6 ADVERSE REACTIONS

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

Infusion reactions [see Warnings and Precautions (5.1)].
Cardiopulmonary arrest [see Warnings and Precautions (5.2)].
Pulmonary toxicity [see Warnings and Precautions (5.3)].
Dermatologic toxicity [see Warnings and Precautions (5.4)].
Hypomagnesemia and Electrolyte Abnormalities [see Warnings and Precautions (5.6)].

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 practice.

The data described in Warnings and Precautions reflect exposure to ERBITUX in 1373 patients with SCCHN or CRC enrolled in clinical trials and treated at the recommended dosage for a median of 7 to 14 weeks [see Clinical Studies (14.1, 14.2)]. The most common adverse reactions in clinical trials with ERBITUX as a single-agent or in combination with radiotherapy or chemotherapy [FOLFIRI, irinotecan and 5-fluorouracil/platinum] (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In Combination with Radiation Therapy

The safety of ERBITUX in combination with radiation therapy compared to radiation therapy alone was evaluated in BONNER. The data described below reflect exposure to ERBITUX in 420 patients with locally or regionally advanced SCCHN. ERBITUX was administered at the recommended dosage (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1 to 11) [see Clinical Studies (14.1)].

Table 2 provides the frequency and severity of adverse reactions in BONNER.

Table 2: Selected Adverse Reactions in ≥10% of Patients with Locoregionally Advanced SCCHN (BONNER)a
Adverse Reaction	ERBITUX with Radiation (n=208)		Radiation Therapy Alone (n=212)
Adverse Reaction	Grades 1–4b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
a Adverse reactions occurring in ≥10% of patients in the ERBITUX combination arm and at a higher incidence (≥5%) compared to the radiation alone arm.
b Adverse reactions were graded using the NCI CTC, version 2.0.
c Includes cases also reported as infusion reaction.
d Infusion reaction defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.
e Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for ERBITUX with Radiation arm; 209–210 for Radiation alone.
f Acneiform rash defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
General
Asthenia	56	4	49	5
Feverc	29	1	13	1
Headache	19	<1	8	<1
Chillsc	16	0	5	0
Infusion Reactiond	15	3	2	0
Infection	13	1	9	1
Gastrointestinal
Nausea	49	2	37	2
Emesis	29	2	23	4
Diarrhea	19	2	13	1
Dyspepsia	14	0	9	1
Metabolism and Nutrition
Weight Loss	84	11	72	7
Dehydration	25	6	19	8
Increased Alanine Transaminasee	43	2	21	1
Increased Aspartate Transaminasee	38	1	24	1
Increased Alkaline Phosphatasee	33	<1	24	0
Respiratory
Pharyngitis	26	3	19	4
Dermatologic
Acneiform Rashf	87	17	10	1
Radiation Dermatitis	86	23	90	18
Application Site Reaction	18	0	12	1
Pruritus	16	0	4	0

The overall incidence of late radiation toxicities (any grade) was higher for patients receiving ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX with radiation treatment groups.

In Combination with Platinum-based Therapy and Fluorouracil

The safety of a cetuximab product in combination with platinum-based therapy and fluorouracil or platinum-based therapy and fluorouracil alone was evaluated in EXTREME. The data described below reflect exposure to a cetuximab product in 434 patients with recurrent locoregional disease or metastatic SCCHN. Because ERBITUX provides approximately 22% higher exposure relative to the cetuximab product, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication; however, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX [see Clinical Pharmacology (12.3)]. Cetuximab was administered intravenously at a dosage of 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1 to 89) [see Clinical Studies (14.1)].

Table 3 provides the frequency and severity of adverse reactions in EXTREME.

Table 3: Selected Adverse Reactions in ≥10% of Patients with Recurrent Locoregional Disease or Metastatic SCCHN (EXTREME)a
Adverse Reaction	Cetuximab with Platinum-based Therapy and fluorouracil (n=219)		Platinum-based Therapy and fluorouracil Alone (n=215)
Adverse Reaction	Grades 1–4b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
a Adverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the platinum-based therapy and fluorouracil alone arm.
b Adverse reactions were graded using the NCI CTC, version 2.0.
c Infusion reaction defined as “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing.
d Infection excludes sepsis-related events which are presented separately.
e Acneiform rash defined as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”.
Chemotherapy = cisplatin and fluorouracil or carboplatin and fluorouracil
Eye
Conjunctivitis	10	0	0	0
Gastrointestinal
Nausea	54	4	47	4
Diarrhea	26	5	16	1
General and Administration Site
Pyrexia	22	0	13	1
Infusion Reactionc	10	2	<1	0
Infections
Infectiond	44	11	27	8
Metabolism and Nutrition
Anorexia	25	5	14	1
Hypocalcemia	12	4	5	1
Hypokalemia	12	7	7	5
Hypomagnesemia	11	5	5	1
Dermatologic
Acneiform Rashe	70	9	2	0
Rash	28	5	2	0
Acne	22	2	0	0
Dermatitis Acneiform	15	2	0	0
Dry Skin	14	0	<1	0
Alopecia	12	0	7	0

