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mechanism of action is HER1 Antagonists [MoA]

Erbitux (Cetuximab)

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Dosage & administration

* Premedicate with an H₁ receptor antagonist. (

2.4 Premedication

Premedicate with a histamine-1 (H₁) receptor antagonist intravenously 30–60 minutes prior to the first dose or subsequent doses as deemed necessary

[see Warnings and Precautions ]

)
*

In Combination With Radiation Therapy:

* Initial dose: 400 mg/m² administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy. (

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In combination with radiation therapy

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
* Complete ERBITUX administration 1 hour prior to radiation therapy.

As a single-agent or in combination with platinum-based therapy and fluorouracil

Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.

)
* Subsequent doses: 250 mg/m² administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks). (

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In combination with radiation therapy

As a single-agent or in combination with platinum-based therapy and fluorouracil

Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.

)
* Complete ERBITUX administration 1 hour prior to radiation therapy. (

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In combination with radiation therapy

As a single-agent or in combination with platinum-based therapy and fluorouracil

Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.

)

*

As Single-Agent or in Combination With Chemotherapy:

* Weekly: Administer initial dose of 400 mg/m² as a 120-minute intravenous infusion, and subsequent doses of 250 mg/m² infused over 60 minutes once weekly. (

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In combination with radiation therapy

As a single-agent or in combination with platinum-based therapy and fluorouracil

Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.

2.3 Recommended Dosage for Colorectal Cancer (CRC)

As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)

Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.

In combination with encorafenib

The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib.
*

The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.

Refer to the encorafenib prescribing information for recommended encorafenib dosage information.

)
* Biweekly: Administer 500 mg/m² as a 120-minute intravenous infusion every two weeks. (

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In combination with radiation therapy

As a single-agent or in combination with platinum-based therapy and fluorouracil

Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.

2.3 Recommended Dosage for Colorectal Cancer (CRC)

As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)

Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.

In combination with encorafenib

The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib.
*

The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.

Refer to the encorafenib prescribing information for recommended encorafenib dosage information.

)
* Complete ERBITUX administration 1 hour prior to chemotherapy. Continue treatment until disease progression or unacceptable toxicity. (

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In combination with radiation therapy

As a single-agent or in combination with platinum-based therapy and fluorouracil

Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.

2.3 Recommended Dosage for Colorectal Cancer (CRC)

As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)

Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.

Weekly Dosage

* Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
* Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week

Biweekly Dosage

Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.

In combination with encorafenib

The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib.
*

The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.

Refer to the encorafenib prescribing information for recommended encorafenib dosage information.

)

* See full prescribing information for dosage adjustments for adverse reactions. (

2.5 Dosage Modifications for Adverse Reactions

Reduce, delay, or discontinue ERBITUX to manage adverse reactions as described in Table 1.

Table 1: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity ^a	Dosage Modification
^aNational Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0.
Infusion reactions [see Warnings and Precautions ]	Grade 1 or 2	Reduce the infusion rate by 50%.
Infusion reactions [see Warnings and Precautions ]	Grade 3 or 4	Immediately and permanently, discontinue ERBITUX.
Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease) [see Warnings and Precautions ]	1^stoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 250 mg/m². If no improvement, discontinue ERBITUX.
	2^ndoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 200 mg/m². If no improvement, discontinue ERBITUX.
	3^rdoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 150 mg/m². If no improvement, discontinue ERBITUX.
	4^thoccurrence; Grade 3 or 4	Discontinue ERBITUX.
Pulmonary toxicity [see Warnings and Precautions ]	Acute onset or worsening pulmonary symptoms	Delay infusion 1 to 2 weeks; if condition improves, continue at the dose that was being administered at the time of occurrence. If no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue ERBITUX.

)

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Erbitux prescribing information

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions

[see Warnings and Precautions (

5.1 Infusion Reactions

ERBITUX can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred in 8.4% of 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients

[see Adverse Reactions ]

. Signs and symptoms included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest.

The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose (alpha-gal). Consider testing patients for alpha-gal IgE antibodies using FDA-cleared methods prior to initiating ERBITUX. Negative results for alpha-gal antibodies do not rule out the risk of severe infusion reactions.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion.

