6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]
Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)]
Infusion-Related Reactions [see Warnings and Precautions (5.3)]
Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]

6.1 Clinical Trials 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 clinical practice.

Metastatic Breast Cancer (MBC)

The adverse reactions described in Table 3 were identified in 804 patients with HER2-positive metastatic breast cancer treated in CLEOPATRA. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. Adverse reactions resulting in permanent discontinuation of all study therapy were 6% in the PERJETA-treated group and 5% for patients in the placebo-treated group. The most common adverse reactions (>1%) that led to discontinuation of all study therapy was left ventricular dysfunction (1% for patients in the PERJETA-treated group and 2% for patients in the placebo-treated group). The most common adverse reactions that led to discontinuation of docetaxel alone were edema, fatigue, edema peripheral, neuropathy peripheral, neutropenia, nail disorder and pleural effusion. Table 3 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months) in CLEOPATRA.

The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in CLEOPATRA
Body System/ Adverse Reactions	PERJETA + trastuzumab + docetaxel n=407 Frequency rate %		Placebo + trastuzumab + docetaxel n=397 Frequency rate %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
* In this table this denotes an adverse reaction that has been reported in association with a fatal outcome
General disorders and administration site conditions
Fatigue	37	2	37	3
Mucosal inflammation	28	1	20	1
Asthenia	26	2	30	2
Edema peripheral	23	0.5	30	0.8
Pyrexia	19	1	18	0.5
Skin and subcutaneous tissue disorders
Alopecia	61	0	60	0.3
Rash	34	0.7	24	0.8
Nail disorder	23	1	23	0.3
Pruritus	14	0	10	0
Dry skin	11	0	4	0
Gastrointestinal disorders
Diarrhea	67	8	46	5
Nausea	42	1	42	0.5
Vomiting	24	1	24	2
Stomatitis	19	0.5	15	0.3
Constipation	15	0	25	1
Blood and lymphatic system disorders
Neutropenia	53	49	50	46
Anemia	23	2	19	4
Leukopenia	18	12	20	15
Febrile neutropenia*	14	13	8	7
Nervous system disorders
Neuropathy peripheral	32	3	34	2
Headache	21	1	17	0.5
Dysgeusia	18	0	16	0
Dizziness	13	0.5	12	0
Musculoskeletal and connective tissue disorders
Myalgia	23	1	24	0.8
Arthralgia	15	0.2	16	0.8
Infections and infestations
Upper respiratory tract infection	17	0.7	13	0
Nasopharyngitis	12	0	13	0.3
Respiratory, thoracic, and mediastinal disorders
Dyspnea	14	1	16	2
Metabolism and nutrition disorders
Decreased appetite	29	2	26	2
Eye disorders
Lacrimation increased	14	0	14	0
Psychiatric disorders
Insomnia	13	0	13	0

The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in CLEOPATRA:

Infections and infestations: Paronychia (7% in the PERJETA-treated group vs. 4% in the placebo-treated group)

Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Docetaxel

In CLEOPATRA, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19%), upper respiratory tract infection (13%), rash (12%), headache (11%), and fatigue (11%).

Neoadjuvant Treatment of Breast Cancer (NeoSphere)

In NeoSphere, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in CLEOPATRA. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 4 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in NeoSphere.

Table 4 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in NeoSphere
Body System/ Adverse Reactions	Trastuzumab + docetaxel n=107 Frequency rate %		PERJETA + trastuzumab + docetaxel n=107 Frequency rate %		PERJETA + trastuzumab n=108 Frequency rate %		PERJETA + docetaxel n=108 Frequency rate %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
General disorders and administration site conditions
Fatigue	27	0	26	0.9	12	0	26	1
Mucosal inflammation	21	0	26	2	3	0	26	0
Asthenia	18	0	21	2	3	0	16	2
Pyrexia	10	0	17	0	8	0	9	0
Edema peripheral	10	0	3	0	0.9	0	5	0
Skin and subcutaneous tissue disorders
Alopecia	66	0	65	0	3	0	67	0
Rash	21	2	26	0.9	11	0	29	1
Gastrointestinal disorders
Diarrhea	34	4	46	6	28	0	54	4
Nausea	36	0	39	0	14	0	36	1
Stomatitis	7	0	18	0	5	0	10	0
Vomiting	12	0	13	0	5	0	16	2
Blood and lymphatic system disorders
Neutropenia	64	59	50	45	0.9	0.9	65	57
Leukopenia	21	11	9	5	0	0	14	9
Nervous system disorders
Dysgeusia	10	0	15	0	5	0	7	0
Headache	11	0	11	0	14	0	13	0
Peripheral Sensory Neuropathy	12	0.9	8	0.9	2	0	11	0
Musculoskeletal and connective tissue disorders
Myalgia	22	0	22	0	9	0	21	0
Arthralgia	8	0	10	0	5	0	10	0
Metabolism and nutrition disorders
Decreased appetite	7	0	14	0	2	0	15	0
Psychiatric disorders
Insomnia	11	0	8	0	4	0	9	0

