IBRANCE® tablets Adverse Reactions

(palbociclib)

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Neutropenia [see Warnings and Precautions (5.1)]
•: ILD/Pneumonitis [see Warnings and Precautions (5.2)]

6.1 Clinical Studies Experience

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

PALOMA-2: IBRANCE plus Letrozole

Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy

The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was evaluated in PALOMA-2. The data described below reflect exposure to IBRANCE in 444 out of 666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of IBRANCE plus letrozole in PALOMA-2. The median duration of treatment for IBRANCE plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in PALOMA-2.

Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (10%) patients receiving IBRANCE plus letrozole and in 13 of 222 (6%) patients receiving placebo plus letrozole. Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).

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

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 4.

Table 4. Adverse Reactions (≥10%) in PALOMA-2
	IBRANCE plus Letrozole (N=444)			Placebo plus Letrozole (N=222)
Adverse Reaction	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable;
* Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. † Most common infections (≥1%) deleteinclude: nasopharyngitis, upper respiratory tract infection, urinary tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis. ‡ Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis. § Grade 1 events – 30%; Grade 2 events – 3%. ¶ Grade 1 events – 15%; Grade 2 events – 1%. # Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.
Infections and infestations
Infections*	60†	6	1	42	3	0
Blood and lymphatic system disorders
Neutropenia	80	56	10	6	1	1
Leukopenia	39	24	1	2	0	0
Anemia	24	5	<1	9	2	0
Thrombocytopenia	16	1	<1	1	0	0
Metabolism and nutrition disorders
Decreased appetite	15	1	0	9	0	0
Nervous system disorders
Dysgeusia	10	0	0	5	0	0
Gastrointestinal disorders
Stomatitis‡	30	1	0	14	0	0
Nausea	35	<1	0	26	2	0
Diarrhea	26	1	0	19	1	0
Vomiting	16	1	0	17	1	0
Skin and subcutaneous tissue disorders
Alopecia	33§	N/A	N/A	16¶	N/A	N/A
Rash#	18	1	0	12	1	0
Dry skin	12	0	0	6	0	0
General disorders and administration site conditions
Fatigue	37	2	0	28	1	0
Asthenia	17	2	0	12	0	0
Pyrexia	12	0	0	9	0	0

Clinically relevant adverse reactions in <10% of patients who received IBRANCE plus letrozole in PALOMA-2 included epistaxis (9%), lacrimation increased (6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%).

Table 5. Laboratory Abnormalities in PALOMA-2
	IBRANCE plus Letrozole (N=444)			Placebo plus Letrozole (N=222)
Laboratory Abnormality	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
N=number of patients; WBC=white blood cells.
WBC decreased	97	35	1	25	1	0
Blood creatinine increased	96	2	<1	91	0	0
Neutrophils decreased	95	56	12	20	1	1
Hemoglobin decreased	78	6	0	42	2	0
Platelets decreased	63	1	1	14	0	0
Aspartate aminotransferase increased	52	3	0	34	1	0
Alanine aminotransferase increased	43	2	<1	30	0	0

PALOMA-3: IBRANCE plus Fulvestrant

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy

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

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

Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant 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 IBRANCE plus fulvestrant 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 IBRANCE plus fulvestrant in descending frequency were neutropenia and leukopenia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 6.

Table 6. Adverse Reactions (≥10%) in PALOMA-3
Adverse Reaction	IBRANCE plus Fulvestrant (N=345)			Placebo plus Fulvestrant (N=172)
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
	%	%	%	%	%	%
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
* 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, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and 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

Clinically relevant adverse reactions in <10% of patients who received IBRANCE plus fulvestrant in PALOMA-3 included asthenia (8%), dysgeusia (7%), epistaxis (7%), lacrimation increased (6%), dry skin (6%), vision blurred (6%), dry eye (3.8%), and febrile neutropenia (0.9%).

Table 7. Laboratory Abnormalities in PALOMA-3
Laboratory Abnormality	IBRANCE plus Fulvestrant (N=345)			Placebo plus Fulvestrant (N=172)
Laboratory Abnormality	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
N=number of patients; WBC=white blood cells.
WBC decreased	99	45	1	26	0	1
Neutrophils decreased	96	56	11	14	0	1
Blood creatinine increased	95	1	0	82	0	0
Hemoglobin decreased	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

INAVO120: IBRANCE plus Inavolisib and Fulvestrant

Adults with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease

The safety of the combination of IBRANCE plus inavolisib and fulvestrant was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer [see Clinical Studies (14)].

