Erbitux

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions (5.1), Adverse Reactions (6).] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

 Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions (5.2, 5.6), Clinical Studies (14.1).]

   INDICATIONS AND USAGE

   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. [See Clinical Studies (14.1).]

 Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1).]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1).]

   Colorectal Cancer

Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Warnings and Precautions (5.7), Clinical Studies (14.2).]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Warnings and Precautions (5.7), Clinical Studies (14.2).]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Pharmacology (12.1), Clinical Studies (14.2)].

   DOSAGE AND ADMINISTRATION

   Squamous Cell Carcinoma of the Head and Neck

Erbitux in combination with radiation therapy or in combination with platinum-based therapy with 5-FU:

•  The recommended initial dose is 400 mg/m2 administered one week prior to initiation of a course of radiation therapy or on the day of initiation of platinum-based therapy with 5-FU as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min). Complete Erbitux administration 1 hour prior to platinum-based therapy with 5-FU.


•  The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) for the duration of radiation therapy (6–7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU. Complete Erbitux administration 1 hour prior to radiation therapy or platinum-based therapy with 5-FU.

Erbitux monotherapy:

• The recommended initial dose is 400 mg/m2 administered as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min).


• The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity.

   Colorectal Cancer

• The recommended initial dose, either as monotherapy or in combination with irinotecan, is 400 mg/m2 administered as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min).


• The recommended subsequent weekly dose, either as monotherapy or in combination with irinotecan, is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity.

   Recommended Premedication

Premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) intravenously 30–60 minutes prior to the first dose; premedication should be administered for subsequent Erbitux doses based upon clinical judgment and presence/severity of prior infusion reactions.

   Dose Modifications

Infusion Reactions

Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC Grade 3 infusion reaction.

Immediately and permanently discontinue Erbitux for serious infusion reactions, requiring medical intervention and/or hospitalization. [See Warnings and Precautions (5.1).]

Dermatologic Toxicity

Recommended dose modifications for severe (NCI CTC Grade 3 or 4) acneiform rash are specified in Table 1. [See Warnings and Precautions (5.4).]

Table 1: Erbitux Dose Modification Guidelines for Rash

Severe Acneiform Rash	Erbitux	Outcome	Erbitux Dose Modification
1st occurrence	Delay infusion 1 to 2 weeks	Improvement	Continue at 250 mg/m2
		No Improvement	Discontinue Erbitux
2nd occurrence	Delay infusion 1 to 2 weeks	Improvement	Reduce dose to 200 mg/m2
		No Improvement	Discontinue Erbitux
3rd occurrence	Delay infusion 1 to 2 weeks	Improvement	Reduce dose to 150 mg/m2
		No Improvement	Discontinue Erbitux
4th occurrence	Discontinue Erbitux

   Preparation for Administration

Do not administer Erbitux as an intravenous push or bolus.

Administer via infusion pump or syringe pump. Do not exceed an infusion rate of 10 mg/min.

Administer through a low protein binding 0.22-micrometer in-line filter.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The solution should be clear and colorless and may contain a small amount of easily visible, white, amorphous, cetuximab particulates. Do not shake or dilute.

   DOSAGE FORMS AND STRENGTHS

100 mg/50 mL, single-use vial

200 mg/100 mL, single-use vial

   CONTRAINDICATIONS

None

   WARNINGS AND PRECAUTIONS

   Infusion Reactions

Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 4, and 5 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1,14.2).]

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4).]

   Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. 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 Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions (5.6).]

   Pulmonary Toxicity

Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD.

   Dermatologic Toxicity

Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae  (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 4, and 5. Severe acneiform rash occurred in 1–17% of patients.

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4).]

   Use of Erbitux in Combination With Radiation and Cisplatin

The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

   Hypomagnesemia and Electrolyte Abnormalities

 In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 4 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.

 In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

   Epidermal Growth Factor Receptor (EGFR) Expression and Response

Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

   ADVERSE REACTIONS

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

• Infusion reactions [See Boxed Warning, Warnings and Precautions (5.1).]


