1    INDICATIONS AND USAGE

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. [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).]

1.2   Colorectal Cancer

Erbitux, as a single agent, is indicated for the treatment of 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 Clinical Studies (14.2) and Warnings and Precautions (5.7).]

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 Clinical Studies (14.2) and Warnings and Precautions (5.7).]

2    DOSAGE AND ADMINISTRATION

2.1   Squamous Cell Carcinoma of the Head and Neck

Erbitux in combination with radiation therapy:

• The recommended initial dose is 400 mg/m2 administered one week prior to initiation of a course of radiation therapy 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) for the duration of radiation therapy (6–7 weeks). Complete Erbitux administration 1 hour prior to radiation therapy.

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.

2.2   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.

2.3   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.

2.4   Dose Modifications

Infusion Reactions

Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC Grades 3–4 infusion reactions.

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) acneform rash are specified in Table 1. [See Warnings and Precautions (5.4).]

2.5   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.

3 DOSAGE FORMS AND STRENGTHS

100 mg/50 mL, single-use vial

200 mg/100 mL, single-use vial

4   CONTRAINDICATIONS

None.

5    WARNINGS AND PRECAUTIONS

5.1   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 clinical trials, with fatal outcome in 1 patient.

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 and Dosage and Administration (2.4).]

5.2   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 a randomized, controlled trial in patients with SCCHN. 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. Carefully consider use of Erbitux in combination with radiation therapy 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 and Warnings and Precautions (5.6).]

5.3   Pulmonary Toxicity

Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD.

5.4   Dermatologic Toxicity

Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis,  conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17 % of patients.

Acneform 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 Dose Modifications (2.4).]

5.5   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.

5.6   Hypomagnesemia and Electrolyte Abnormalities

In patients eva luated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. 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