Premedicate with a histamine-1(H₁) receptor antagonist as recommended

[see Dosage and Administration ]

. Monitor patients for at least 1 hour following each ERBITUX infusion, in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity

[see Dosage and Administration ]

), Adverse Reactions (

6 ADVERSE REACTIONS

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

Infusion reactions
[see Warnings and Precautions ]
.
Cardiopulmonary arrest
[see Warnings and Precautions ]
.
Pulmonary toxicity
[see Warnings and Precautions ]
.
Dermatologic toxicity
[see Warnings and Precautions ]
.
Hypomagnesemia and Electrolyte Abnormalities
[see Warnings and Precautions ]
.

The most common adverse reactions (incidence ≥25%) with Erbitux as a single-agent or in combination with radiotherapy or chemotherapy (FOLFIRI, Irinotecan and 5-Fluorouracil/Platinum) are: cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

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

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ]

.
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/m²initial dose, followed by 250 mg/m²weekly). Patients received a median of 8 infusions (range 1 to 11)

[see Clinical Studies ]

Table 2provides 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 1–4 ^b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
^aAdverse reactions occurring in ≥10% of patients in the ERBITUX combination arm and at a higher incidence (≥5%) compared to the radiation alone arm.
^bAdverse reactions were graded using the NCI CTC, version 2.0.
^cIncludes cases also reported as infusion reaction.
^dInfusion 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”.
^eBased 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.
^fAcneiform rash defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
General
Asthenia	56	4	49	5
Fever^c	29	1	13	1
Headache	19	<1	8	<1
Chills^c	16	0	5	0
Infusion Reaction^d	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 Transaminase^e	43	2	21	1
Increased Aspartate Transaminase^e	38	1	24	1
Increased Alkaline Phosphatase^e	33	<1	24	0
Respiratory
Pharyngitis	26	3	19	4
Dermatologic
Acneiform Rash^f	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 ]

. Cetuximab was administered intravenously at a dosage of 400 mg/m²for the initial dose, followed by 250 mg/m²weekly. Patients received a median of 17 infusions (range 1 to 89)

[see Clinical Studies ]

Table 3provides 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 1–4 ^b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
^aAdverse 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.
^bAdverse reactions were graded using the NCI CTC, version 2.0.
^cInfusion reaction defined as “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing.
^dInfection excludes sepsis-related events which are presented separately.
^eAcneiform 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 Reaction^c	10	2	<1	0
Infections
Infection^d	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 Rash^e	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/m²initial dose, followed by 250 mg/m²weekly. Patients received a median of 24 infusions (range 1 to 224)

[see Clinical Studies ]

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 4provides 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 1–4 ^b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
^aAdverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the FOLFIRI alone arm.
^bAdverse reactions were graded using the NCI CTC, version 2.0.
^cInfusion 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”.
^dAcne-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 Reaction^c	14	2	<1	0
Infections
Paronychia	20	4	<1	0
Metabolism and Nutrition
Anorexia	30	3	23	2
Dermatologic
Acne-like Rash^d	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 ]

. ERBITUX was administered intravenously at the recommended dosage (400 mg/m²initial dose, followed by 250 mg/m²weekly). Patients received a median of 17 infusions (range 1 to 51)

[see Clinical Studies ]

Table 5provides 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 1–4 ^b	Grades 3 and 4	Grades 1–4	Grades 3 and 4
^aAdverse reactions occurring in ≥10% of patients in the ERBITUX with BSC arm and at a higher incidence (≥5%) compared to the BSC alone arm.
^bAdverse reactions were graded using the NCI CTC, version 2.0.
^cInfusion 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 Reactions^c	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/m²initial dose, followed by 250 mg/m²weekly) 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 ]

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 6and Table 7present 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 CRC^a
Adverse Reaction	ERBITUX with encorafenib N=216		ERBITUX with irinotecan or ERBITUX with FOLFIRI N=193
Adverse Reaction	All Grades (%)	≥ Grade 3^b(%)	All Grades (%)	≥ Grade 3 (%)
^aGrades per National Cancer Institute CTCAE v4.03.
^bGrade 4-5 adverse reactions in the ERBITUX with encorafenib arm were limited to Grade 5 hemorrhage (n=1).
^cRepresents a composite of multiple, related preferred terms.
General Disorders and Administration Site Conditions
Fatigue^c	51	7	50	8
Pyrexia^c	17	1	15	1
Gastrointestinal Disorders
Nausea	34	1	41	1
Diarrhea^c	33	2	48	10
Abdominal pain^c	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
Arthralgia^c	27	4	3	0
Myopathy^c	15	1	4	0
Pain in extremity	10	0	1	0
Skin and Subcutaneous Tissue Disorders
Dermatitis acneiform^c	32	1	43	3
Rash^c	26	0	26	2
Pruritus^c	14	0	6	0
Melanocytic nevus	14	0	0	0
Dry skin^c	13	0	12	1
Nervous System Disorders
Headache^c	20	0	3	0
Peripheral neuropathy^c	12	1	6	0
Vascular Disorders
Hemorrhage^c	19	2	9	0
Psychiatric Disorders
Insomnia^c	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 CRC^a
Laboratory Abnormality^b	ERBITUX with encorafenib		ERBITUX with irinotecan or ERBITUX with FOLFIRI
Laboratory Abnormality^b	All Grades (%)^b ^b	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
^aGrades per National Cancer Institute CTCAE v4.03.
^bBased 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

