IBRANCE Adverse Reactions

palbociclib

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Adverse Drug Reaction Overview

The safety of IBRANCE has been assessed in 2 randomized studies of patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer.

The most common adverse drug reactions of any grade reported in ≥10% of patients receiving palbociclib in combination with endocrine treatment were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, thrombocytopenia, diarrhea, alopecia, vomiting, decreased appetite, and rash.

Most patients treated with IBRANCE (palbociclib) experienced myelosuppressive effects with over half experiencing Grade 3 neutropenia at some point during treatment. Thrombocytopenia and anemia were less commonly observed. Myelosuppressive effects can be expected to occur from Cycle 1 forward.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The adverse reactions are listed by system organ class, frequency category and grade of severity.

Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

IBRANCE plus Letrozole for the initial endocrine-based therapy of patients with ER‑positive, HER2‑negative locally advanced or metastatic breast cancer (PALOMA-2)

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. Patients were randomized 2:1 to receive the combination IBRANCE plus letrozole versus placebo plus letrozole. 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 treatment 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%) 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 serious adverse reactions (≥1%) in patients receiving IBRANCE plus letrozole were Infections (20%) and Febrile neutropenia (2%).

Adverse reactions (≥5%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 1.

Table 1. Adverse Reactions Reported (With a Frequency of ≥5% on the IBRANCE plus letrozole arm) 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 %
Blood and lymphatic system disorders
Neutropenia^a	80	56	10	6	1	1
Leukopenia^b	39	24	1	2	0	0
Anemia^c	24	5	<1	9	2	0
Thrombocytopenia^d	16	1	<1	1	0	0
Eye Disorders
lacrimation increased	6	0	0	1	0	0
Gastrointestinal disorders
Stomatitis^e	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
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
Infections and infestations
Infections^{f, g}	60	6	1	42	3	0
Investigations
Alanine aminotransferase increased	10	2	<1	4	0	0
Aspartate aminotransferase increased	10	3	0	5	1	0
Metabolism and nutrition disorders
Decreased appetite	15	1	0	9	0	0
Nervous system disorders
Dysgeusia	10	0	0	5	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	9	0	0	6	0	0
Skin and subcutaneous tissue disorders
Alopecia	33	N/A	N/A	16	N/A	N/A
Rash^h	18	1	0	12	1	0
Dry skin	12	0	0	6	0	0
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable; a Neutropenia includes: Neutropenia and Neutrophil count decreased b Leukopenia includes: Leukopenia and White blood cell count decreased c Anemia includes: Anaemia, Haematocrit decreased and Haemoglobin decreased d Thrombocytopenia includes: Platelet count decreased and Thrombocytopenia e Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis. f Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. g Most common infections (>1%) are: 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. h Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Less Common Clinical Trial Adverse Reactions

Additional adverse reactions occurring at an overall incidence of <5% of patients receiving IBRANCE plus letrozole in PALOMA-2 included dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%).

Abnormal Hematologic and Clinical Chemistry Findings

Table 2. Laboratory Test Abnormalities in PALOMA-2
	IBRANCE plus Letrozole (N=444)			Placebo plus Letrozole (N=222)
Laboratory Test Abnormality	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
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
N=number of patients; WBC=white blood cells.

IBRANCE plus fulvestrant for the treatment of patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy (PALOMA-3)

The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in a randomized, controlled, Phase 3 trial (PALOMA-3). The data described below reflect exposure to IBRANCE in 345 out of 517 patients with HR-positive, HER2-negative metastatic breast cancer who received at least 1 dose of IBRANCE in PALOMA-3. Patients were randomized 2:1 to receive the combination IBRANCE plus fulvestrant versus placebo plus fulvestrant.

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

The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Adverse reactions reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 3.

Discontinuation and dose reduction due to AEs

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 permanent discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).

Treatment-emergent adverse events presented in Table 3 below are based on a median duration of treatment of approximately 5 months for patients on the IBRANCE plus fulvestrant arm, and approximately 4 months for patients on the placebo plus fulvestrant arm.

