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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Cetuximab may be confused with bevacizumab
Pronunciation
(se TUK see mab)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of metastatic colorectal cancer; treatment of squamous cell cancer of the head and neck
Note: Subset analyses (retrospective) in metastatic colorectal cancer trials have not shown a benefit with EGFR inhibitor treatment in patients whose tumors have codon 12 or 13 KRAS mutations; use is not recommended in these patients.
Use: Unlabeled/Investigational
Treatment of EGFR-expressing advanced nonsmall cell lung cancer (NSCLC)
Pregnancy Risk Factor
C
Pregnancy Considerations
In pregnant cynomolgus monkeys, cetuximab was detected in the amniotic fluid and in the serum of embryos. Although teratogenic effects were not observed in animal studies, increases in embryolethality and fetal loss were noted. There are no adequate and well-controlled studies in pregnant women. It is not known whether cetuximab can cause fetal harm or affect reproductive capacity. Because cetuximab inhibits epidermal growth factor (EGF), a component of fetal development, adverse effects on pregnancy would be expected. Cetuximab should only be given to a pregnant woman if the potential benefit justifies the potential risk to the fetus.
Lactation
Excretion in breast milk is unknown/not recommended
Breast-Feeding Considerations
Breast-feeding should be discontinued during treatment and for at least 60 days following the last dose.
Contraindications
There are no contraindications listed in the manufacturer's labeling
Warnings/Precautions
Boxed warnings:
• Cardiopulmonary arrest: See “Concerns related to adverse effects” below.
• Infusion/hypersensitivity reactions: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Cardiopulmonary arrest: [U.S. Boxed Warning]: Cardiopulmonary arrest has occurred in 2% of patients receiving radiation therapy in combination with cetuximab. Closely monitor serum electrolytes (magnesium, potassium, calcium) during and after (for at least 8 weeks) cetuximab therapy. Use caution with history of coronary artery disease, HF, and arrhythmias.
• 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. Acneiform rash should be treated with topical and/or oral antibiotics; topical corticosteroids are not recommended. Other dermatologic toxicities, including dry skin, fissures, hypertrichosis, paronychial inflammation, and skin infections have been reported; related ocular toxicities (blepharitis, conjunctivitis, keratitis) may also occur. Sunlight may exacerbate skin reactions (limit sun exposure). In colorectal cancer, the presence of acneiform rash correlates with treatment response and prolonged survival (Cunningham, 2004).
• Electrolyte abnormality: Hypomagnesemia is common; the onset of electrolyte disturbance may occur within days to months after initiation of treatment; monitor during treatment and for at least 8 weeks after completion.
• Infusion/hypersensitivity reactions: [U.S. Boxed Warning]: Severe infusion reactions (bronchospasm, stridor, hoarseness, urticaria, hypotension, loss of consciousness, shock, MI, cardiac arrest) have been reported in ~3% of patients; fatal outcome has been reported rarely. Approximately 90% of reactions occur with the first infusion despite the use of prophylactic antihistamines. Note: Although a 20 mg test dose was used in some studies, it did not reliably predict the risk of an infusion reaction, and is not recommended. In case of severe reaction, treatment should be stopped and permanently discontinued. 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 pre-existing IgE antibody against cetuximab (specific for galactose-?-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 (O'Neil, 2007; Chung, 2008).
• Interstitial lung disease (ILD): Has been reported; use with caution in patients with pre-existing lung disease. Permanently discontinue with confirmed ILD.
Disease-related concerns:
• Colorectal cancer/tumor KRAS mutation status: Patients with a codon 12 or 13 KRAS mutation are unlikely to benefit from EGFR inhibitor therapy and should not receive cetuximab treatment.
Concurrent drug therapy issues:
• Combination with cisplatin and radiation therapy: Safety and efficacy have not been established when used in combination with radiation therapy and cisplatin.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Anticetuximab antibodies: Non-neutralizing anticetuximab 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 Reactions
Except where noted, percentages reported for cetuximab monotherapy.
