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Description for Poherdy

Pertuzumab-dpzb is a recombinant humanized monoclonal antibody and HER2/neu receptor antagonist that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2). Pertuzumab-dpzb is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. Pertuzumab-dpzb has an approximate molecular weight of 148 kDa.

POHERDY (pertuzumab-dpzb) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for intravenous infusion. Each 14 mL single-dose vial contains 420 mg of pertuzumab-dpzb, and histidine (21.14 mg), L-histidine hydrochloride monohydrate (30.1 mg), polysorbate 20 (2.8 mg), sorbitol (420 mg) and Water for Injection, with a pH of 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)]

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)

CLEOPATRA

The safety of pertuzumab in combination with trastuzumab and docetaxel was evaluated in a randomized trial (CLEOPATRA) in patients with HER2-positive metastatic breast cancer [see Clinical Studies (14.1)]. Patients received either pertuzumab administered at an initial dose of 840 mg followed by 420 mg every 3 weeks thereafter or placebo in combination with trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks thereafter) and docetaxel (75 mg/m2 by intravenous infusion every 3 weeks for 6 cycles). The median duration of study treatment was 18.1 months for patients in the pertuzumab-treated group.

Permanent discontinuation of pertuzumab, trastuzumab, and docetaxel due to adverse reactions occurred in 6% of patients. Adverse reactions that led to permanent discontinuation of pertuzumab, trastuzumab, and docetaxel in >1% of patients were left ventricular dysfunction.

The safety profile of pertuzumab 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%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common 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 summarizes the adverse reactions in CLEOPATRA that occurred ≥ 10% of patients in the pertuzumab-treated group.

Table 3: Adverse Reactions (≥ 10%) in Patients Who Received Pertuzumab in Combination with Trastuzumab and Docetaxel in CLEOPATRA

Adverse Reactions	Pertuzumab + trastuzumab + docetaxel n=407 %		Placebo + trastuzumab + docetaxel n=397 %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
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
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
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
General disorders and administration site conditions
Fatigue	37	2	37	3
Mucosal inflammation	28	1	20	1
Asthenia	26	2	30	2
Peripheral edema	23	0.5	30	0.8
Pyrexia	19	1	18	0.5
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
Metabolism and nutrition disorders
Decreased appetite	29	2	26	2
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
Eye disorders
Lacrimation increased	14	0	14	0
Psychiatric disorders
Insomnia	13	0	13	0
* In this table this denotes an adverse reaction that has been reported in association with a fatal outcome

Clinically relevant adverse reactions in < 10% of patients in the pertuzumab-treated group in CLEOPATRA included paronychia (7%).

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

In CLEOPATRA, adverse reactions that occurred after discontinuation of docetaxel included diarrhea (19%), upper respiratory tract infection (13%), rash (12%), headache (11%), and fatigue (11%).

Neoadjuvant Treatment of Breast Cancer

NeoSphere

The safety of pertuzumab was evaluated in a randomized trial (NeoSphere) in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy [see Clinical Studies (14.2)].

In combination with trastuzumab and docetaxel, pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. After surgery, patients in the pertuzumab plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC.

Permanent discontinuation of neoadjuvant pertuzumab due to an adverse reaction occurred in 0.9% of patients.

The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea.

Table 4 summarizes the adverse reactions in NeoSphere that occurred ≥ 10% of patients who received neoadjuvant pertuzumab with trastuzumab and docetaxel followed by FEC.

Table 4: Adverse Reactions(≥ 10%) in Patients who Received Neoadjuvant Pertuzumab in NeoSphere

Adverse Reactions	Trastuzumab + docetaxel n = 107 %		Pertuzumab + trastuzumab + docetaxel n = 107 %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
Skin and subcutaneous tissue disorders
Alopecia	66	0	65	0
Rash	21	2	26	0.9
Blood and lymphatic system disorders
Neutropenia	64	59	50	45
Leukopenia	21	11	9	5
Gastrointestinal disorders
Nausea	36	0	39	0
Diarrhea	34	4	46	6
Vomiting	12	0	13	0
Stomatitis	7	0	18	0
General disorders and administration site conditions
Fatigue	27	0	26	0.9
Mucosal inflammation	21	0	26	2
Asthenia	18	0	21	2
Pyrexia	10	0	17	0
Peripheral edema	10	0	3	0
Musculoskeletal and connective tissue disorders
Myalgia	22	0	22	0
Arthralgia	8	0	10	0
Nervous system disorders
Peripheral Sensory Neuropathy	12	0.9	8	0.9
Headache	11	0	11	0
Dysgeusia	10	0	15	0
Psychiatric disorders
Insomnia	11	0	8	0
Metabolism and nutrition disorders
Decreased appetite	7	0	14	0

Clinically relevant adverse reactions in < 10% of patients receiving neoadjuvant pertuzumab with trastuzumab and docetaxel followed by FEC included anemia, febrile neutropenia, dizziness, upper respiratory tract infection, and increased lacrimation.