Table 3. Adverse Events* Reported (With a Frequency of ≥5% on the IBRANCE Arm) for Patients Who Received IBRANCE Plus Fulvestrant or Placebo Plus Fulvestrant 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
	%	%	%	%	%	%
Blood and lymphatic system disorders
Neutropenia^a	79	53	9	4	0	<1
Leukopenia^b	46	25	<1	4	0	1
Anemia^c	26	3	0	10	2	0
Thrombocytopenia^d	19	2	<1	0	0	0
Gastrointestinal disorders
Nausea	29	0	0	26	<1	0
Stomatitis^e	25	<1	0	11	0	0
Diarrhea	19	0	0	17	<1	0
Constipation	17	0	0	14	0	0
Vomiting	15	<1	0	12	<1	0
Abdominal Pain	6	<1	0	5	0	0
General disorders and administration site conditions
Fatigue	38	2	0	27	1	0
Asthenia	7	0	0	5	1	0
Pyrexia	9	<1	0	4	0	0
Oedema peripheral	8	0	0	5	0	0
Infections and infestations
Infections^f	34	1	<1	24	2	0
Metabolism and nutrition disorders
Decreased appetite	13	<1	0	8	0	0
Nervous system disorders
Headache	21	<1	0	17	0	0
Dysgeusia	6	0	0	2	0	0
Dizziness	11	<1	0	9	0	0
Psychiatric disorders
Insomnia	11	<1	0	7	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	6	0	0	1	0	0
Cough	13	0	0	11	0	0
Dyspnoea	7	0	0	4	0	0
Skin and subcutaneous tissue disorders
Alopecia	15	N/A	N/A	6	N/A	N/A
Rash^g	14	<1	0	5	0	0
SOC Investigations
Aspartate aminotransferase increased	6	2	0	5	1	0
* Adverse events reported with a frequency of ≥5% on the IBRANCE arm and a higher frequency on the IBRANCE arm compared to the placebo arm Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable. a Neutropenia includes: neutropenia and neutrophil count decreased b Leukopenia includes: leukopenia and white blood cell count decreased c Anemia includes: anaemia, haemoglobin decreased, and hematocrit decreased d Thrombocytopenia includes: thrombocytopenia and platelet count decreased e Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. f Infections includes any reported PTs that are part of the System Organ Class Infections and infestations. g Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Less Common Clinical Trial Adverse Reactions

Additional adverse reactions occurring at an overall incidence of <5% of patients receiving IBRANCE plus fulvestrant in Study PALOMA-3 included dry skin (4.9%), Vision blurred (4.9%), alanine aminotransferase increased (4.6%), lacrimation increased (4.3%), dry eye (2.9%), and febrile neutropenia (0.6%).

Abnormal Hematologic and Clinical Chemistry Findings

Table 4. Incidence of Hematology Laboratory Abnormality for Patients Who Received IBRANCE Plus Fulvestrant or Placebo Plus Fulvestrant in PALOMA-3
	IBRANCE + Fulvestrant (N=345)			Placebo Plus Fulvestrant (N=172)
Laboratory Abnormality	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
	%	%	%	%	%	%
White blood cells decreased	98	40	1	22	0	<1
Neutrophils decreased	95	53	9	11	0	1
Anemia	76	3	0	36	2	0
Platelets decreased	57	2	1	8	0	0
N=number of subjects.

Updated safety data for patients on the IBRANCE plus fulvestrant arm, based on an approximate 6-month increase in the median duration of treatment, were generally consistent with the safety table provided in Tables 3 and 4. No new safety concerns have been identified.

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, including fatal cases.

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Adverse Reactions

Adverse Drug Reaction Overview

Clinical Trial Adverse Drug Reactions

The adverse reactions are listed by system organ class, frequency category and grade of severity.

IBRANCE plus Letrozole for the initial endocrine-based therapy of patients with ER‑positive, HER2‑negative locally advanced or metastatic breast cancer (PALOMA-2)

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 serious adverse reactions (≥1%) in patients receiving IBRANCE plus letrozole were Infections (20%) and Febrile neutropenia (2%).

Adverse reactions (≥5%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 1.

