders	18	18
Peripheral Edema	9	10
Musculoskeletal System	26	28
Bone Pain	16	14
Arthritis	3	6
Nervous System	34	34
Dizziness	7	7
Insomnia	7	9
Paresthesia	6	8
Depression	6	7
Anxiety	5	4
Respiratory System	39	34
Pharyngitis	16	12
Dyspnea	15	12
Cough Increased	10	10
Skin and Appendages	22	23
Rash	7	8
Sweating	5	5
Urogenital System	18	15
Urinary Tract Infection	6	4

Combination Therapy

Combination Therapy with Palbociclib (PALOMA-3)

The safety of FASLODEX 500 mg plus palbociclib 125 mg/day versus FASLODEX plus placebo was evaluated in PALOMA-3. The data described below reflect exposure to FASLODEX plus palbociclib in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of treatment in PALOMA-3. The median duration of treatment for FASLODEX plus palbociclib was 10.8 months while the median duration of treatment for FASLODEX plus placebo arm was 4.8 months.

No dose reduction was allowed for FASLODEX in PALOMA-3. Dose reductions of palbociclib due to an adverse reaction of any grade occurred in 36% of patients receiving FASLODEX plus palbociclib.

Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving FASLODEX plus placebo. Adverse reactions leading to discontinuation for those patients receiving FASLODEX plus palbociclib included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).

The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX plus palbociclib arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving FASLODEX plus palbociclib in descending frequency were neutropenia and leukopenia.

Adverse reactions (≥10%) reported in patients who received FASLODEX plus palbociclib or FASLODEX plus placebo in PALOMA-3 are listed in Table 5, and laboratory abnormalities are listed in Table 6.

Table 5: Adverse Reactions (≥10%) in PALOMA-3
Adverse Reactions	FASLODEX plus Palbociclib N=345			FASLODEX plus Placebo N=172
Adverse Reactions	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
* Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. † Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, paronychia. ‡ Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. § Grade 1 events – 17%; Grade 2 events – 1%. ¶ Grade 1 events – 6%. # Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption.
Infections and Infestations
Infections*	47†	3	1	31	3	0
Blood and Lymphatic System Disorders
Neutropenia	83	55	11	4	1	0
Leukopenia	53	30	1	5	1	1
Anemia	30	4	0	13	2	0
Thrombocytopenia	23	2	1	0	0	0
Metabolism and Nutrition Disorders
Decreased appetite	16	1	0	8	1	0
Gastrointestinal Disorders
Nausea	34	0	0	28	1	0
Stomatitis‡	28	1	0	13	0	0
Diarrhea	24	0	0	19	1	0
Vomiting	19	1	0	15	1	0
Skin and Subcutaneous Tissue Disorders
Alopecia	18§	N/A	N/A	6¶	N/A	N/A
Rash#	17	1	0	6	0	0
General Disorders and Administration Site Conditions
Fatigue	41	2	0	29	1	0
Pyrexia	13	<1	0	5	0	0
Grading according to CTCAE v.4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving FASLODEX plus palbociclib in PALOMA-3 included asthenia (7.5%), aspartate aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).

Table 6: Laboratory Abnormalities in PALOMA-3
Laboratory Parameters	FASLODEX plus Palbociclib N=345			FASLODEX plus Placebo N=172
Laboratory Parameters	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
WBC decreased	99	45	1	26	0	1
Neutrophils decreased	96	56	11	14	0	1
Anemia	78	3	0	40	2	0
Platelets decreased	62	2	1	10	0	0
Aspartate aminotransferase increased	43	4	0	48	4	0
Alanine aminotransferase increased	36	2	0	34	0	0

N=number of patients; WBC=white blood cells.

Combination Therapy with Abemaciclib (MONARCH 2)

The safety of FASLODEX (500 mg) plus abemaciclib (150 mg twice daily) versus FASLODEX plus placebo was evaluated in MONARCH 2. The data described below reflect exposure to FASLODEX in 664 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of FASLODEX plus abemaciclib or placebo in MONARCH 2.

Median duration of treatment was 12 months for patients receiving FASLODEX plus abemaciclib and 8 months for patients receiving FASLODEX plus placebo.