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in NeoSphere: (Ptz=pertuzumab; H=trastuzumab; D=docetaxel)

Blood and lymphatic system disorders: Anemia (7% in the H+D arm, 3% in the Ptz+H+D arm, 5% in the Ptz+H arm and 9% in the Ptz+D arm), Febrile neutropenia (7% in the H+D arm, 8% in the Ptz+H+D arm, 0% in the Ptz+H arm and 7% in the Ptz+D arm)

Nervous system disorders: Dizziness (4% in the H+D arm, 3% in the Ptz+H+D arm, 6% in the Ptz+H arm and 3% in the Ptz+D arm)

Infections and infestations: Upper respiratory tract infection (3% in the H+D arm, 5% in the Ptz+H+D arm, 2% in the Ptz+H arm and 7% in the Ptz+D arm)

Eye disorders: Lacrimation increased (2% in the H+D arm, 4% in the Ptz+H+D arm, 0.9% in the Ptz+H arm, and 4% in the Ptz+D arm)

Neoadjuvant Treatment of Breast Cancer (TRYPHAENA)

In TRYPHAENA, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.

Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.

Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment occurred in 7% of patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC, and 8% for patients receiving PERJETA in combination with TCH. The most common adverse reactions (>2%) resulting in permanent discontinuation of PERJETA were left ventricular dysfunction, drug hypersensitivity, and neutropenia. Table 5 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in TRYPHAENA.

Table 5 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in TRYPHAENA
Body System/Adverse Reactions	PERJETA + trastuzumab + FEC followed by PERJETA + trastuzumab + docetaxel		PERJETA + trastuzumab + docetaxel following FEC		PERJETA + TCH
	n=72		n=75		n=76
	Frequency rate %		Frequency rate %		Frequency rate %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab
General disorders and administration site conditions
Fatigue	36	0	36	0	42	4
Mucosal inflammation	24	0	20	0	17	1
Pyrexia	17	0	9	0	16	0
Asthenia	10	0	15	1	13	1
Edema peripheral	11	0	4	0	9	0
Skin and subcutaneous tissue disorders
Alopecia	49	0	52	0	55	0
Rash	19	0	11	0	21	1
Palmar-Plantar Erythrodysaesthesia Syndrome	7	0	11	0	8	0
Dry skin	6	0	9	0	11	0
Gastrointestinal disorders
Diarrhea	61	4	61	5	72	12
Nausea	53	0	53	3	45	0
Vomiting	40	0	36	3	39	5
Dyspepsia	25	1	8	0	22	0
Constipation	18	0	23	0	16	0
Stomatitis	14	0	17	0	12	0
Blood and lymphatic system disorders
Neutropenia	51	47	47	43	49	46
Leukopenia	22	19	16	12	17	12
Anemia	19	1	9	4	38	17
Febrile neutropenia	18	18	9	9	17	17
Thrombocytopenia	7	0	1	0	30	12
Immune system disorders
Hypersensitivity	10	3	1	0	12	3
Nervous system disorders
Headache	22	0	15	0	17	0
Dysgeusia	11	0	13	0	21	0
Dizziness	8	0	8	1	16	0
Neuropathy peripheral	6	0	1	0	11	0
Musculoskeletal and connective tissue disorders
Myalgia	17	0	11	1	11	0
Arthralgia	11	0	12	0	7	0
Respiratory, thoracic, and mediastinal disorders
Dyspnea	13	0	8	3	11	1
Epistaxis	11	0	11	0	16	1
Cough	10	0	5	0	12	0
Oropharyngeal pain	8	0	7	0	12	0
Metabolism and nutrition disorders
Decreased appetite	21	0	11	0	21	0
Eye disorders
Lacrimation increased	13	0	5	0	8	0
Psychiatric disorders
Insomnia	11	0	13	0	21	0
Investigations
ALT increased	7	0	3	0	11	4