Table 1. Adverse Reactions Reported (With a Frequency of ≥5% on the IBRANCE plus letrozole arm) 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 %
Blood and lymphatic system disorders
Neutropenia^a	80	56	10	6	1	1
Leukopenia^b	39	24	1	2	0	0
Anemia^c	24	5	<1	9	2	0
Thrombocytopenia^d	16	1	<1	1	0	0
Eye Disorders
lacrimation increased	6	0	0	1	0	0
Gastrointestinal disorders
Stomatitis^e	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
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
Infections and infestations
Infections^{f, g}	60	6	1	42	3	0
Investigations
Alanine aminotransferase increased	10	2	<1	4	0	0
Aspartate aminotransferase increased	10	3	0	5	1	0
Metabolism and nutrition disorders
Decreased appetite	15	1	0	9	0	0
Nervous system disorders
Dysgeusia	10	0	0	5	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	9	0	0	6	0	0
Skin and subcutaneous tissue disorders
Alopecia	33	N/A	N/A	16	N/A	N/A
Rash^h	18	1	0	12	1	0
Dry skin	12	0	0	6	0	0
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable; a Neutropenia includes: Neutropenia and Neutrophil count decreased b Leukopenia includes: Leukopenia and White blood cell count decreased c Anemia includes: Anaemia, Haematocrit decreased and Haemoglobin decreased d Thrombocytopenia includes: Platelet count decreased and Thrombocytopenia e Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis. f Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. g Most common infections (>1%) are: 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. h Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Less Common Clinical Trial Adverse Reactions

Abnormal Hematologic and Clinical Chemistry Findings

Table 2. Laboratory Test Abnormalities in PALOMA-2
	IBRANCE plus Letrozole (N=444)			Placebo plus Letrozole (N=222)
Laboratory Test Abnormality	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
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
N=number of patients; WBC=white blood cells.

IBRANCE plus fulvestrant for the treatment of patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy (PALOMA-3)

The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Adverse reactions reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 3.

Discontinuation and dose reduction due to AEs

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.

Table 3. Adverse Events* Reported (With a Frequency of ≥5% on the IBRANCE Arm) for Patients Who Received IBRANCE Plus Fulvestrant or Placebo Plus Fulvestrant 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
	%	%	%	%	%	%
Blood and lymphatic system disorders
Neutropenia^a	79	53	9	4	0	<1
Leukopenia^b	46	25	<1	4	0	1
Anemia^c	26	3	0	10	2	0
Thrombocytopenia^d	19	2	<1	0	0	0
Gastrointestinal disorders
Nausea	29	0	0	26	<1	0
Stomatitis^e	25	<1	0	11	0	0
Diarrhea	19	0	0	17	<1	0
Constipation	17	0	0	14	0	0
Vomiting	15	<1	0	12	<1	0
Abdominal Pain	6	<1	0	5	0	0
General disorders and administration site conditions
Fatigue	38	2	0	27	1	0
Asthenia	7	0	0	5	1	0
Pyrexia	9	<1	0	4	0	0
Oedema peripheral	8	0	0	5	0	0
Infections and infestations
Infections^f	34	1	<1	24	2	0
Metabolism and nutrition disorders
Decreased appetite	13	<1	0	8	0	0
Nervous system disorders
Headache	21	<1	0	17	0	0
Dysgeusia	6	0	0	2	0	0
Dizziness	11	<1	0	9	0	0
Psychiatric disorders
Insomnia	11	<1	0	7	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	6	0	0	1	0	0
Cough	13	0	0	11	0	0
Dyspnoea	7	0	0	4	0	0
Skin and subcutaneous tissue disorders
Alopecia	15	N/A	N/A	6	N/A	N/A
Rash^g	14	<1	0	5	0	0
SOC Investigations
Aspartate aminotransferase increased	6	2	0	5	1	0
* Adverse events reported with a frequency of ≥5% on the IBRANCE arm and a higher frequency on the IBRANCE arm compared to the placebo arm Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable. a Neutropenia includes: neutropenia and neutrophil count decreased b Leukopenia includes: leukopenia and white blood cell count decreased c Anemia includes: anaemia, haemoglobin decreased, and hematocrit decreased d Thrombocytopenia includes: thrombocytopenia and platelet count decreased e Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. f Infections includes any reported PTs that are part of the System Organ Class Infections and infestations. g Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Less Common Clinical Trial Adverse Reactions

Abnormal Hematologic and Clinical Chemistry Findings

Table 4. Incidence of Hematology Laboratory Abnormality for Patients Who Received IBRANCE Plus Fulvestrant or Placebo Plus Fulvestrant in PALOMA-3
	IBRANCE + Fulvestrant (N=345)			Placebo Plus Fulvestrant (N=172)
Laboratory Abnormality	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
	%	%	%	%	%	%
White blood cells decreased	98	40	1	22	0	<1
Neutrophils decreased	95	53	9	11	0	1
Anemia	76	3	0	36	2	0
Platelets decreased	57	2	1	8	0	0
N=number of subjects.

Postmarketing Experience

Respiratory disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis, including fatal cases.

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