Dose reductions due to an adverse reaction occurred in 43% of patients receiving FASLODEX plus abemaciclib. Adverse reactions leading to dose reductions ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reduction due to diarrhea of any grade occurred in 19% of patients receiving FASLODEX plus abemaciclib compared to 0.4% of patients receiving FASLODEX plus placebo. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving FASLODEX plus abemaciclib compared to no patients receiving FASLODEX plus placebo.

Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients receiving FASLODEX plus abemaciclib and in 3% of patients receiving FASLODEX plus placebo. Adverse reactions leading to permanent discontinuation for patients receiving FASLODEX plus abemaciclib were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of FASLODEX plus abemaciclib treated patients versus 10 cases (5%) of FASLODEX plus placebo treated patients. Causes of death for patients receiving FASLODEX plus abemaciclib included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.

The most common adverse reactions reported (≥20%) in the FASLODEX plus abemaciclib arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 7). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

Table 7: Adverse Reactions ≥10% of Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2
* Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness. † Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis. ‡ Includes neutropenia, neutrophil count decreased. § Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased. ¶ Includes leukopenia, white blood cell count decreased. # Includes platelet count decreased, thrombocytopenia. Þ Includes asthenia, fatigue.
Adverse Reactions	FASLODEX plus Abemaciclib N=441			FASLODEX plus Placebo N=223
	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Gastrointestinal Disorders
Diarrhea	86	13	0	25	<1	0
Nausea	45	3	0	23	1	0
Abdominal pain*	35	2	0	16	1	0
Vomiting	26	<1	0	10	2	0
Stomatitis	15	<1	0	10	0	0
Infections and Infestations
Infections†	43	5	<1	25	3	<1
Blood and Lymphatic System Disorders
Neutropenia‡	46	24	3	4	1	<1
Anemia§	29	7	<1	4	1	0
Leukopenia¶	28	9	<1	2	0	0
Thrombocytopenia#	16	2	1	3	0	<1
General Disorders and Administration Site Conditions
FatigueÞ	46	3	0	32	<1	0
Edema peripheral	12	0	0	7	0	0
Pyrexia	11	<1	<1	6	<1	0
Metabolism and Nutrition Disorders
Decreased appetite	27	1	0	12	<1	0
Respiratory, Thoracic, and Mediastinal Disorders
Cough	13	0	0	11	0	0
Skin and Subcutaneous Tissue Disorders
Alopecia	16	0	0	2	0	0
Pruritus	13	0	0	6	0	0
Rash	11	1	0	4	0	0
Nervous System Disorders
Headache	20	1	0	15	<1	0
Dysgeusia	18	0	0	3	0	0
Dizziness	12	1	0	6	0	0
Investigations
Alanine aminotransferase increased	13	4	<1	5	2	0
Aspartate aminotransferase increased	12	2	0	7	3	0
Creatinine increased	12	<1	0	<1	0	0
Weight decreased	10	<1	0	2	<1	0

Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with FASLODEX plus abemaciclib as compared to 0.9% of patients treated with FASLODEX plus placebo.

Table 8: Laboratory Abnormalities ≥10% in Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2
Laboratory Parameters	Fulvestrant plus Abemaciclib N=441			Fulvestrant plus Placebo N=223
	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Creatinine increased	98	1	0	74	0	0
White blood cell decreased	90	23	<1	33	<1	0
Neutrophil count decreased	87	29	4	30	4	<1
Anemia	84	3	0	33	<1	0
Lymphocyte count decreased	63	12	<1	32	2	0
Platelet count decreased	53	<1	1	15	0	0
Alanine aminotransferase increased	41	4	<1	32	1	0
Aspartate aminotransferase increased	37	4	0	25	4	<1

Combination Therapy with Ribociclib (MONALEESA-3)

The safety of FASLODEX 500 mg plus ribociclib 600 mg versus FASLODEX plus placebo was evaluated in MONALEESA-3. The data described below reflect exposure to FASLODEX plus ribociclib in 483 out of 724 postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy who received at least one dose of FASLODEX plus ribociclib or placebo in MONALEESA-3. Median duration of treatment was 15.8 months for FASLODEX plus ribociclib and 12 months for FASLODEX plus placebo.