The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in TRYPHAENA: (Ptz=pertuzumab; H=trastuzumab; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab)

Skin and subcutaneous tissue disorders: Nail disorder (10% in the Ptz+H+FEC/Ptz+H+D arm, 7% in the FEC/Ptz+H+D arm, and 9% in the Ptz+TCH arm), Paronychia (0% in the Ptz+H+FEC/Ptz+H+D arm, and 1% in both the FEC/Ptz+H+D and Ptz+TCH arms), Pruritus (3% in the Ptz+H+FEC/Ptz+H+D arm, 4% in the FEC/Ptz+H+D arm, and 4% in the Ptz+TCH arm)

Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+H+FEC/Ptz+H+D arm, 4.0% in the FEC/Ptz+H+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+H+FEC/Ptz+H+D arm, 6.7% in the FEC/Ptz+H+D arm, and 7.9% in the Ptz+TCH arm)

Neoadjuvant Treatment of Breast Cancer (BERENICE)

In BERENICE, when PERJETA was administered in combination with trastuzumab and paclitaxel for 4 cycles following 4 cycles of ddAC, the most common adverse reactions (> 30%) were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy and headache. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, neutrophil count decreased, white blood cell count decreased, anemia, diarrhea, peripheral neuropathy, alanine aminotransferase increased and nausea.

When PERJETA was administered in combination with trastuzumab and docetaxel for 4 cycles following 4 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia. The most common Grade 3 – 4 adverse reactions (> 2%) were febrile neutropenia, diarrhea, neutropenia, neutrophil count decreased, stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis and anemia.

Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment were 14% for patients receiving PERJETA in combination with trastuzumab and paclitaxel following ddAC and 8% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC. The most common adverse reactions (>1%) resulting in permanent discontinuation of any component of neoadjuvant treatment were neuropathy peripheral, ejection fraction decreased, diarrhea, neutropenia and infusion related reaction. Table 6 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in BERENICE.

Table 6 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in BERENICE
Body System/Adverse Reactions	PERJETA + trastuzumab + paclitaxel following ddAC n=199 Frequency rate %		PERJETA + trastuzumab + docetaxel following FEC n=198 Frequency rate %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
ddAC = dose-dense doxorubicin, cyclophosphamide, FEC=5-fluorouracil, epirubicin, cyclophosphamide
General disorders and administration site conditions
Fatigue	58	1	38	5
Asthenia	19	2	41	0
Mucosal inflammation	22	1	37	4
Pyrexia	15	0	18	0
Edema peripheral	9	0	12	1
Skin and subcutaneous tissue disorders
Alopecia	62	0	59	0
Rash	14	0	11	0
Dry skin	14	0	10	0
Nail discoloration	15	0	2	0
Palmar-Plantar Erythrodysaesthesia Syndrome	6	0	10	0.5
Gastrointestinal disorders
Nausea	71	3	69	2
Diarrhea	67	3	69	10
Constipation	35	0.5	38	0.5
Vomiting	23	1	35	4
Stomatitis	25	0	27	5
Dyspepsia	19	0	16	0
Abdominal pain upper	6	0	13	0
Abdominal pain	5	0	10	0
Gastroesophageal reflux disease	12	0	2	0
Blood and lymphatic system disorders
Anemia	27	3	30	3
Neutropenia	22	12	16	9
Febrile neutropenia	7	7	17	17
Nervous system disorders
Headache	30	0.5	14	0.5
Dysgeusia	20	0	19	0.5
Neuropathy peripheral	42	3	26	0.5
Paresthesia	15	0	9	0
Dizziness	12	0	8	0
Musculoskeletal and connective tissue disorders
Myalgia	20	0	33	1
Arthralgia	20	0	21	1
Back pain	10	0	9	0
Pain in extremity	10	0	8	0
Bone pain	12	0.5	5	0
Infections and infestations
Urinary tract infection	11	1	2	0
Respiratory, thoracic, and mediastinal disorders
Epistaxis	25	0	19	0
Dyspnea	15	0.5	15	0.5
Cough	20	0.5	9	0
Oropharyngeal pain	10	0	8	0.5
Metabolism and nutrition disorders
Decreased appetite	20	0	23	0
Eye disorders
Lacrimation increased	9	0	18	0
Psychiatric disorders
Insomnia	19	0	13	0
Vascular disorders
Hot flush	19	0	13	0
Investigations
White blood cell count decreased	11	4	3	2
Injury, poisoning and procedural complications
Infusion related reaction	16	1	13	1