For cardiac disorders, approximately 9% of patients in both treatment arms in EXTREME experienced a cardiac event. The majority of these events occurred in patients who received cisplatin and fluorouracil with or without cetuximab. Cardiac disorders were observed in 11% and 12% of patients who received cisplatin and fluorouracil with or without cetuximab, respectively, and 6% and 4% in patients who received carboplatin and fluorouracil with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin and fluorouracil containing subgroup. Death attributed to cardiovascular events or sudden death was reported in 3% of the patients in the cetuximab with platinum-based therapy and fluorouracil arm and in 2% of the patients in the platinum-based therapy and fluorouracil alone arm.

K-Ras Wild-type, EGFR-expressing, Metastatic Colorectal Cancer (mCRC)

In Combination with FOLFIRI

The safety of a cetuximab product in combination with FOLFIRI or FOLFIRI alone was evaluated in CRYSTAL. The data described below reflect exposure to a cetuximab product in 667 patients with K-Ras wild-type, EGFR-expressing, mCRC. ERBITUX provides approximately 22% higher exposure compared to this product; however, the safety data from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. Cetuximab was administered intravenously at a dosage of 400 mg/m2 initial dose, followed by 250 mg/m2 weekly. Patients received a median of 24 infusions (range 1 to 224) [see Clinical Studies (14.2)].

Serious adverse reactions included pulmonary embolism, which was reported in 4.4% of patients treated with cetuximab with FOLFIRI as compared to 3.4% of patients treated with FOLFIRI alone.

Table 4 provides the frequency and severity of adverse reactions in CRYSTAL.

Table 4: Selected Adverse Reactions in ≥10% of Patients with K-Ras Wild-type and EGFR-expressing, Metastatic Colorectal Cancer (CRYSTAL)a
Adverse Reaction	Cetuximab with FOLFIRI (n=317)		FOLFIRI Alone (n=350)
Adverse Reaction	Grades 1–4b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
a Adverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the FOLFIRI alone arm.
b Adverse reactions were graded using the NCI CTC, version 2.0.
c Infusion reaction defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”.
d Acne-like rash defined by the following events: “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”.
Hematologic
Neutropenia	49	31	42	24
Eye
Conjunctivitis	18	<1	3	0
Gastrointestinal
Diarrhea	66	16	60	10
Stomatitis	31	3	19	1
Dyspepsia	16	0	9	0
General and Administration Site
Pyrexia	26	1	14	1
Weight Decreased	15	1	9	1
Infusion Reactionc	14	2	<1	0
Infections
Paronychia	20	4	<1	0
Metabolism and Nutrition
Anorexia	30	3	23	2
Dermatologic
Acne-like Rashd	86	18	13	<1
Rash	44	9	4	0
Dermatitis Acneiform	26	5	<1	0
Dry Skin	22	0	4	0
Acne	14	2	0	0
Pruritus	14	0	3	0
Palmar-plantar Erythrodysesthesia Syndrome	19	4	4	<1
Skin Fissures	19	2	1	0

As Single-Agent

The safety of ERBITUX with best supportive care (BSC) or BSC alone was evaluated in Study CA225-025. The data described below reflect exposure to ERBITUX in 242 patients with K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) [see Warnings and Precautions (5.8)]. ERBITUX was administered intravenously at the recommended dosage (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1 to 51) [see Clinical Studies (14.2)].

Table 5 provides the frequency and severity of adverse reactions in Study CA225-025.

Table 5: Selected Adverse Reactions in ≥10% of Patients with K-Ras Wild-type, EGFR-expressing, Metastatic Colorectal Cancer Treated with Single-Agent ERBITUX (Study CA225-025)a
Adverse Reaction	ERBITUX with BSC (n=118)		BSC alone (n=124)
Adverse Reaction	Grades 1–4b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
a Adverse reactions occurring in ≥10% of patients in the ERBITUX with BSC arm and at a higher incidence (≥5%) compared to the BSC alone arm.
b Adverse reactions were graded using the NCI CTC, version 2.0.
c Infusion reaction defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related.
Dermatologic
Rash/Desquamation	95	16	21	1
Dry Skin	57	0	15	0
Pruritus	47	2	11	0
Other-Dermatology	35	0	7	2
Nail Changes	31	0	4	0
General
Fatigue	91	31	79	29
Fever	25	3	16	0
Infusion Reactionsc	18	3	0	0
Rigors, Chills	16	1	3	0
Pain
Pain-Other	59	18	37	10
Headache	38	2	11	0
Bone Pain	15	4	8	2
Pulmonary
Dyspnea	49	16	44	13
Cough	30	2	19	2
Gastrointestinal
Nausea	64	6	50	6
Constipation	53	3	38	3
Diarrhea	42	2	23	2
Vomiting	40	5	26	5
Stomatitis	32	1	10	0
Other	22	12	16	5
Dehydration	13	5	3	0
Mouth Dryness	12	0	6	0
Taste Disturbance	10	0	5	0
Infection
Infection without neutropenia	38	11	19	5
Musculoskeletal
Arthralgia	14	3	6	0
Neurological
Neuropathy-sensory	45	1	38	2
Insomnia	27	0	13	0
Confusion	18	6	10	2
Anxiety	14	1	5	1
Depression	14	0	5	0