Dose reductions due to adverse reactions occurred in 32% of patients receiving FASLODEX plus ribociclib and in 3% of patients receiving FASLODEX plus placebo. Among patients receiving FASLODEX plus ribociclib, 8% were reported to have permanently discontinued both FASLODEX plus ribociclib, and 9% were reported to have discontinued ribociclib alone due to ARs. Among patients receiving FASLODEX plus placebo, 4% were reported to have permanently discontinued both FASLODEX and placebo and 2% were reported to have discontinued placebo alone due to ARs.

Adverse reactions leading to treatment discontinuation of FASLODEX plus ribociclib (as compared to FASLODEX plus placebo) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).

The most common adverse reactions (reported at a frequency ≥20% on the FASLODEX plus ribociclib arm and ≥2% higher than FASLODEX plus placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most frequently reported Grade 3/4 adverse reactions (reported at a frequency ≥5%) in patients receiving FASLODEX plus ribociclib in descending frequency were neutropenia, leukopenia, infections, and abnormal liver function tests.

Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 9 and Table 10, respectively.

Table 9: Adverse Reactions Occurring in ≥10% and ≥2% higher than FASLODEX plus Placebo Arm in MONALEESA-3 (All Grades)
* Infections; urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (<1%).
Adverse Reactions	FASLODEX plus Ribociclib N=483			FASLODEX plus Placebo N=241
Adverse Reactions	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Infections and Infestations
Infections*	42	5	0	30	2	0
Blood and Lymphatic System Disorders
Neutropenia	69	46	7	2	0	0
Leukopenia	27	12	<1	<1	0	0
Anemia	17	3	0	5	2	0
Metabolism and Nutrition Disorders
Decreased appetite	16	<1	0	13	0	0
Nervous System Disorders
Dizziness	13	<1	0	8	0	0
Respiratory, Thoracic, and Mediastinal Disorders
Cough	22	0	0	15	0	0
Dyspnea	15	1	<1	12	2	0
Gastrointestinal Disorders
Nausea	45	1	0	28	<1	0
Diarrhea	29	<1	0	20	<1	0
Vomiting	27	1	0	13	0	0
Constipation	25	<1	0	12	0	0
Abdominal pain	17	1	0	13	<1	0
Skin and Subcutaneous Tissue Disorders
Alopecia	19	0	0	5	0	0
Pruritus	20	<1	0	7	0	0
Rash	23	<1	0	7	0	0
General Disorders and Administration Site Conditions
Edema peripheral	15	0	0	7	0	0
Pyrexia	11	<1	0	7	0	0
Investigations
Alanine aminotransferase increased	15	7	2	5	<1	0
Aspartate aminotransferase increased	13	5	1	5	<1	0
Grading according to CTCAE 4.03. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients

Additional adverse reactions in MONALEESA-3 for patients receiving FASLODEX plus ribociclib included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%), dry skin (8%), dysgeusia (7%), electrocardiogram QT prolonged (6%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%).

Table 10: Laboratory Abnormalities Occurring in ≥10% of Patients in MONALEESA-3
Laboratory parameters	FASLODEX plus Ribociclib N=483			FASLODEX plus Placebo N=241
Laboratory parameters	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Hematology
Leukocyte count decreased	95	25	<1	26	<1	0
Neutrophil count decreased	92	46	7	21	<1	0
Hemoglobin decreased	60	4	0	35	3	0
Lymphocyte count decreased	69	14	1	35	4	<1
Platelet count decreased	33	<1	1	11	0	0
Chemistry
Creatinine increased	65	<1	<1	33	<1	0
Gamma-glutamyl transferase increased	52	6	1	49	8	2
Aspartate aminotransferase increased	49	5	2	43	3	0
Alanine aminotransferase increased	44	8	3	37	2	0
Glucose serum decreased	23	0	0	18	0	0
Phosphorous decreased	18	5	0	8	<1	0
Albumin decreased	12	0	0	8	0	0

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FASLODEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions, including angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).