Patients received either IBRANCE 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days plus fulvestrant in combination with inavolisib (n=162) or placebo (n=162). The median duration of treatment for IBRANCE plus inavolisib and fulvestrant was 9 months (range: 0 to 39 months).

Serious adverse reactions occurred in 24% of patients who received IBRANCE plus inavolisib and fulvestrant. Serious adverse reactions occurring in ≥1% of patients receiving IBRANCE plus inavolisib and fulvestrant included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%).

Fatal adverse reactions occurred in 3.7% of patients who received IBRANCE plus inavolisib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal hemorrhage.

Permanent discontinuation of IBRANCE associated with an adverse reaction occurred in 8 of 162 (4.9%) patients receiving IBRANCE plus inavolisib and fulvestrant and in 0 of 162 patients receiving IBRANCE plus placebo and fulvestrant. Adverse reactions leading to discontinuation of IBRANCE in patients receiving IBRANCE plus inavolisib and fulvestrant were neutropenia, infections, alanine aminotransferase increased, gastric ulcer, intestinal perforation, hyperglycemia, type 2 diabetes mellitus, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury (0.6% each).

Dose reduction of IBRANCE due to an adverse reaction occurred in 38% of patients receiving IBRANCE plus inavolisib and fulvestrant and in 30% of patients receiving IBRANCE plus placebo and fulvestrant. Adverse reactions leading to dose reductions of IBRANCE in ≥2% patients receiving IBRANCE plus inavolisib and fulvestrant were neutropenia (30%), leukopenia (6%), and thrombocytopenia (3.7%).

Dose interruption of IBRANCE due to an adverse reaction occurred in 71% of patients receiving IBRANCE plus inavolisib and fulvestrant and in 61% of patients receiving IBRANCE plus placebo and fulvestrant. Adverse reactions leading to dose interruption of IBRANCE in ≥2% patients receiving IBRANCE plus inavolisib and fulvestrant were neutropenia (56%), infections (29%), leukopenia (12%), stomatitis (4.9%), anemia (6%), thrombocytopenia (4.3%), diarrhea (3.7%), pyrexia (3.1%), alanine aminotransferase increased (2.5%), hyperglycemia (2.5%), and nausea (2.5%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased alanine aminotransferase (ALT), nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.

Adverse reactions and laboratory abnormalities in INAVO120 are summarized in Table 8 and Table 9, respectively.

Table 8. Adverse Reactions (≥10% with ≥5% [All Grades] or ≥2% [Grade 3-4] Higher Incidence in the IBRANCE plus inavolisib and fulvestrant Arm) in INAVO120

Adverse Reaction	IBRANCE plus Inavolisib and Fulvestrant (N=162)		IBRANCE plus Placebo and Fulvestrant (N=162)
Adverse Reaction	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
* Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis. † No Grade 4 adverse reactions were observed. ‡ Includes other related terms. § Includes dry skin, skin fissures, xerosis, and xeroderma.
Gastrointestinal Disorders
Stomatitis*	51	6†	27	0
Diarrhea	48	3.7†	16	0
Nausea	28	0.6†	17	0
Vomiting	15	0.6†	4.9	1.2†
General Disorders and Administration Site Conditions
Fatigue	38	1.9†	25	1.2†
Skin and Subcutaneous Tissue Disorders
Rash‡	26	0	19	0
Alopecia	19	0	6	0
Dry skin§	13	0	4.3	0
Metabolism and Nutrition Disorders
Decreased appetite	24	0	9	0
Infections and Infestations
COVID-19 infection	23	1.9	10	0.6
Urinary tract infection‡	15	1.2†	9	0
Nervous System Disorders
Headache‡	22	0	14	0
Investigations
Decreased weight	17	3.7†	0.6	0

Clinically relevant adverse reactions occurring in <10% of patients who received the triplet combination of IBRANCE plus inavolisib and fulvestrant included abdominal pain, dry eye, dysgeusia, and dyspepsia.