• Cardiopulmonary arrest [See Boxed Warning, 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).]

The most common adverse reactions with Erbitux (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across Studies 1, 3, 4, and 5, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

   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 below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 4) or Phase 2 (Studies 3 and 5) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14).]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy

Table 2 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 2: Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN

Body System Preferred Term	Erbitux plus Radiation (n=208)		Radiation Therapy Alone (n=212)
	Grades 1–4	Grades 3 and 4	Grades 1–4	Grades 3 and 4
	% of Patients
a Includes cases also reported as infusion reaction.
b Infusion reaction is 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”.
c Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.
d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
Body as a Whole
Asthenia	56	4	49	5
Fevera	29	1	13	1
Headache	19	<1	8	<1
Infusion Reactionb	15	3	2	0
Infection	13	1	9	1
Chillsa	16	0	5	0
Digestive
Nausea	49	2	37	2
Emesis	29	2	23	4
Diarrhea	19	2	13	1
Dyspepsia	14	0	9	1
Metabolic/Nutritional
Weight Loss	84	11	72	7
Dehydration	25	6	19	8
Alanine Transaminase, highc	43	2	21	1
Aspartate Transaminase, highc	38	1	24	1
Alkaline Phosphatase, highc	33	<1	24	0
Respiratory
Pharyngitis	26	3	19	4
Skin/Appendages
Acneiform Rashd	87	17	10	1
Radiation Dermatitis	86	23	90	18
Application Site Reaction	18	0	12	1
Pruritus	16	0	4	0

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity

The overall incidence of late radiation toxicities (any grade) was higher in 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 plus radiation treatment groups.

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil

Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, 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)].

Table 3 contains selected adverse events in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).

Table 3: Incidence of Selected Adverse Events (≥10%) in Patients with Recurrent Locoregional Disease and/or Metastatic SCCHN

System Organ Class Preferred Term	EU-Approved Cetuximab plus Platinum-based Therapy with 5-FU (n=219)		Platinum-based Therapy with 5-FU Alone (n=215)
	Grades 1–4	Grades 3 and 4	Grades 1–4	Grades 3 and 4
	% of Patients
a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, “pyrexia” on the first day of dosing.
b Infection – this term excludes sepsis-related events which are presented separately.
c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”.
Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil
Eye Disorders
Conjunctivitis	10	0	0	0
Gastrointestinal Disorders
Nausea	54	4	47	4
Diarrhea	26	5	16	1
General Disorders and Administration Site Conditions
Pyrexia	22	0	13	1
Infusion Reactiona	10	2	<1	0
Infections and Infestations
Infectionb	44	11	27	8
Metabolism and Nutrition Disorders
Anorexia	25	5	14	1
Hypocalcemia	12	4	5	1
Hypokalemia	12	7	7	5
Hypomagnesemia	11	5	5	1
Skin and Subcutaneous Tissue Disorders
Acneiform Rashc	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 subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.

Colorectal Cancer Erbitux Monotherapy

Table 4 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux monotherapy for metastatic colorectal cancer in Study 4. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 4: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinomaa Treated with Erbitux Monotherapy

Body System Preferred Term	Erbitux plus BSC (n=288)		BSC alone (n=274)
	Any Gradesb	Grades 3 and 4	Any Grades	Grades 3 and 4
	% of Patients
a Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.
b Adverse events were graded using the NCI CTC, V 2.0.
c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusion-related.
BSC = best supportive care
Dermatology
Rash/Desquamation	89	12	16	<1
Dry Skin	49	0	11	0
Pruritus	40	2	8	0
Other-Dermatology	27	1	6	1
Nail Changes	21	0	4	0
Body as a Whole
Fatigue	89	33	76	26
Fever	30	1	18	<1
Infusion Reactionsc	20	5
Rigors, Chills	13	<1	4	0
Pain
Abdominal Pain	59	14	52	16
Pain-Other	51	16	34	7
Headache	33	4	11	0
Bone Pain	15	3	7	2
Pulmonary
Dyspnea	48	16	43	12
Cough	29	2	19	1
Gastrointestinal
Constipation	46	4