)]

. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions

[see Dosage and Administration (

2.5 Dosage Modifications for Adverse Reactions

Reduce, delay, or discontinue ERBITUX to manage adverse reactions as described in Table 1.

Table 1: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity ^a	Dosage Modification
^aNational Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0.
Infusion reactions [see Warnings and Precautions ]	Grade 1 or 2	Reduce the infusion rate by 50%.
Infusion reactions [see Warnings and Precautions ]	Grade 3 or 4	Immediately and permanently, discontinue ERBITUX.
Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease) [see Warnings and Precautions ]	1^stoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 250 mg/m². If no improvement, discontinue ERBITUX.
	2^ndoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 200 mg/m². If no improvement, discontinue ERBITUX.
	3^rdoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 150 mg/m². If no improvement, discontinue ERBITUX.
	4^thoccurrence; Grade 3 or 4	Discontinue ERBITUX.
Pulmonary toxicity [see Warnings and Precautions ]	Acute onset or worsening pulmonary symptoms	Delay infusion 1 to 2 weeks; if condition improves, continue at the dose that was being administered at the time of occurrence. If no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue ERBITUX.

)]

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration

[see Warnings and Precautions (

5.2 Cardiopulmonary Arrest

ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death occurred in 2% of 208 patients treated with radiation therapy and ERBITUX in BONNER. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX.

In EXTREME, fatal cardiac disorders and/or sudden death occurred in 3% of 219 patients treated with a cetuximab product in combination with platinum-based therapy and fluorouracil.

Carefully consider use of ERBITUX with radiation therapy or platinum-based therapy with fluorouracil in patients with SCCHN with a history of coronary artery disease, congestive heart failure, or arrhythmias. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

[see Warnings and Precautions ]

5.6 Hypomagnesemia and Accompanying Electrolyte Abnormalities

ERBITUX can cause hypomagnesemia. Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%.

In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and fluorouracil resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. No patient experienced Grade 3 or 4 hypomagnesemia

[see Adverse Reactions ].

Hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX. Monitor patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at least 8 weeks following the completion of ERBITUX. Replete electrolytes as necessary.

)]

Indications and Usage ( 1.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) ERBITUX is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy [see Dosage and Administration ] . )		09/2021
Dosage and Administration
	Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN) ( 2.1 Patient Selection Select patients with metastatic colorectal cancer (CRC) for treatment with ERBITUX based on the presence of: Ras wild-type, EGFR-expressing CRC [see Clinical Studies ], or BRAF V600E mutation-positive metastatic CRC [see Clinical Studies ] Information on FDA-approved tests for the detection of K-Ras or BRAF V600E mutations in CRC in patients with metastatic CRC is available at: http://www.fda.gov/CompanionDiagnostics. )	04/2021
	Recommended Dosage for Colorectal Cancer (CRC) ( 2.3 Recommended Dosage for Colorectal Cancer (CRC) As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule. Weekly Dosage Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week Biweekly Dosage Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity. In combination with encorafenib The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib. The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosage information. )	04/2021
Dosage and Administration ( 2.1 Patient Selection Select patients with metastatic colorectal cancer (CRC) for treatment with ERBITUX based on the presence of: Ras wild-type, EGFR-expressing CRC [see Clinical Studies ], or BRAF V600E mutation-positive metastatic CRC [see Clinical Studies ] Information on FDA-approved tests for the detection of K-Ras or BRAF V600E mutations in CRC in patients with metastatic CRC is available at: http://www.fda.gov/CompanionDiagnostics. , 2.3 Recommended Dosage for Colorectal Cancer (CRC) As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule. Weekly Dosage Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week Biweekly Dosage Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity. In combination with encorafenib The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib. The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosage information. )		09/2021
Warnings and Precautions, Infusion Reactions ( 5.1 Infusion Reactions ERBITUX can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred in 8.4% of 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients [see Adverse Reactions ] . Signs and symptoms included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose (alpha-gal). Consider testing patients for alpha-gal IgE antibodies using FDA-cleared methods prior to initiating ERBITUX. Negative results for alpha-gal antibodies do not rule out the risk of severe infusion reactions. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion. Premedicate with a histamine-1(H₁) receptor antagonist as recommended [see Dosage and Administration ] . Monitor patients for at least 1 hour following each ERBITUX infusion, in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity [see Dosage and Administration ] . )		11/2020

