Erbitux® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture.

Erbitux® is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous cetuximab particulates. Erbitux® is supplied at a concentration of 2 mg/mL in either 100 mg (50 mL) or 200 mg (100 mL), single-use vials. Cetuximab is formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP.

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.]

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.]

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 and Warnings and PRECAUTIONS.]

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 and Warnings and PRECAUTIONS.]

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.

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 3-4 infusion reactions.

Immediately and permanently discontinue Erbitux® for serious infusion reactions, requiring medical intervention and/or hospitalization. [See Warnings and PRECAUTIONS.]

Dermatologic Toxicity

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

Table 1: Erbitux® Dose Modification Guidelines for Rash

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

Storage And Handling

Erbitux® (cetuximab) is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, single-use vial or as a 200 mg/100 mL, single-use vial as a sterile, preservative-free, injectable liquid.

NDC 66733-948-23 100 mg/50 mL, single-use vial, individually packaged in a carton
NDC 66733-958-23 200 mg/100 mL, single-use vial, individually packaged in a carton

Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Increased particulate formation may occur at temperatures at or below 0° C. This product contains no preservatives. Preparations of Erbitux® in infusion containers are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C. Discard any unused portion of the vial.

Erbitux® is a registered trademark of ImClone Systems Incorporated. Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876. Distributed and Marketed by: Bristol-Myers Squibb Company, Princeton, NJ 08543. Rev October 2007. FDA Rev date: 10/2/2007

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

• Infusion reactions [See BOXED WARNING and Warnings and PRECAUTIONS.]
• Cardiopulmonary arrest [See BOXED WARNING and 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 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 all studies, 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 3) or phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies.]

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

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

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.

Colorectal Cancer

Table 3 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux® monotherapy for metastatic colorectal cancer in Study 3. Erbitux® was administered at the recommended dose and schedule (400 mg/m² initial dose, followed by 250 mg/m² weekly).

Table 3: Incidence of Selected Adverse Events Occurring in ≥ 10% of Patients with Advanced Colorectal Carcinoma¹ Treated with Erbitux® Monotherapy

The most frequently reported adverse events in 354 patients treated with Erbitux® plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grade 3/4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux® has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux®.

The incidence 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 Erbitux® with the incidence of antibodies to other products may be misleading.

A drug interaction study was performed in which Erbitux® was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux® and irinotecan.

Included as part of the PRECAUTIONS section.

Infusion Reactions

Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux® included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, and/or cardiac arrest. Severe (NCI CTC Grade 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.]

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.]

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.

Dermatologic Toxicity

Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, and infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, cheilitis) 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®. [See Dose Modifications.]

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 patients (199/365) receiving Erbitux® and was severe (NCI-CTC Grade 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 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.

NonClinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with cetuximab. However, the EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. In addition, human IgG1 is known to cross the placental barrier; therefore, cetuximab has the potential to be transmitted from the mother to the developing fetus. It is not known whether Erbitux® can cause fetal harm when administered to a pregnant woman or whether Erbitux® can affect reproductive capacity. There are no adequate and well-controlled studies of Erbitux® in pregnant women. Erbitux® should only be given to a pregnant woman, or any woman not employing adequate contraception if the potential benefit justifies the potential risk to the fetus. All patients should be counseled regarding the potential risk of Erbitux® treatment to the developing fetus prior to initiation of therapy. If the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus and/or the potential risk for loss of the pregnancy.

Nursing Mothers

It is not known whether Erbitux® is secreted in human milk. IgG antibodies, such as Erbitux®, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see CLINICAL PHARMACOLOGY], nursing should not be resumed earlier than 60 days following the last dose of Erbitux®.

Pediatric Use

The safety and effectiveness of Erbitux® in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use

Of the 1062 patients who received Erbitux® with irinotecan or Erbitux® monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux® conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux® with radiation therapy, 45 patients were 65 years of age or older.

The maximum single dose of Erbitux® administered is 1000 mg/m² in one patient. No adverse events were reported for this patient.

None.

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. 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.

Pharmacokinetics

Erbitux® administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m² as the dose increased from 20 to 200 mg/m², and at doses > 200 mg/m², it appeared to plateau. The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2-3 L/m².