Neoadjuvant Treatment of Breast Cancer

TRYPHAENA

The safety of pertuzumab was evaluated in patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer in TRYPHAENA [see Clinical Studies (14.2)].

Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment occurred in 7% of patients receiving pertuzumab in combination with trastuzumab and docetaxel following FEC, and 8% for patients receiving pertuzumab in combination with TCH.

The most common adverse reactions (>2%) resulting in permanent discontinuation of pertuzumab were left ventricular dysfunction, drug hypersensitivity, and neutropenia.

For pertuzumab 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 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.

For pertuzumab 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 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.

Table 5 summarizes the adverse reactions in TRYPHAENA that occurred in > 10% of patients who received neoadjuvant pertuzumab with trastuzumab and docetaxel following FEC or who received neoadjuvant pertuzumab in combination with TCH.

Table 5: Adverse Reactions (≥ 10%) in Patients Receiving Neoadjuvant Treatment with Pertuzumab in TRYPHAENA

Adverse Reactions	Pertuzumab + trastuzumab + docetaxel following FEC n = 75 %		Pertuzumab + TCH n = 76 %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
Gastrointestinal disorders
Diarrhea	61	5	72	12
Nausea	53	3	45	0
Vomiting	36	3	39	5
Dyspepsia	8	0	22	0
Constipation	23	0	16	0
Stomatitis	17	0	12	0
Skin and subcutaneous tissue disorders
Alopecia	52	0	55	0
Rash	11	0	21	1
Palmar-Plantar Erythrodysaesthesia Syndrome	11	0	8	0
Dry skin	9	0	11	0
Blood and lymphatic system disorders
Neutropenia	47	43	49	46
Leukopenia	16	12	17	12
Anemia	9	4	38	17
Febrile neutropenia	9	9	17	17
Thrombocytopenia	1	0	30	12
General disorders and administration site conditions
Fatigue	36	0	42	4
Mucosal inflammation	20	0	17	1
Pyrexia	9	0	16	0
Asthenia	15	1	13	1
Edema peripheral	0	9	0
Psychiatric disorders
Insomnia	13	0	21	0
Nervous system disorders
Headache	15	0	17	0
Dysgeusia	13	0	21	0
Dizziness	8	1	16	0
Neuropathy peripheral	1	0	11	0
Metabolism and nutrition disorders
Decreased appetite	11	0	21	0
Respiratory, thoracic, and mediastinal disorders
Epistaxis	11	0	16	1
Dyspnea	8	3	11	1
Oropharyngeal pain	7	0	12	0
Cough	5	0	12	0
Musculoskeletal and connective tissue disorders
Myalgia	11	1	11	0
Arthralgia	12	0	7	0
Eye disorders
Lacrimation increased	5	0	8	0
Investigations
ALT increased	3	0	11	4
Immune system disorders
Hypersensitivity	1	0	12	3

Clinically relevant adverse reactions in < 10% of patients who received neoadjuvant pertuzumab with trastuzumab and docetaxel following FEC or who received neoadjuvant pertuzumab in combination with TCH included nail disorder, paronychia, pruritus, upper respiratory tract infection, and nasopharyngitis.

Neoadjuvant Treatment of Breast Cancer

BERENICE

The safety of pertuzumab was evaluated in a two-arm non-randomized study (BERENICE) in patient with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer [see Clinical Studies (14.2)].

Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment were 14% for patients receiving pertuzumab in combination with trastuzumab and paclitaxel following ddAC and 8% for patients receiving pertuzumab 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 peripheral neuropathy, decreased ejection fraction, diarrhea, neutropenia and infusion-related reaction.

For pertuzumab 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, decreased neutrophil count, decreased white blood cell count, anemia, diarrhea, peripheral neuropathy, increased ALT, and nausea.

For pertuzumab 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, decreased neutrophil count stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis and anemia.