In Combination with Irinotecan

ERBITUX at the recommended dosage was administered in combination with irinotecan in 354 patients with EGFR-expressing recurrent mCRC in Study CP02-9923 and BOND.

The most common adverse reactions were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) in Combination with Encorafenib

The safety of ERBITUX (400 mg/m2 initial dose, followed by 250 mg/m2 weekly) in combination with encorafenib (300 mg once daily) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.3)] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with ERBITUX in combination with encorafenib and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with ERBITUX.

The most common (≥ 25%) adverse reactions in patients receiving ERBITUX in combination with encorafenib were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

Table 6 and Table 7 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.

Table 6: Adverse Reactions Occurring in ≥10% of Patients Receiving ERBITUX in Combination with Encorafenib in BEACON CRCa
Adverse Reaction	ERBITUX with encorafenib N=216		ERBITUX with irinotecan or ERBITUX with FOLFIRI N=193
Adverse Reaction	All Grades (%)	≥ Grade 3b (%)	All Grades (%)	≥ Grade 3 (%)
a Grades per National Cancer Institute CTCAE v4.03.
b Grade 4-5 adverse reactions in the ERBITUX with encorafenib arm were limited to Grade 5 hemorrhage (n=1).
c Represents a composite of multiple, related preferred terms.
General Disorders and Administration Site Conditions
Fatiguec	51	7	50	8
Pyrexiac	17	1	15	1
Gastrointestinal Disorders
Nausea	34	1	41	1
Diarrheac	33	2	48	10
Abdominal painc	30	4	32	5
Vomiting	21	1	29	3
Constipation	15	0	18	1
Metabolism and Nutrition Disorders
Decreased appetite	27	2	27	3
Musculoskeletal and Connective Tissue Disorders
Arthralgiac	27	4	3	0
Myopathyc	15	1	4	0
Pain in extremity	10	0	1	0
Skin and Subcutaneous Tissue Disorders
Dermatitis acneiformc	32	1	43	3
Rashc	26	0	26	2
Pruritusc	14	0	6	0
Melanocytic nevus	14	0	0	0
Dry skinc	13	0	12	1
Nervous System Disorders
Headachec	20	0	3	0
Peripheral neuropathyc	12	1	6	0
Vascular Disorders
Hemorrhagec	19	2	9	0
Psychiatric Disorders
Insomniac	13	0	6	0

Other clinically important adverse reactions occurring in <10% of patients who received ERBITUX in combination with encorafenib were:

Gastrointestinal disorders: Pancreatitis

Table 7: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving ERBITUX in Combination with Encorafenib in BEACON CRCa
Laboratory Abnormalityb	ERBITUX with encorafenib		ERBITUX with irinotecan or ERBITUX with FOLFIRI
Laboratory Abnormalityb	All Grades (%)bb	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
a Grades per National Cancer Institute CTCAE v4.03.
b Based on the number of patients with available baseline and at least one on-treatment laboratory test.
Hematology
Anemia	34	4	48	5
Lymphopenia	24	7	35	5
Increased Activated Partial Thromboplastin Time	13	1	7	1
Chemistry
Hypomagnesemia	19	0	22	1
Increased Alkaline Phosphatase	18	4	30	7
Increased ALT	17	0	29	3
Increased AST	15	1	22	2
Hypokalemia	12	3	32	5
Hyponatremia	11	2	13	2

6.2 Immunogenicity

As with all therapeutic proteins, there is 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 cetuximab in the studies below with the incidence of antibodies to cetuximab in other studies or to other products may be misleading.

An ELISA methodology was used to characterize the incidence of anti-cetuximab antibodies. The incidence of anti-cetuximab binding antibodies in 105 patients (from studies I4E-MC-JXBA, I4E-MC-JXBB, and I4E-MC-JXBD) with at least one post-baseline blood sample (≥4 weeks post first ERBITUX administration) was <5%.

6.3 Postmarketing Experience

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

Neurologic: Aseptic meningitis
Gastrointestinal: Mucosal inflammation
Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis, life-threatening and fatal bullous mucocutaneous disease