Table 9. Select Laboratory Abnormalities (≥10% with a ≥2% [All Grades or Grade 3-4] Higher Incidence in the IBRANCE plus Inavolisib and Fulvestrant Arm) in INAVO120

ALT=alanine aminotransferase.
* The denominator used to calculate the rate varied from 122 to 160 based on the number of patients with a baseline value and at least one post-treatment value. † The denominator used to calculate the rate varied from 131 to 161 based on the number of patients with a baseline value and at least one post-treatment value. ‡ No Grade 4 laboratory abnormalities were observed. § Grading according to CTCAE version 4.03.
Laboratory Abnormality	IBRANCE plus Inavolisib and Fulvestrant*		IBRANCE plus Placebo and Fulvestrant†
Laboratory Abnormality	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Hematology
Neutrophils (total, absolute) decreased	95	82	97	79
Hemoglobin decreased	88	8‡	85	2.5‡
Platelets decreased	8	16	71	3.7
Lymphocytes (absolute) decreased	72	9	68	14
Chemistry
Glucose (fasting) increased§	85	12	43	0
Calcium decreased	42	3.1	32	3.7
Potassium decreased	38	6	21	0.6‡
Creatinine increased	38	1.9‡	30	1.2‡
ALT increased	34	3.1‡	29	1.2‡
Sodium decreased	28	2.5‡	19	2.5
Magnesium decreased	27	0.6	21	0
Lipase (fasting) increased	16	1.4‡	7	0

Other Clinical Trials Experience

The following adverse reaction has been reported following administration of IBRANCE: venous thromboembolism.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of IBRANCE. 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.

Respiratory Disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES)

Male Patients with HR-Positive, HER2-Negative Advanced or Metastatic Breast Cancer

Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.

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Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Neutropenia [see Warnings and Precautions (5.1)]
•: ILD/Pneumonitis [see Warnings and Precautions (5.2)]

6.1 Clinical Studies Experience

PALOMA-2: IBRANCE plus Letrozole

Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in PALOMA-2.

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 4.

Table 4. Adverse Reactions (≥10%) in PALOMA-2
	IBRANCE plus Letrozole (N=444)			Placebo plus Letrozole (N=222)
Adverse Reaction	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable;
* Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. † Most common infections (≥1%) deleteinclude: nasopharyngitis, upper respiratory tract infection, urinary tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis. ‡ Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis. § Grade 1 events – 30%; Grade 2 events – 3%. ¶ Grade 1 events – 15%; Grade 2 events – 1%. # Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.
Infections and infestations
Infections*	60†	6	1	42	3	0
Blood and lymphatic system disorders
Neutropenia	80	56	10	6	1	1
Leukopenia	39	24	1	2	0	0
Anemia	24	5	<1	9	2	0
Thrombocytopenia	16	1	<1	1	0	0
Metabolism and nutrition disorders
Decreased appetite	15	1	0	9	0	0
Nervous system disorders
Dysgeusia	10	0	0	5	0	0
Gastrointestinal disorders
Stomatitis‡	30	1	0	14	0	0
Nausea	35	<1	0	26	2	0
Diarrhea	26	1	0	19	1	0
Vomiting	16	1	0	17	1	0
Skin and subcutaneous tissue disorders
Alopecia	33§	N/A	N/A	16¶	N/A	N/A
Rash#	18	1	0	12	1	0
Dry skin	12	0	0	6	0	0
General disorders and administration site conditions
Fatigue	37	2	0	28	1	0
Asthenia	17	2	0	12	0	0
Pyrexia	12	0	0	9	0	0

Table 5. Laboratory Abnormalities in PALOMA-2
	IBRANCE plus Letrozole (N=444)			Placebo plus Letrozole (N=222)
Laboratory Abnormality	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
N=number of patients; WBC=white blood cells.
WBC decreased	97	35	1	25	1	0
Blood creatinine increased	96	2	<1	91	0	0
Neutrophils decreased	95	56	12	20	1	1
Hemoglobin decreased	78	6	0	42	2	0
Platelets decreased	63	1	1	14	0	0
Aspartate aminotransferase increased	52	3	0	34	1	0
Alanine aminotransferase increased	43	2	<1	30	0	0

PALOMA-3: IBRANCE plus Fulvestrant

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy

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

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

Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 6.