ERBITUX^® is an epidermal growth factor receptor (EGFR) antagonist indicated for treatment of:

Head and Neck Cancer

Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy. (

1.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

ERBITUX^®is indicated:

in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).
in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN.
as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.

14.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In Combination with Radiation Therapy

BONNER (NCT00004227) was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either ERBITUX in combination with radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily). Radiation therapy was administered for 6–7 weeks as once-daily, twice-daily, or concomitant boost. ERBITUX was administered intravenously as a 400 mg/m²initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m²weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6–7 weeks). The main efficacy outcome measure was duration of locoregional control. Another outcome measure was overall survival (OS).

Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were White, and 90% had baseline Karnofsky performance status ≥80. There were 258 patients enrolled in U.S. sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen.

Efficacy results are presented in Table 8.

Table 8: Efficacy Results in Locoregionally Advanced SCCHN in BONNER
	ERBITUX plus Radiation (n=211)	Radiation Alone (n=213)	Hazard Ratio (95% CI ^a )	Stratified Log-rank p-value
^aCI = confidence interval.
Locoregional Control
Median duration (months)	24.4	14.9	0.68 (0.52–0.89)	0.005
Overall Survival
Median duration (months)	49.0	29.3	0.74 (0.57–0.97)	0.03

In Combination with Platinum-based Therapy with Fluorouracil

EXTREME (NCT00122460) was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN. Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive a cetuximab product in combination with platinum-based therapy and fluorouracil or platinum-based therapy and fluorouracil alone. Choice of cisplatin or carboplatin was at the discretion of the investigator. Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. Cisplatin (100 mg/m²intravenously on Day 1) or carboplatin (AUC 5 mg/mL*min intravenously on Day 1) and fluorouracil (1000 mg/m²/day intravenously on Days 1–4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered intravenously at a 400 mg/m²initial dose, followed by a 250 mg/m²weekly dose. In the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity. If chemotherapy was delayed because of adverse reactions, weekly cetuximab was continued. If chemotherapy was discontinued for adverse reactions, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity. The main efficacy outcome measure was OS. Other outcome measures were PFS and objective response rate (ORR).

Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were White, and 88% had baseline Karnofsky performance status ≥80. Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease. Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period.

Efficacy results are presented in Table 9and Figure 1.

Table 9: Efficacy Results in Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME
	Cetuximab with Platinum-based Therapy and Fluorouracil (n=222)	Platinum-based Therapy and Fluorouracil (n=220)
^aCI = confidence interval.
^bCMH = Cochran-Mantel-Haenszel.
Overall Survival
Median Duration (months)	10.1	7.4
Hazard Ratio (95% CI^a)	0.80 (0.64, 0.98)
Stratified Log-rank p-value	0.034
Progression-free Survival
Median Duration (months)	5.5	3.3
Hazard Ratio (95% CI^a)	0.57 (0.46, 0.72)
Stratified Log-rank p-value	<0.0001
Objective Response Rate	35.6%	19.5%
Odds Ratio (95% CI^a)	2.33 (1.50, 3.60)
CMH^bTest p-value	0.0001

Figure 1: Kaplan-Meier Curves for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME

CT = Platinum-based therapy with fluorouracil

CET = another cetuximab product

In exploratory subgroup analyses by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab in combination with cisplatin and fluorouracil compared to cisplatin and fluorouracil alone, the difference in median OS was 3.3 months (10.6 versus 7.3 months; HR 0.71; 95% CI 0.54, 0.93). The difference in median PFS was 2.1 months (5.6 versus 3.5 months; HR 0.55; 95% CI 0.41, 0.73). The ORR was 39% and 23%, respectively (OR 2.18; 95% CI 1.29, 3.69).