Table 6 summarizes the adverse reactions in BERENICE that occurred in ≥ 10% of patients who received neoadjuvant pertuzumab with trastuzumab and paclitaxel following ddAC or who received neoadjuvant pertuzumab with trastuzumab and docetaxel following FEC.

Table 6: Adverse Reactions (≥ 10%) of Patients Receiving Neoadjuvant Pertuzumab in Combination with Trastuzumab and Taxane Chemotherapy Following ddAC or FEC in BERENICE

Adverse Reactions	Pertuzumab + trastuzumab + paclitaxel following ddAC n=199 %		Pertuzumab + trastuzumab + docetaxel following FEC n=198 %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
Gastrointestinal disorders
Nausea	71	3	69	2
Diarrhea	67	3	69	10
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
Upper abdominal pain	6	0	13	0
Abdominal pain	5	0	10	0
Gastroesophageal reflux disease	12	0	2	0
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
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
Peripheral edema	9	0	12	1
Nervous system disorders
Peripheral neuropathy	42	3	26	0.5
Headache	30	0.5	14	0.5
Dysgeusia	20	0	19	0.5
Paresthesia	15	0	9	0
Dizziness	12	0	8	0
Blood and lymphatic system disorders
Anemia	27	3	30	3
Neutropenia	22	12	16	9
Febrile neutropenia	7	7	17	17
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
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
Psychiatric disorders
Insomnia	19	0	13	0
Vascular disorders
Hot flush	19	0	13	0
Injury, poisoning and procedural complications
Infusion related reaction	16	1	13	1
Eye disorders
Increased lacrimation	9	0	18	0
Investigations
Decreased white blood cell count	11	4	3	2
Infections and infestations
Urinary tract infection	11	1	2	0

Clinically relevant adverse reactions in < 10% of patients who received pertuzumab in combination with trastuzumab and paclitaxel following ddAC or patients receiving pertuzumab in combination with trastuzumab and docetaxel following FEC included pruritus, nail disorder, paronychia, upper respiratory tract infection, and nasopharyngitis.

Adjuvant Treatment of Breast Cancer

APHINITY

The safety of pertuzumab was evaluated in a multicenter, randomized, double-blind, placebo- controlled study (APHINITY) conducted in patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization [see Clinical Studies (14.3)].

Patients were randomized to receive either pertuzumab in combination with trastuzumab and chemotherapy or placebo in combination withtrastuzumab and chemotherapy. Investigators selected one of three anthracycline-based or non-anthracycline-based chemotherapy regimens for patients. Pertuzumab and trastuzumab were administered intravenously every 3 weeks starting on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity.

Serious adverse reactions (hospitalization) due to diarrhea in the pertuzumab-treated group was 2.4%. The incidence of diarrhea was higher when chemotherapy was administered with pertuzumab (61%) and was higher when administered with non-anthracycline based therapy (85%) than with anthracycline based therapy (67%). The median duration of diarrhea was 8 days. The median duration of Grade ≥ 3 diarrhea was 20 days. The incidence of diarrhea during the period pertuzumab and trastuzumab were administered without chemotherapy was 18% in the pertuzumab-treated group.

Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for patients in the pertuzumab-treated group. Adverse reactions resulting in permanent discontinuation of pertuzumab was 7%. 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.

When pertuzumab 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.

Table 7 summarizes the adverse reactions that occurred in ≥ 10% of patients who received adjuvant pertuzumab in combination with trastuzumab and chemotherapy followed by pertuzumab and trastuzumab for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity.

Table 7: Adverse Reactions (≥ 10%) of Patients Receiving Adjuvant Pertuzumab in Combination with Trastuzumab and Chemotherapy Followed by Pertuzumab and Trastuzumab in APHINITY

Adverse Reactions	Pertuzumab trastuzumab + chemotherapy n=2364 %		Placebo + trastuzumab + chemotherapy n=2405 %
	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
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
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
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
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
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
Metabolism and nutrition disorders
Decreased appetite	24	0.8	20	0.4
Vascular disorders
Hot flush	20	0.2	21	0.4
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
Psychiatric disorders
Insomnia	17	0.3	17	<0.1
Investigations
Neutrophil count decreased	14	10	14	10
Eye disorders
Lacrimation increased	13	0	13	<0.1
Infections and infestations
Nasopharyngitis	13	<0.1	12	0.1
Injury, poisoning and procedural complications
Radiation skin injury	13	0.3	11	0.3
* In this table this denotes an adverse reaction that has been reported in association with afatal outcome

Clinically relevant adverse reactions in < 10% of patients who received pertuzumab in combination with trastuzumab and anthracycline-based or non-anthracycline-based chemotherapy regimens included leukopenia, upper respiratory tract infection, and paronychia

Adverse Reactions in Patients Receiving Pertuzumab and Trastuzumab After Discontinuation of Chemotherapy

In APHINITY, adverse reactions that occurred after discontinuation of chemotherapy in > 10% included diarrhea (18%), arthralgia (15%), radiation skin injury (12%), and hot flush (12%).