Following the recommended dose regimen (400 mg/m² initial dose; 250 mg/m² weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 µg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (range 63-230 hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer.

Based on a population pharmacokinetic analysis, female patients with colorectal cancer had a 25% lower intrinsic clearance of cetuximab than male patients. Qualitatively similar, but smaller gender differences in cetuximab clearance were observed in patients with SCCHN. The gender differences in clearance do not necessitate any alteration of dosing because of a similar safety profile.

Animal Pharmacology and/or Toxicology

In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

Clinical Studies

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Study 1 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® plus 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 as a 400 mg/m² initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m² weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6-7 weeks).

Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were Caucasian, and 90% had baseline Karnofsky Performance Status ≥ 80. There were 258 patients enrolled in US 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.

The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented in Table 4.

Table 4: Study 1: Clinical Efficacy in Locoregionally Advanced SCCHN

Study 2 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 received a 20-mg test dose of Erbitux® on Day 1, followed by a 400-mg/m² initial dose, and 250 mg/m² weekly until disease progression or unacceptable toxicity.

The median age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky Performance Status of ≥ 80.

The objective response rate was 13% (95% confidence interval 7%-21%). Median duration of response was 5.8 months (range 1.2-5.8 months).

Colorectal Cancer

Study 3 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent, metastatic colorectal cancer. Patients were randomized (1:1) to receive either Erbitux® plus best supportive care (BSC) or BSC alone. Erbitux® was administered as a 400-mg/m² initial dose, followed by 250 mg/m² weekly until disease progression or unacceptable toxicity.

Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG Performance Status of 0-1. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.

The main outcome measure of the study was overall survival. The results are presented in Figure 1.

Figure 1: Kaplan Meier Curve for Overall Survival in Patients with Metastatic Colorectal Cancer

Study 4 was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent metatstatic colorectal cancer. Patients were randomized (2:1) to receive either Erbitux® plus irinotecan (218 patients) or Erbitux® monotherapy (111 patients). Erbitux® was administered as a 400-mg/m² initial dose, followed by 250 mg/m² weekly until disease progression or unacceptable toxicity. In the Erbitux® plus irinotecan arm, irinotecan was added to Erbitux® using the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m² every 3 weeks, 180 mg/m² every 2 weeks, or 125 mg/m² weekly times four doses every 6 weeks. Of the 329 patients, the median age was 59 years, 63% were male, 98% were Caucasian, and 88% had baseline Karnofsky Performance Status ≥ 80. Approximately two-thirds had previously failed oxaliplatin treatment.

The efficacy of Erbitux® plus irinotecan or Erbitux® monotherapy, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory patients, and irinotecan and oxaliplatin failures. In patients receiving Erbitux® plus irinotecan, the objective response rate was 23% (95% confidence interval 18%-29%), median duration of response was 5.7 months, and median time to progression was 4.1 months. In patients receiving Erbitux® monotherapy, the objective response rate was 11% (95% confidence interval 6%-18%), median duration of response 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 monotherapy arm of the study.

Advise patients

• To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.
• Of the potential risks of using Erbitux® during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux® therapy.
• That nursing is not recommended during, and for 2 months following the last dose of Erbitux® therapy.
• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux®.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CETUXIMAB - INJECTION

(see-TUX-ih-mab)

COMMON BRAND NAME(S): Erbitux

WARNING: Severe (sometimes fatal) infusion reactions have occurred with cetuximab. Seek immediate medical attention if you have difficulty breathing, hoarseness, itching, or dizziness, as your treatment should be stopped.

Rare deaths (due to heart attack, sudden death) have occurred in patients with head and neck cancer treated with radiation therapy and cetuximab. This may rarely occur days to a few months after the last dose of this medication. Tell your doctor if you have heart disease (e.g., coronary artery disease, congestive heart failure, arrhythmias). Blood levels of certain minerals should be checked often (see Notes section). Seek immediate medical attention if you develop: chest pain, unexplained jaw/left arm pain.