For patients (N=149) receiving cetuximab in combination with carboplatin and fluorouracil compared to carboplatin and fluorouracil alone, the difference in median OS was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median PFS was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The ORR was 30% and 15%, respectively (OR 2.45; 95% CI 1.10, 5.46).

As Single-Agent

EMR 62202-016 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients were administered intravenously a 20-mg test dose of ERBITUX on Day 1, followed by a 400 mg/m²initial dose, and 250 mg/m²weekly until disease progression or unacceptable toxicity.

The median age was 57 years, 82% were male, 100% White, and 62% had a Karnofsky performance status of ≥80.

The ORR was 13% (95% CI 7%, 21%). Median duration of response (DoR) was 5.8 months (range 1.2 to 5.8 months).

)

Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with fluorouracil. (

1.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

ERBITUX^®is indicated:

in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).
in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN.
as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.

14.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In Combination with Radiation Therapy

Efficacy results are presented in Table 8.

Table 8: Efficacy Results in Locoregionally Advanced SCCHN in BONNER
	ERBITUX plus Radiation (n=211)	Radiation Alone (n=213)	Hazard Ratio (95% CI ^a )	Stratified Log-rank p-value
^aCI = confidence interval.
Locoregional Control
Median duration (months)	24.4	14.9	0.68 (0.52–0.89)	0.005
Overall Survival
Median duration (months)	49.0	29.3	0.74 (0.57–0.97)	0.03

In Combination with Platinum-based Therapy with Fluorouracil

Efficacy results are presented in Table 9and Figure 1.

Table 9: Efficacy Results in Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME
	Cetuximab with Platinum-based Therapy and Fluorouracil (n=222)	Platinum-based Therapy and Fluorouracil (n=220)
^aCI = confidence interval.
^bCMH = Cochran-Mantel-Haenszel.
Overall Survival
Median Duration (months)	10.1	7.4
Hazard Ratio (95% CI^a)	0.80 (0.64, 0.98)
Stratified Log-rank p-value	0.034
Progression-free Survival
Median Duration (months)	5.5	3.3
Hazard Ratio (95% CI^a)	0.57 (0.46, 0.72)
Stratified Log-rank p-value	<0.0001
Objective Response Rate	35.6%	19.5%
Odds Ratio (95% CI^a)	2.33 (1.50, 3.60)
CMH^bTest p-value	0.0001

Figure 1: Kaplan-Meier Curves for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME

CT = Platinum-based therapy with fluorouracil

CET = another cetuximab product

As Single-Agent

The median age was 57 years, 82% were male, 100% White, and 62% had a Karnofsky performance status of ≥80.

The ORR was 13% (95% CI 7%, 21%). Median duration of response (DoR) was 5.8 months (range 1.2 to 5.8 months).

)

Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy. (

1.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

ERBITUX^®is indicated:

in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).
in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN.
as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.

14.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In Combination with Radiation Therapy

Efficacy results are presented in Table 8.

Table 8: Efficacy Results in Locoregionally Advanced SCCHN in BONNER
	ERBITUX plus Radiation (n=211)	Radiation Alone (n=213)	Hazard Ratio (95% CI ^a )	Stratified Log-rank p-value
^aCI = confidence interval.
Locoregional Control
Median duration (months)	24.4	14.9	0.68 (0.52–0.89)	0.005
Overall Survival
Median duration (months)	49.0	29.3	0.74 (0.57–0.97)	0.03

In Combination with Platinum-based Therapy with Fluorouracil

Efficacy results are presented in Table 9and Figure 1.

Table 9: Efficacy Results in Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME
	Cetuximab with Platinum-based Therapy and Fluorouracil (n=222)	Platinum-based Therapy and Fluorouracil (n=220)
^aCI = confidence interval.
^bCMH = Cochran-Mantel-Haenszel.
Overall Survival
Median Duration (months)	10.1	7.4
Hazard Ratio (95% CI^a)	0.80 (0.64, 0.98)
Stratified Log-rank p-value	0.034
Progression-free Survival
Median Duration (months)	5.5	3.3
Hazard Ratio (95% CI^a)	0.57 (0.46, 0.72)
Stratified Log-rank p-value	<0.0001
Objective Response Rate	35.6%	19.5%
Odds Ratio (95% CI^a)	2.33 (1.50, 3.60)
CMH^bTest p-value	0.0001

Figure 1: Kaplan-Meier Curves for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME

CT = Platinum-based therapy with fluorouracil

CET = another cetuximab product

As Single-Agent

The median age was 57 years, 82% were male, 100% White, and 62% had a Karnofsky performance status of ≥80.