The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in BERENICE: (Ptz=pertuzumab; H=trastuzumab; P=paclitaxel; ddAC=dose-dense doxorubicin and cyclophosphamide; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide)

Skin and Subcutaneous tissue disorders: Pruritus (9% in the ddAC/Ptz+H+P arm, and 8% in the FEC/Ptz+H+D arm), Nail disorder (7% in the ddAC/Ptz+H+P arm, and 10% in the FEC/Ptz+H+D arm)

Infections and infestations: Upper respiratory tract infection (7% in the ddAC/Ptz+H+P arm, and 2% in the FEC/Ptz+H+D arm), nasopharyngitis (7% in the ddAC/Ptz+H+P arm, and 9% in the FEC/Ptz+H+D arm), paronychia (0.5% in the ddAC/Ptz+H+P arm, and 1% in the FEC/Ptz+H+D arm)

Adjuvant Treatment of Breast Cancer (APHINITY)

The adverse reactions described in Table 7 were identified in 4769 patients with HER2-positive early breast cancer treated in APHINITY. Patients were randomized to receive either PERJETA in combination with trastuzumab and chemotherapy or placebo in combination with trastuzumab and chemotherapy.

Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for patients in the PERJETA-treated group and 12% for patients in the placebo-treated group. Adverse reactions resulting in permanent discontinuation of PERJETA or placebo was 7% and 6%, respectively. The most common adverse reactions (>0.5%) resulting in permanent discontinuation of any study treatment were ejection fraction decreased, neuropathy peripheral, diarrhea, and cardiac failure. Table 7 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group.

When PERJETA was administered in combination with trastuzumab and chemotherapy, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell count decreased, leukopenia, fatigue, nausea, and stomatitis.

The incidence of diarrhea, all Grades, was higher when chemotherapy was administered with targeted therapy (61% in the PERJETA-treated group vs. 34% in the placebo-treated group), and was higher when administered with non-anthracycline based therapy (85% in the PERJETA-treated group vs. 62% in the placebo-treated group) than with anthracycline based therapy (67% in the PERJETA-treated group vs. 41% in the placebo-treated group). The incidence of diarrhea during the period that targeted therapy was administered without chemotherapy was 18% in the PERJETA-treated group vs. 9% in the placebo-treated group. The median duration of all Grades diarrhea was 8 days for the PERJETA-treated group vs. 6 days for the placebo-treated group. The median duration of Grade ≥3 diarrhea was 20 days for the PERJETA-treated group vs. 8 days for the placebo-treated group. More patients required hospitalization for diarrhea as a serious adverse event in the PERJETA-treated group (2.4%) than in the placebo-treated group (0.7%).

