Cetuximab

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 solution with no preservatives, which contains 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.

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, injectable liquid containing no preservatives.

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.

Manufactured by: ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA. Revised: Oct 2016

>10%

Acneform rash (90%)

Fatigue (89%)

Hypomagnesemia (55%)

Asthenia/malaise (49%)

Fever (33%)

Nausea (29%)

Constipation (28%)

Diarrhea (28%)

Abdominal pain (25%)

Anorexia (25%)

Headache (25%)

Infusion reaction (25%)

Vomiting (25%)

Dyspnea (20%)

Pain (19%)

Nail disorder (16%)

Back pain (11%)

Stomatitis (11%)

Anemia (10%)

Cough increased (10%)

Infection (11%)

1-10%

Insomnia (10%)

Peripheral edema (10%)

Pruritus (10%)

Dehydration (9%)

Depression (9%)

Weight loss (9%)

Conjunctivitis (7%)

Dyspepsia (7%)

Alopecia (5%)

Skin disorder (5%)

Leukopenia (1%)

Frequency Not Defined

Electrolyte depletion

Postmarketing Reports

Aseptic meningitis

Mucosal inflammation

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Life-threatening and fatal bullous mucocutaneous disease

IV Preparation

Do not shake or dilute

Discard unused portion after 8 hr at room temp & 12 hr if refrigerated

IV Administration

Infusion Pump

• Draw up volume of a vial using a sterile syringe attached to an appropriate needle (a vented spike or other appropriate transfer device may be used)
• Fill a sterile evacuated container or bag such as glass containers, polyolefin bags (eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter Clintec), DEHP plasticized PVC bags (eg, Abbott Lifecare), or PVC bags
• Repeat procedure until the calculated volume has been put into the container; use a new needle for each vial
• Admin through a low protein binding 0.22-micron in-line filter (placed as proximal to pt. as practical)
• Affix infusion line & prime before starting infusion
• Infuse initial dose over 120 min; Subsequent doses infused over 60 min, Max infusion rate is 10 mg/min
• Use NS to flush line at the end of infusion

Syringe Pump

• Draw up volume of vial using a sterile syringe attached to an appropriate needle (a vented spike may be used)
• Place the syringe into syringe driver of a syringe pump and set rate
• Admin through a low protein binding 0.22-micron in-line filter rated for syringe pump use (placed as proximal to pt. as practical)
• Connect up infusion line & start infusion after priming the line
• Repeat procedure until calculated volume infused, Use a new needle and filter for each vial
• Infuse initial dose over 120 min, Subsequent doses infused over 60 min, Max infusion rate is 10 mg/min
• Use NS to flush line at end of infusion, Piggybacked to infusion line

Following infusion, a 1 hr observation period is recommended

Cetuximab may be found in some form under the following brand names:

• Erbitux

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people receiving a cetuximab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel short of breath, weak or dizzy, nauseated, itchy, or have wheezing, noisy breathing, or a hoarse voice during the injection.

Call your doctor at once if you have:

• an acne-like skin rash or any severe skin rash;

• redness, swelling, or puffiness under your skin;

• eye pain or redness, puffy eyelids, drainage or crusting in your eyes, vision problems, or increased sensitivity to light;

• sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath, coughing up blood;

• chest pain spreading to your jaw or shoulder;

• a light-headed feeling, like you might pass out, slow heart rate, weak pulse, slow breathing;

• symptoms of infection--fever, flu symptoms, mouth and throat ulcers, rapid heart rate, rapid and shallow breathing, fainting;

• symptoms of an electrolyte imbalance--leg cramps, constipation, irregular heartbeats, fluttering in your chest, extreme thirst, numbness or tingling, vision problems, muscle pain or weakness;

• kidney problems--little or no urinating; painful or difficult urination; swelling in your feet or ankles; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• mild itching or rash;

• changes in your fingernails or toenails;

• dry, cracked, or swollen skin;

• headache;

• diarrhea; or

• infection.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Antineoplastic agent; a recombinant chimeric (human-murine) monoclonal antibody that binds to epidermal growth factor receptors (EGFR).1 6 7

Non-small cell lung cancer, EGFR-expressing, advanced

Data from a phase III clinical trial evaluating the use of cetuximab monotherapy (after administration of first-line chemotherapy [ie, cisplatin and vinorelbine with or without cetuximab]) in patients with EGFR-expressing advanced non–small cell lung cancer supports the use of cetuximab in the treatment of this condition [Pirker 2012].