The ORR was 13% (95% CI 7%, 21%). Median duration of response (DoR) was 5.8 months (range 1.2 to 5.8 months).

)

Colorectal Cancer

K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test

in combination with FOLFIRI for first-line treatment,
in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,

as a single-agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. (

1.2 K-Ras Wild-type, EGFR-expressing Colorectal Cancer (CRC)

ERBITUX is indicated for the treatment of K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test

[see
Dosage and Administration ]

in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment,
in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,
as a single-agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.

Limitations of Use:

ERBITUX is not indicated for treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown

[see Warnings and Precautions ]

5.7 Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras-Mutant mCRC

ERBITUX is not indicated for the treatment of patients with CRC that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either K-Ras or N-Ras and hereafter is referred to as “Ras” or when the Ras status is unknown.

Retrospective subset analyses of Ras-mutant and wild-type populations across several randomized clinical trials, including CRYSTAL, were conducted to investigate the role of Ras mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies. Use of cetuximab in patients with Ras mutations resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX

[see Indications and Usage ]

12.1 Mechanism of Action

The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha.

In vitro

assays and

in vivo

animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal transduction through the EGFR results in activation of wild-type Ras proteins, but in cells with activating Ras somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR regulation.

In vitro

, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types.

In vitro

assays and

in vivo

animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.

In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of cetuximab and encorafenib had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.

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

In Combination with FOLFIRI

CRYSTAL (NCT00154102) was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing, mCRC. Patients were randomized (1:1) to receive either a cetuximab product in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (Western Europe versus Eastern Europe versus other).

FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m²intravenously on Day 1), folinic acid (400 mg/m²[racemic] or 200 mg/m²[L-form] intravenously on Day 1), and fluorouracil (400 mg/m²bolus on Day 1 followed by 2400 mg/m²as a 46-hour continuous infusion). Cetuximab was administered intravenously as a 400 mg/m²initial dose , followed by 250 mg/m²weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity. The main efficacy outcome measure was PFS assessed by an independent review committee (IRC). Other outcome measures were OS and ORR.

Of the 1217 randomized patients, the median age was 61 years, 60% were male, 86% were White, and 96% had a baseline ECOG performance status 0–1, 60% had primary tumor localized in colon, 84% had 1–2 metastatic sites and 20% had received prior adjuvant and/or neoadjuvant chemotherapy. Demographics and baseline characteristics were similar between study arms.

K-Ras mutation status was available for 89% of the patients: 63% had K-Ras wild-type tumors and 37% had K-Ras mutant tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D. Baseline characteristics and demographics in the K-Ras wild-type subset were similar to that seen in the overall population.

A statistically significant improvement in PFS was observed for the cetuximab with FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-value=0.036). OS was not significantly different at the planned, final analysis based on 838 events (HR=0.93, 95% CI [0.8, 1.1], p-value 0.327).

Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 10and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras wild-type tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutant tumors.

Table 10: Efficacy Results in First-line EGFR-expressing, Metastatic Colorectal Cancer in CRYSTAL (All Randomized and K-Ras Status)
	All Randomized		K-Ras Wild-type		K-Ras Mutant
	Cetuximab with FOLFIRI (n=608)	FOLFIRI (n=609)	Cetuximab with FOLFIRI (n=320)	FOLFIRI (n=356)	Cetuximab with FOLFIRI (n=216)	FOLFIRI (n=187)
^aBased on the Stratified Log-rank test.
^bPost-hoc updated OS analysis, results based on an additional 162 events.
Progression-Free Survival
Number of Events (%)	343 (56)	371 (61)	165 (52)	214 (60)	138 (64)	112 (60)
Median (months) (95% CI)	8.9 (8.0, 9.4)	8.1 (7.6, 8.8)	9.5 (8.9, 11.1)	8.1 (7.4, 9.2)	7.5 (6.7, 8.7)	8.2 (7.4, 9.2)
HR (95% CI)	0.85 (0.74, 0.99)		0.70 (0.57, 0.86)		1.13 (0.88, 1.46)
p-value^a	0.0358
Overall Survival ^b
Number of Events (%)	491 (81)	509 (84)	244 (76)	292 (82)	189 (88)	159 (85)
Median (months) (95% CI)	19.6 (18, 21)	18.5 (17, 20)	23.5 (21, 26)	19.5 (17, 21)	16.0 (15, 18)	16.7 (15, 19)
HR (95% CI)	0.88 (0.78, 1.0)		0.80 (0.67, 0.94)		1.04 (0.84, 1.29)
Objective Response Rate
ORR (95% CI)	46% (42, 50)	38% (34, 42)	57% (51, 62)	39% (34, 44)	31% (25, 38)	35% (28, 43)