Table 7 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Adjuvant Treatment with PERJETA in APHINITY
Body System/ Adverse Reactions	PERJETA + trastuzumab + chemotherapy n=2364		Placebo + trastuzumab + chemotherapy n=2405
Body System/ Adverse Reactions	Frequency rate %		Frequency rate %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
* In this table this denotes an adverse reaction that has been reported in association with a fatal outcome
General disorders and administration site conditions
Fatigue	49	4	44	3
Mucosal inflammation	23	2	19	0.7
Asthenia	21	1	21	2
Pyrexia	20	0.6	20	0.7
Edema peripheral	17	0	20	0.2
Skin and subcutaneous tissue disorders
Alopecia	67	<0.1	67	<0.1
Rash	26	0.4	20	0.2
Pruritus	14	0.1	9	<0.1
Dry skin	13	0.1	11	<0.1
Nail disorder	12	0.2	12	0.1
Gastrointestinal disorders
Diarrhea	71	10	45	4
Nausea	69	2	65	2
Vomiting	32	2	30	2
Constipation	29	0.5	32	0.3
Stomatitis	28	2	24	1
Dyspepsia	14	0	14	0
Abdominal pain	12	0.5	11	0.6
Abdominal pain upper	10	0.3	9	0.2
Blood and lymphatic system disorders
Anemia	28	7	23	5
Neutropenia	25	16	23	16
Febrile neutropenia*	12	12	11	11
Nervous system disorders
Dysgeusia	26	0.1	22	<0.1
Neuropathy peripheral	33	1	32	1
Headache	22	0.3	23	0.4
Paresthesia	12	0.5	10	0.2
Dizziness	11	0	11	0.2
Musculoskeletal and connective tissue disorders
Arthralgia	29	0.9	33	1
Myalgia	26	0.9	30	1
Pain in extremity	10	0.2	10	0.2
Infections and infestations
Nasopharyngitis	13	<0.1	12	0.1
Respiratory, thoracic, and mediastinal disorders
Epistaxis	18	<0.1	14	0
Cough	16	<0.1	15	<0.1
Dyspnea	12	0.4	12	0.5
Metabolism and nutrition disorders
Decreased appetite	24	0.8	20	0.4
Vascular disorders
Hot flush	20	0.2	21	0.4
Eye disorders
Lacrimation increased	13	0	13	<0.1
Psychiatric disorders
Insomnia	17	0.3	17	<0.1
Investigations
Neutrophil count decreased	14	10	14	10
Injury, poisoning and procedural complications
Radiation skin injury	13	0.3	11	0.3

For the adverse reactions that were reported in ≥10% of patients with at least 5% difference between the PERJETA-treated group and the placebo-treated group in APHINITY, the breakdown per chemotherapy regimen is provided: (Ptz=pertuzumab; H=trastuzumab; AC=anthracyclines; TCH=docetaxel, carboplatin, and trastuzumab)

Gastrointestinal disorders: Diarrhea (67% in the Ptz+H+AC chemo arm, 85% in the Ptz+TCH arm, 41% in the Pla+H+AC chemo arm, 62% in the Pla+TCH arm)

Skin and subcutaneous disorders: Rash (26% in the Ptz+H+AC chemo arm, 25% in the Ptz+TCH arm, 21% in the Pla+H+AC chemo arm, 19% in the Pla+TCH arm), Pruritus (14% in the Ptz+H+AC chemo arm, 15% in the Ptz+TCH arm, 9% in the Pla+H+AC chemo arm, 9% in the Pla+TCH arm)

The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in APHINITY:

Blood and lymphatic system disorders: Leukopenia (9% in the PERJETA-treated group vs. 9% in the placebo-treated group)

Infections and infestations: Upper respiratory tract infection (8% in the PERJETA-treated group vs. 7% in the placebo-treated group), paronychia (4% in the PERJETA-treated group vs. 2% in the placebo-treated group)

Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Chemotherapy

In the APHINITY study, during the targeted treatment alone phase, all adverse reactions in the PERJETA treatment group occurred in < 10% of patients with the exception of diarrhea (18%), arthralgia (15%), radiation skin injury (12%), and hot flush (12%).

6.2 Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to pertuzumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Patients in CLEOPATRA were tested at multiple time-points for antibodies to PERJETA. 3% (13/389) of patients in the PERJETA-treated group and 7% (25/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 38 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-drug antibodies (ADA). The presence of pertuzumab in patient serum at the levels expected at the time of ADA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development.

In the neoadjuvant period of BERENICE, 0.3% (1/383) of patients treated with PERJETA tested positive for anti-PERJETA antibodies. This patient did not experience any anaphylactic/hypersensitivity reactions.

6.3 Post-Marketing Experience

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

Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with PERJETA. Patients with significant tumor burden (e.g., bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.