Squamous cell skin cancer, unresectable

Data from a multicenter phase II study evaluating the use of cetuximab in patients with unresectable squamous cell skin cancer supports the use of cetuximab for the treatment of this condition [Maubec 2011]. Additional data may be necessary to further define the role of cetuximab for patients with unresectable squamous cell skin cancer.

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Known severe hypersensitivity to cetuximab or any component of the formulation

Note: Premedicate with an H1 antagonist (eg, diphenhydramine) IV 30 to 60 minutes prior to the first dose; premedication for subsequent doses is based on clinical judgment.

Colorectal cancer, metastatic, KRAS wild-type (without mutation): IV:

Initial loading dose: 400 mg/m2 infused over 120 minutes

Maintenance dose: 250 mg/m2 infused over 60 minutes weekly until disease progression or unacceptable toxicity

Note: If given in combination with FOLFIRI (irinotecan, fluorouracil, and leucovorin), complete cetuximab infusion 1 hour prior to FOLFIRI.

Head and neck cancer (squamous cell): IV:

Initial loading dose: 400 mg/m2 infused over 120 minutes

Maintenance dose: 250 mg/m2 infused over 60 minutes weekly

Note: If given in combination with radiation therapy, administer loading dose 1 week prior to initiation of radiation course; weekly maintenance dose should be completed 1 hour prior to radiation for the duration of radiation therapy (6 to 7 weeks). If given in combination with chemotherapy, administer loading dose on the day of initiation of platinum and fluorouracil-based chemotherapy, cetuximab infusion should be completed 1 hour prior to initiation of chemotherapy; weekly maintenance dose should be completed 1 hour prior to chemotherapy; continue until disease progression or unacceptable toxicity. Monotherapy weekly doses should be continued until disease progression or unacceptable toxicity

Colorectal cancer, advanced, biweekly administration (off-label dosing): IV: 500 mg/m2 every 2 weeks (initial dose infused over 120 minutes, subsequent doses infused over 60 minutes) in combination with irinotecan (Pfeiffer 2008)

Non-small cell lung cancer (NSCLC), EGFR-expressing, advanced (off-label use): IV: Initial loading dose: 400 mg/m2, followed by maintenance dose: 250 mg/m2 weekly in combination with cisplatin and vinorelbine for up to 6 cycles, then as monotherapy until disease progression or unacceptable toxicity (Pirker 2009; Pirker 2012)

Squamous cell skin cancer, unresectable (off-label use): IV: Initial loading dose: 400 mg/m2, followed by maintenance dose: 250 mg/m2 weekly until disease progression (Maubec 2011)

Concerns related to adverse effects:

• Cardiopulmonary arrest: [US Boxed Warning]: In patients with squamous cell head and neck cancer, cardiopulmonary arrest and/or sudden death has occurred in 2% of patients receiving radiation therapy in combination with cetuximab and in 3% of patients receiving combination chemotherapy (platinum and fluorouracil-based) with cetuximab. Closely monitor serum electrolytes (magnesium, potassium, calcium) during and after cetuximab treatment (monitor for at least 8 weeks after treatment). Use with caution in patients with a history of coronary artery disease, heart failure, and arrhythmias; fatalities have been reported.

• Dermatologic toxicity: Acneiform rash has been reported in 76% to 88% of patients (severe in 1% to 17%), usually developing within the first 2 weeks of therapy; may require dose modification; generally resolved after discontinuation in most patients, although persisted beyond 28 days in some patients. Acneiform rash should be treated with topical and/or oral antibiotics; topical corticosteroids are not recommended. In colorectal cancer, the presence of acneiform rash correlates with treatment response and prolonged survival (Cunningham, 2004). Life-threatening and fatal bullous mucocutaneous disease (with blisters, erosions, and skin sloughing) has been observed with cetuximab; etiology is not determined; may be due to epidermal growth factor receptor (EGFR) inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Other dermatologic toxicities, including dry skin, fissures, hypertrichosis, paronychial inflammation, and skin infections, have been reported; related ocular toxicities (blepharitis, conjunctivitis, keratitis, ulcerative keratitis with decreased visual acuity) may also occur. Monitor closely for dermatologic toxicities and potential infectious sequelae. Sunlight may exacerbate skin reactions (limit sun exposure).