Figure 2: Kaplan-Meier Curves for Overall Survival in the K-Ras Wild-type Population in CRYSTAL

As Single-Agent

Study CA225-025 (NCT00079066) was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent mCRC. Patients were randomized (1:1) to receive either ERBITUX with best supportive care (BSC) or BSC alone. ERBITUX was administered intravenously as a 400 mg/m²initial dose, followed by 250 mg/m²weekly until disease progression or unacceptable toxicity. The main efficacy outcome measure was OS.

Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were White, and 77% had baseline ECOG performance status of 0–1. Demographics and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.

K-Ras status was available for 79% of the patients: 54% had K-Ras wild-type tumors and 46% had K-Ras mutant tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D.

Efficacy results are presented in Table 11and Figure 3.

Table 11: Overall Survival in Previously Treated EGFR-expressing, Metastatic Colorectal Cancer in Study CA225-025 (All Randomized and K-Ras Status)
^aBased on the Stratified Log-rank test.
	All Randomized		K-Ras Wild-type		K-Ras Mutant
	ERBITUX with BSC (N=287)	BSC (N=285)	ERBITUX with BSC (N=117)	BSC (N=128)	ERBITUX with BSC (N=108)	BSC (N=100)
Median (months) (95% CI)	6.1 (5.4, 6.7)	4.6 (4.2, 4.9)	8.6 (7.0, 10.3)	5.0 (4.3, 5.7)	4.8 (3.9, 5.6)	4.6 (3.6, 4.9)
HR (95% CI)	0.77 (0.64, 0.92)		0.63 (0.47, 0.84)		0.91 (0.67, 1.24)
p-value^a	0.0046

Figure 3: Kaplan-Meier Curves for Overall Survival in Patients with K-Ras Wild-type Metastatic Colorectal Cancer in Study CA225-025

In Combination with Irinotecan

BOND was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mCRC. Tumor specimens were not available for testing for K-Ras mutation status. Patients were randomized (2:1) to receive either ERBITUX in combination with irinotecan (218 patients) or ERBITUX single-agent (111 patients). ERBITUX was administered intravenously as a 400 mg/m²initial dose, followed by 250 mg/m²weekly until disease progression or unacceptable toxicity. In the ERBITUX with irinotecan arm, irinotecan was added to ERBITUX using the same dosage for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m²every 3 weeks, 180 mg/m²every 2 weeks, or 125 mg/m²weekly times four doses every 6 weeks. The efficacy of ERBITUX with irinotecan or ERBITUX single-agent, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory and irinotecan and oxaliplatin failures.

Of the 329 patients, the median age was 59 years, 63% were male, 98% were White, and 88% had baseline Karnofsky performance status ≥80. Approximately two-thirds had previously failed oxaliplatin treatment.

In patients receiving ERBITUX with irinotecan, the ORR was 23% (95% CI 18%, 29%), median DoR was 5.7 months, and median time to progression was 4.1 months. In patients receiving ERBITUX as a single-agent, the ORR was 11% (95% CI 6%, 18%), median DoR was 4.2 months, and median time to progression was 1.5 months. Similar response rates were observed in the pre-defined subsets in both the combination arm and single-agent arm.

)

Limitations of Use: ERBITUX is not indicated for treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown. (

5.7 Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras-Mutant mCRC

[see Indications and Usage ]

)

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
- in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy. (
  
  1.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
  ERBITUX is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy
  [see Dosage and Administration ]
  .
  )