Table 6. Adverse Reactions (≥10%) in PALOMA-3
Adverse Reaction	IBRANCE plus Fulvestrant (N=345)			Placebo plus Fulvestrant (N=172)
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
	%	%	%	%	%	%
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
* 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, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and 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

Table 7. Laboratory Abnormalities in PALOMA-3
Laboratory Abnormality	IBRANCE plus Fulvestrant (N=345)			Placebo plus Fulvestrant (N=172)
Laboratory Abnormality	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
N=number of patients; WBC=white blood cells.
WBC decreased	99	45	1	26	0	1
Neutrophils decreased	96	56	11	14	0	1
Blood creatinine increased	95	1	0	82	0	0
Hemoglobin decreased	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

INAVO120: IBRANCE plus Inavolisib and Fulvestrant

Adverse reactions and laboratory abnormalities in INAVO120 are summarized in Table 8 and Table 9, respectively.

Table 8. Adverse Reactions (≥10% with ≥5% [All Grades] or ≥2% [Grade 3-4] Higher Incidence in the IBRANCE plus inavolisib and fulvestrant Arm) in INAVO120

Adverse Reaction	IBRANCE plus Inavolisib and Fulvestrant (N=162)		IBRANCE plus Placebo and Fulvestrant (N=162)
Adverse Reaction	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
* Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis. † No Grade 4 adverse reactions were observed. ‡ Includes other related terms. § Includes dry skin, skin fissures, xerosis, and xeroderma.
Gastrointestinal Disorders
Stomatitis*	51	6†	27	0
Diarrhea	48	3.7†	16	0
Nausea	28	0.6†	17	0
Vomiting	15	0.6†	4.9	1.2†
General Disorders and Administration Site Conditions
Fatigue	38	1.9†	25	1.2†
Skin and Subcutaneous Tissue Disorders
Rash‡	26	0	19	0
Alopecia	19	0	6	0
Dry skin§	13	0	4.3	0
Metabolism and Nutrition Disorders
Decreased appetite	24	0	9	0
Infections and Infestations
COVID-19 infection	23	1.9	10	0.6
Urinary tract infection‡	15	1.2†	9	0
Nervous System Disorders
Headache‡	22	0	14	0
Investigations
Decreased weight	17	3.7†	0.6	0

Table 9. Select Laboratory Abnormalities (≥10% with a ≥2% [All Grades or Grade 3-4] Higher Incidence in the IBRANCE plus Inavolisib and Fulvestrant Arm) in INAVO120

ALT=alanine aminotransferase.
* The denominator used to calculate the rate varied from 122 to 160 based on the number of patients with a baseline value and at least one post-treatment value. † The denominator used to calculate the rate varied from 131 to 161 based on the number of patients with a baseline value and at least one post-treatment value. ‡ No Grade 4 laboratory abnormalities were observed. § Grading according to CTCAE version 4.03.
Laboratory Abnormality	IBRANCE plus Inavolisib and Fulvestrant*		IBRANCE plus Placebo and Fulvestrant†
Laboratory Abnormality	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Hematology
Neutrophils (total, absolute) decreased	95	82	97	79
Hemoglobin decreased	88	8‡	85	2.5‡
Platelets decreased	8	16	71	3.7
Lymphocytes (absolute) decreased	72	9	68	14
Chemistry
Glucose (fasting) increased§	85	12	43	0
Calcium decreased	42	3.1	32	3.7
Potassium decreased	38	6	21	0.6‡
Creatinine increased	38	1.9‡	30	1.2‡
ALT increased	34	3.1‡	29	1.2‡
Sodium decreased	28	2.5‡	19	2.5
Magnesium decreased	27	0.6	21	0
Lipase (fasting) increased	16	1.4‡	7	0

Other Clinical Trials Experience

The following adverse reaction has been reported following administration of IBRANCE: venous thromboembolism.

6.2 Postmarketing Experience

Respiratory Disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES)

Male Patients with HR-Positive, HER2-Negative Advanced or Metastatic Breast Cancer

Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.

Medication Guide

Health Professional Information

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