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 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.

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 (9.7%) patients receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) 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%) include: 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

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus letrozole in PALOMA-2 included alanine aminotransferase increased (9.9%), aspartate aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), 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
Neutrophils decreased	95	56	12	20	1	1
Anemia	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

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus fulvestrant 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 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
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

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.