Premedicate with an H₁ receptor antagonist. (
2.4 Premedication
Premedicate with a histamine-1 (H₁) receptor antagonist intravenously 30–60 minutes prior to the first dose or subsequent doses as deemed necessary
[see Warnings and Precautions ]
.
)
In Combination With Radiation Therapy:
- Initial dose: 400 mg/m² administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy. (
  2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  In combination with radiation therapy
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
  Complete ERBITUX administration 1 hour prior to radiation therapy.
  As a single-agent or in combination with platinum-based therapy and fluorouracil
  Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
  )
- Subsequent doses: 250 mg/m² administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks). (
  2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  In combination with radiation therapy
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
  Complete ERBITUX administration 1 hour prior to radiation therapy.
  As a single-agent or in combination with platinum-based therapy and fluorouracil
  Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
  )
- Complete ERBITUX administration 1 hour prior to radiation therapy. (
  2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  In combination with radiation therapy
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
  Complete ERBITUX administration 1 hour prior to radiation therapy.
  As a single-agent or in combination with platinum-based therapy and fluorouracil
  Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
  )
As Single-Agent or in Combination With Chemotherapy:
- Weekly: Administer initial dose of 400 mg/m² as a 120-minute intravenous infusion, and subsequent doses of 250 mg/m² infused over 60 minutes once weekly. (
  2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  In combination with radiation therapy
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
  Complete ERBITUX administration 1 hour prior to radiation therapy.
  As a single-agent or in combination with platinum-based therapy and fluorouracil
  Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
  ,
  2.3 Recommended Dosage for Colorectal Cancer (CRC)
  As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)
  Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.
  In combination with encorafenib
  The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib.
  The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.
  Refer to the encorafenib prescribing information for recommended encorafenib dosage information.
  )
- Biweekly: Administer 500 mg/m² as a 120-minute intravenous infusion every two weeks. (
  2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  In combination with radiation therapy
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
  Complete ERBITUX administration 1 hour prior to radiation therapy.
  As a single-agent or in combination with platinum-based therapy and fluorouracil
  Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
  ,
  2.3 Recommended Dosage for Colorectal Cancer (CRC)
  As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)
  Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.
  In combination with encorafenib
  The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib.
  The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.
  Refer to the encorafenib prescribing information for recommended encorafenib dosage information.
  )
- Complete ERBITUX administration 1 hour prior to chemotherapy. Continue treatment until disease progression or unacceptable toxicity. (
  2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  In combination with radiation therapy
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
  Complete ERBITUX administration 1 hour prior to radiation therapy.
  As a single-agent or in combination with platinum-based therapy and fluorouracil
  Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
  ,
  2.3 Recommended Dosage for Colorectal Cancer (CRC)
  As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)
  Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.
  Weekly Dosage
  Initial dose: 400 mg/m²administered as a 120-minute intravenous infusion
  Subsequent doses: 250 mg/m²administered as a 60-minute infusion every week
  Biweekly Dosage
  Initial and subsequent doses: 500 mg/m²administered as a 120-minute intravenous infusion every 2 weeks
  Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.
  In combination with encorafenib
  The recommended initial dose is 400 mg/m²administered as a 120-minute intravenous infusion in combination with encorafenib.
  The recommended subsequent dosage is 250 mg/m²weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.
  Refer to the encorafenib prescribing information for recommended encorafenib dosage information.
  )

See full prescribing information for dosage adjustments for adverse reactions. (

2.5 Dosage Modifications for Adverse Reactions

Reduce, delay, or discontinue ERBITUX to manage adverse reactions as described in Table 1.

Table 1: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity ^a	Dosage Modification
^aNational Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0.
Infusion reactions [see Warnings and Precautions ]	Grade 1 or 2	Reduce the infusion rate by 50%.
Infusion reactions [see Warnings and Precautions ]	Grade 3 or 4	Immediately and permanently, discontinue ERBITUX.
Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease) [see Warnings and Precautions ]	1^stoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 250 mg/m². If no improvement, discontinue ERBITUX.
	2^ndoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 200 mg/m². If no improvement, discontinue ERBITUX.
	3^rdoccurrence; Grade 3 or 4	Delay infusion 1 to 2 weeks; if condition improves, continue at 150 mg/m². If no improvement, discontinue ERBITUX.
	4^thoccurrence; Grade 3 or 4	Discontinue ERBITUX.
Pulmonary toxicity [see Warnings and Precautions ]	Acute onset or worsening pulmonary symptoms	Delay infusion 1 to 2 weeks; if condition improves, continue at the dose that was being administered at the time of occurrence. If no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue ERBITUX.

)

Lactation: Advise not to breastfeed. (
8.2 Lactation
Risk Summary
There is no information regarding the presence of ERBITUX in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants from ERBITUX, advise women not to breastfeed during treatment with ERBITUX and for 2 months after the last dose of ERBITUX.
)

Erbitux (Cetuximab)

Dosage & administration

Erbitux prescribing information

Erbitux prior authorization resources

Most recent Erbitux prior authorization forms

Most recent state uniform prior authorization forms

Brand Resources

Erbitux PubMed™ news

Erbitux patient education

Patient toolkit