Drug Interactions for Poherdy

No information provided

Warnings for Poherdy

Included as part of the PRECAUTIONS section.

Precautions for Poherdy

Left Ventricular Dysfunction

Pertuzumab products can cause left ventricular dysfunction, including symptomatic heart failure. Decreases in LVEF have been reported with drugs that block HER2 activity, including pertuzumab products.

Assess LVEF prior to initiation of POHERDY and at regular intervals during treatment to ensure that LVEF is within normal limits. If the LVEF declines and has not improved, or has declined further at the subsequent assessment, consider permanent discontinuation of POHERDY and trastuzumab [see Dosage Modification for Adverse Reactions (2.5)].

In the pertuzumab-treated patients with MBC in CLEOPATRA, left ventricular dysfunction occurred in 4% of patients and symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) occurred in 1% of patients. Patients who received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF or left ventricular dysfunction.

In patients receiving pertuzumab as a neoadjuvant treatment in combination with trastuzumab and docetaxel in NeoSphere, LVEF decline > 10% and a drop to < 50% occurred in 8% of patients and left ventricular dysfunction occurred in 3% of patients. LVEF recovered to ≥ 50% in all these patients.

In patients receiving neoadjuvant pertuzumab in TRYPHAENA, LVEF decline > 10% and a drop to < 50% occurred in 7% of patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel, 16% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, and 11% of patients treated with pertuzumab in combination with TCH. Left ventricular dysfunction occurred in 6% of patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel, 4% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, and 3% of patients treated with pertuzumab in combination with TCH. Symptomatic LVSD occurred in 4% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, 1% of patients treated with pertuzumab in combination with TCH, and none of the patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.

In patients receiving neoadjuvant pertuzumab in BERENICE, in the neoadjuvant period, LVEF decline ≥ 10% and a drop to < 50% as measured by ECHO/MUGA assessment occurred in 7% of patients treated with pertuzumab plus trastuzumab and paclitaxel following ddAC, and 2% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC. Ejection fraction decreased (asymptomatic LVD) occurred in 7% of patients treated with pertuzumab plus trastuzumab and paclitaxel following ddAC and 4% of the patients treated with pertuzumab plus trastuzumab and docetaxel following FEC in the neoadjuvant period. Symptomatic LVSD (NYHA Class III/IV Congestive Heart Failure) occurred in 2% of patients treated with pertuzumab plus trastuzumab and paclitaxel following ddAC and none of the patients treated with pertuzumab plus trastuzumab and docetaxel following FEC in the neoadjuvant period.

In patients receiving adjuvant pertuzumab in APHINITY, the incidence of symptomatic heart failure (NYHA Class III/IV) with a LVEF decline ≥ 10% and a drop to < 50% was 0.6%. Of the patients who experienced symptomatic heart failure, 47% of pertuzumab-treated patients had recovered (defined as 2 consecutive LVEF measurements above 50%) at the data cutoff. The majority of the events (86%) were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF ≥ 10% and a drop to < 50% were reported in 3% of pertuzumab-treated patients, of whom 80% recovered at the data cutoff.

Pertuzumab products have not been studied in patients with a pretreatment LVEF value of < 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animal studies, pertuzumab products can cause fetalharm when administered to a pregnant woman. Pertuzumab products are HER2/neu receptor antagonists. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported with use of another HER2/neu receptor antagonist (trastuzumab) during pregnancy. In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on Cmax.

Verify the pregnancy status of females of reproductive potential prior to the initiation of POHERDY. Advise pregnant women and females of reproductive potential that exposure to POHERDY in combination with trastuzumab during pregnancy or within 7 months prior to conception can result in fetal harm, including embryo-fetal death or birth defects. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of POHERDY in combination with trastuzumab [see Use in Specific Populations (8.1, 8.3)].

Infusion-Related Reactions

Pertuzumab products can cause serious infusion reactions, including fatal events [see Adverse Reactions (6.1)].