• Electrolyte abnormality: Hypomagnesemia is common (may be severe); the onset of electrolyte disturbance may occur within days to months after initiation of treatment; monitor magnesium, calcium, and potassium during treatment and for at least 8 weeks after completion. May require electrolyte replacement.

• Infusion reactions: [US Boxed Warning]: In clinical trials, serious infusion reactions have been reported in approximately 3% of patients; fatal outcome has been reported rarely (less than 1 in 1,000); interrupt infusion promptly and permanently discontinue for serious infusion reactions. Reactions have included airway obstruction (bronchospasm, stridor, hoarseness), hypotension, loss of consciousness, shock, myocardial infarction (MI), and/or cardiac arrest. Premedicate with anintravenous (IV) H1 antagonist 30 to 60 minutes prior to the first dose; premedication for subsequent doses is based on clinical judgment and with consideration of prior reaction to the initial infusion. The use of nebulized albuterol-based premedication to prevent infusion reaction has been reported (Tra, 2008). Approximately 90% of reactions occur with the first infusion despite the use of prophylactic antihistamines. Immediate treatment for anaphylactic/anaphylactoid reactions should be available during administration. The manufacturer recommends monitoring patients for at least 1 hour following completion of infusion, or longer if a reaction occurs. Mild to moderate infusion reactions (chills, fever, dyspnea) are managed by slowing the infusion rate (by 50%) and administering antihistamines. Patients with preexisting IgE antibody against cetuximab (specific for galactose-α-1,3-galactose) are reported to have a higher incidence of severe hypersensitivity reaction. Severe hypersensitivity reaction has been reported more frequently in patients living in the middle south area of the United States, including North Carolina and Tennessee (Chung, 2008; O’Neil, 2007).

• Interstitial lung disease: Has been reported; use with caution in patients with preexisting lung disease. Interrupt treatment for acute onset or worsening of pulmonary symptoms. Permanently discontinue with confirmed interstitial lung disease.

Disease-related concerns:

• Colorectal cancer and RAS mutation status: Cetuximab is only indicated for patients with EGFR-expressing metastatic colorectal cancer without RAS (KRAS or NRAS) mutations. Determine RAS mutation status prior to treatment (with an approved test). Patients with a codon 12 and 13 (exon 2), codon 59 and 61 (exon 3), and codon 117 and 146 (exon 4) RAS mutation are unlikely to benefit from EGFR inhibitor therapy (while experiencing toxicities) and should not receive cetuximab treatment; cetuximab is not effective for colorectal cancer with RAS mutations. Cetuximab is also reported to be ineffective in patients with BRAF V600E mutation (Di Nicolantonio, 2008). The American Society of Clinical Oncology (ASCO) provisional clinical opinion (Allegra, 2009) recommends genotyping tumor tissue for KRAS mutation in all patients with metastatic colorectal cancer (genotyping may be done on archived specimens).

• EGFR expression testing: In trials for colorectal cancer, evidence of EGFR expression was required, although the response rate did not correlate with either the percentage of cells positive for EGFR or the intensity of expression. EGFR expression has been detected in nearly all patients with head and neck cancer; therefore, laboratory evidence of EGFR expression is not necessary for head and neck cancers.

Concurrent drug therapy issues:

• Combination with cisplatin and radiation therapy: In a study of radiation therapy and cisplatin with or without cetuximab in patients with squamous cell head and neck cancer, an increase in the incidence of adverse reactions (eg, grade 3/4 mucositis, radiation recall, acneiform rash, electrolyte abnormalities, and cardiac events including ischemia) was noted in patients receiving cetuximab, including fatal reactions. There was no improvement in the primary end point of progression-free survival.

Other warnings/precautions:

• Anti-cetuximab antibodies: Non-neutralizing anti-cetuximab antibodies were detected in 5% of evaluable patients. Relationship between the appearance of antibodies and the safety or antitumor activity of the molecule is unknown.

Adverse events were observed in animal reproduction studies. Human IgG is known to cross the placenta. Because cetuximab inhibits epidermal growth factor (EGF), a component of fetal development, adverse effects on pregnancy would be expected. The manufacturer recommends that males and females use effective contraception during therapy and for 6 months following the last dose of cetuximab.

Data not available

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: -Studies in animals or sufficient data from lactating women are not available. -Women should not breastfeed during treatment with this drug and for 2 months after the last dose. -Because this drug is a large protein molecule, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant GI tract. #349603