USES: Cetuximab is used alone or with other anti-cancer drugs to treat colorectal cancer that has spread to other parts of the body. These patients generally cannot tolerate or have not responded to another drug called irinotecan. This medication is also used to treat head and neck cancer. Cetuximab works by slowing cancer cell growth. This action occurs when this drug binds to a specific protein (epidermal growth factor receptor-EGFR) on the cancer cells. Cetuximab is a man-made protein (monoclonal antibody).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Cetuximab may also be used for kidney cancer.

HOW TO USE: Cetuximab is given by vein (intravenously-IV) usually once a week by a healthcare professional. Another drug (e.g., diphenhydramine) may be given before you receive cetuximab to lessen the chance of certain side effects. Do not shake or dilute this medication. The first dose (loading dose) is larger and is given over 2 hours. All other doses (maintenance doses) are smaller and are given over 1 hour if tolerated. The dosage is based on your medical condition and response to therapy.

A healthcare professional should watch you for at least 1 hour after your infusion is finished to make sure you do not have an infusion reaction. (See Warning section). If you experience a severe infusion reaction, your infusion will be stopped and your doctor may decide to stop further treatments.

This medication may contain small particles. It is very important to use an IV filter ("in-line" filter) while giving this medication. Consult your pharmacist about the proper use of this filter.

SIDE EFFECTS: (see also Warning section)

Nausea, vomiting, constipation, diarrhea, headache, stomachache, backache, fever/chills, trouble sleeping, weight loss, fatigue, drowsiness, eye redness/itching, nail changes, and dry skin may occur. Nausea and vomiting can be quite severe. In some cases, drug therapy may be necessary to prevent or relieve nausea and vomiting. Not eating before your treatment may help relieve vomiting. Changes in diet such as eating several small meals or limiting activity may help lessen some of these effects. If these effects persist or worsen, notify your doctor or pharmacist promptly.

Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

An acne-like rash may occur. Depending on how severe this rash is, your doctor may delay your cetuximab treatment, lower your dose, treat the rash with antibiotics, or stop treatment with cetuximab to decrease this potentially serious side effect.

Tell your doctor immediately if any of these unlikely but serious side effects occur: confusion, depression, swelling of hands/feet/lower legs, dehydration, serious infection (e.g., high fever, chills, persistent sore throat), change in amount of urine, severe dizziness, fast/slow/irregular heartbeat.

Rarely, very serious lung problems may occur. Seek immediate medical attention if you develop: trouble breathing.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving cetuximab, tell your doctor or pharmacist if you are allergic to it or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: lung disease, radiation therapy, heart disease (e.g., coronary artery disease, congestive heart failure, arrhythmias).

This medication may make you drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

Sunlight may worsen any skin reactions that may occur while you are using this drug. Avoid prolonged sun exposure, tanning booths, and sunlamps during treatment and for 2 months after your last treatment with cetuximab. Use a sunscreen and wear protective clothing when outdoors.

This medication may harm an unborn baby. It must not be used during pregnancy, and both males and females using this drug must avoid becoming pregnant or causing pregnancy. Therefore, both males and females using this drug must use at least 2 reliable forms of birth control (e.g., condoms, birth control pills) while using this medication and for 6 months after treatment is ended. Consult your doctor for information on reliable birth control. If you or your partner becomes pregnant while using this drug or during the 6 months after the last treatment, tell both of your doctors immediately.

Based on information from related drugs, cetuximab may pass into breast milk. Because of potential harm to the infant, breast-feeding is not recommended while using cetuximab and for 2 months after the end of treatment. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Medical tests and regular physical exams should be performed to check for side effects. Laboratory tests should be performed before giving cetuximab to check for the EGFR protein on your tumor. Certain laboratory tests (e.g., calcium, magnesium, potassium levels) will be performed from time to time while you are being treated with cetuximab and up to 8 weeks after your last infusion. Consult your doctor for more details. Keep all scheduled medical appointments.

MISSED DOSE: It is important that you receive cetuximab as scheduled by your doctor. If you miss a dose, contact your doctor immediately to obtain a new dosing schedule.

STORAGE: Refrigerate this drug between 36-46 degrees F (2-8 degrees C). Once prepared, cetuximab should be given within 8 hours if left at room temperature or 12 hours if refrigerated. Small, white, lint-like strands should be visible in the solution. This is normal.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.