In CLEOPATRA, on the first day, when only pertuzumab was administered, infusion-related reactions occurred in 13% of patients and <1% were Grade 3 or 4. The most common infusion reactions (≥ 1%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the pertuzumab-treated group (≥ 1%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.

In APHINITY, when pertuzumab was administered in combination with trastuzumab and chemotherapy on the same day, infusion-related reactions occurred in 21% of patients with <1% of patients experiencing Grade 3-4 events.

Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of POHERDY. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.5)].

Hypersensitivity Reactions/Anaphylaxis

Pertuzumab products can cause hypersensitivity reactions, including anaphylaxis.

In CLEOPATRA, the overall frequency of hypersensitivity/anaphylaxis reactions was 11% in pertuzumab-treated patients, with Grade 3 – 4 hypersensitivity reactions and anaphylaxis occurring in 2% of patients.

In NeoSphere, TRYPHAENA, BERENICE, and APHINITY, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In APHINITY, the overall frequency of hypersensitivity/anaphylaxis was 5% in the pertuzumab treated group. The incidence was highest in the pertuzumab plus TCH treated group (8%) with 1% Grade 3 – 4 events.

Observe patients closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis and fatal events, have been observed in patients treated with pertuzumab products [see Clinical Trials Experience (6.1)]. Angioedema has been described in post-marketing reports. Medications to treat such reactions, as well as emergency equipment, should beavailable for immediate use prior to administration of POHERDY. POHERDY is contraindicated in patients with known hypersensitivity to pertuzumab products or to any of its excipients [see Contraindications (4)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of pertuzumab products.

Studies have not been performed to evaluate the mutagenic potential of pertuzumab products.

No specific fertility studies in animals have been performed to evaluate the effect ofpertuzumab  products. No adverse effects on male and female reproductive organs were observed in repeatdose toxicity studies of up to six months duration in cynomolgus monkeys.

OVERDOSAGE

No information provided

Contraindications for Poherdy

POHERDY is contraindicated in patients with known hypersensitivity to pertuzumab products or to any of its excipients [see Warnings and Precautions (5.4)].

Clinical Pharmacology for Poherdy

Mechanism of Action

Pertuzumab products target the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab products inhibit ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab products mediate antibody-dependent cellmediated cytotoxicity (ADCC).

While pertuzumab products alone inhibited the proliferation of human tumor cells, the combination of pertuzumab products and trastuzumab augmented anti-tumor activity in HER2overexpressing xenograft models.

Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of pertuzumab products have not been fully characterized.

Cardiac Electrophysiology

The effect of pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2- positive breast cancer in CLEOPATRA. At the recommended dose of pertuzumab, a mean increase in the QTc interval >20 ms was not observed. A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.

Pharmacokinetics

Based on a population PK analysis that included 481 patients, pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg.

With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose.

Elimination

The median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of pertuzumab were observed based on age, sex, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant or adjuvant vs. metastatic setting). No dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant.

Pertuzumab exposure in patients with mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200). The pharmacokinetics of pertuzumab in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of pertuzumab or of other pertuzumab products.

Patients in CLEOPATRA were tested at multiple time-points for anti-pertuzumab antibodies. 3% (13/389) of patients in the pertuzumab-treated group and 7% (25/372) of patients in the placebotreated group tested positive for anti-pertuzumab antibodies. Of these 38 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to anti-pertuzumab antibodies. The presence of pertuzumab in patient serum at the levels expected at the time of anti-drug antibodies sampling can interfere with the ability of this assay to detect antipertuzumab 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 pertuzumab tested positive for anti-pertuzumab antibodies. This patient did not experience any anaphylactic/hypersensitivity reactions.

Because of limited immunogenicity data, the clinical impact of anti-pertuzumab antibodies is unknown. There was no identified clinically significant effect of anti-pertuzumab antibodies on the safety of pertuzumab.

Patient Information for Poherdy

Left Ventricular Dysfunction

• Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential that exposure to POHERDY in combination with trastuzumab during pregnancy or within 7 months prior to conception can result in fetal harm [see Warnings and Precautions (2)]. Advise female patients to contact their healthcare provider with aknown or suspected pregnancy [see Use in Specific Populations (8.1)].
• Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of POHERDY in combination with trastuzumab [see Use in Specific Populations (3)].

Hypersensitivity and Anaphylaxis

• Advise patients to contact their healthcare provider immediately and to report any symptoms of hypersensitivity or anaphylaxis including angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.4)].