>10%:
Central nervous system: Fatigue (89%), pain (17% to 51%), headache (26% to 33%), insomnia (10% to 30%), fever (27% to 30%), confusion (15%), anxiety (14%), chills/rigors (13%), depression (7% to 13%)
Dermatologic: Acneiform rash (76% to 90%; grades 3/4: 1% to 17%; onset: ?14 days), rash (89%), dry skin (49%), pruritus (11% to 40%), nail changes/disorder (16% to 21%)
Endocrine & metabolic: Hypomagnesemia (55%; grades 3/4: 6% to 17%)
Gastrointestinal: Abdominal pain (26% to 59%), constipation (26% to 46%), diarrhea (25% to 39%), vomiting (25% to 37%), nausea (mild-to-moderate 29%), weight loss (7% to 27%), anorexia (23%), stomatitis (10% to 25%), xerostomia (11%)
Neuromuscular & skeletal: Weakness (45% to 48%), bone pain (15%)
Respiratory: Dyspnea (17% to 48%), cough (11% to 29%)
Miscellaneous: Infection (13% to 35%), infusion reaction (15% to 21%; grades 3/4: 2% to 5%; 90% of severe reactions occurred with first infusion)
1% to 10%:
Cardiovascular: Peripheral edema (10%), cardiopulmonary arrest (2%; with radiation therapy)
Dermatologic: Alopecia (4%), skin disorder (4%)
Endocrine & metabolic: Dehydration (2% to 10%)
Gastrointestinal: Dyspepsia (6%)
Hematologic: Anemia (9%)
Hepatic: Alkaline phosphatase increased (5% to 10%), transaminases increased (5% to 10%)
Neuromuscular & skeletal: Back pain (10%)
Ocular: Conjunctivitis (7%)
Renal: Renal failure (1%)
Respiratory: Pulmonary embolus (1%)
Miscellaneous: Sepsis (1% to 4%)
<1%, postmarketing, and/or case reports: Abscess formation, arrhythmia, blepharitis, bronchospasm, cardiac arrest, cellulitis, cheilitis, hoarseness, hypertrichosis, hypotension, interstitial lung disease (occurred between the fourth and eleventh doses), keratitis, leukopenia, loss of consciousness, MI, paronychial inflammation, sepsis, shock, skin fissure, skin infection, stridor
Drug Interactions
There are no known significant interactions.
Storage
Store unopened vials under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Preparations in infusion containers are stable for up to 12 hours under refrigeration at 2°C to 8°C (36°F to 46°F) and up to 8 hours at room temperature of 20°C to 25°C (68°F to 77°F).
Reconstitution
Reconstitution is not required. Appropriate dose should be added to empty sterile container; do not shake or dilute.
Mechanism of Action
Recombinant human/mouse chimeric monoclonal antibody which binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands. Binding 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. EGFR signal transduction results in KRAS wild-type activation; cells with KRAS mutations appear to be unaffected by EGFR inhibition.
Pharmacodynamics/Kinetics
Distribution: Vd: ~2-3 L/m2
Half-life elimination: ~112 hours (range: 63-230 hours)
Dosage
I.V.: Adults: Note: Premedicate with an H1 antagonist (eg, diphenhydramine) I.V. 30-60 minutes prior to the first dose; premedication for subsequent doses is based on clinical judgement.
Colorectal cancer:
Initial loading dose: 400 mg/m2 infused over 120 minutes
Maintenance dose: 250 mg/m2 infused over 60 minutes weekly
Biweekly administration (unlabeled dosing): 500 mg/m2 every 2 weeks (initial dose infused over 120 minutes, subsequent doses infused over 60 minutes) (Pfeiffer, 2007)
Head and neck cancer:
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 (6-7 weeks).
NSCLC (unlabeled use): Initial loading dose: 400 mg/m2, followed by maintenance dose: 250 mg/m2 weekly (Pirker, 2008)
Dosage adjustment for toxicity:
Infusion reactions, grade 1 or 2 and nonserious grades 3 or 4: Reduce the infusion rate by 50% and continue to use prophylactic antihistamines
Infusion reactions, severe: Immediately and permanently discontinue treatment
Pulmonary toxicity:
Acute onset or worsening pulmonary symptoms: Hold treatment
Interstitial lung disease: Permanently discontinue
Skin toxicity, mild-to-moderate: No dosage modification required
Acneiform rash, severe (grade 3 or 4):
First occurrence: Delay cetuximab infusion 1-2 weeks
If improvement, continue at 250 mg/m2
If no improvement, discontinue therapy
Second occurrence: Delay cetuximab infusion 1-2 weeks
If improvement, continue at reduced dose of 200 mg/m2
If no improvement, discontinue therapy
Third occurrence: Delay cetuximab infusion 1-2 weeks
If improvement, continue at reduced dose of 150 mg/m2
If no improvement, discontinue therapy
Fourth occurrence: Discontinue therapy
Note: Dose adjustments are not recommended for severe radiation dermatitis.
Dosage: Combination Regimens
Colorectal cancer:
Cetuximab (Biweekly)-Irinotecan
Cetuximab-FOLFOX4
Cetuximab-Irinotecan
Head and neck cancer:
Carboplatin-Cetuximab
Cetuximab-Carboplatin-Fluorouracil
Cetuximab-Cisplatin-Fluorouracil
Cisplatin-Cetuximab
Paclitaxel-Cetuximab
Lung cancer, nonsmall cell: Cetuximab-Cisplatin-Vinorelbine
Administration: I.V.
I.V. infusion; loading dose over 2 hours, weekly maintenance dose over 1 hour. Do not administer as I.V. push or bolus. Do not shake or dilute. Administer via infusion pump or syringe pump. Following the infusion, an observation period (1 hour) is recommended; longer observation time (following an infusion reaction) may be required. Premedication with an H1 antagonist prior to the initial dose is recommended. The maximum infusion rate is 10 mg/minute. Administer through a low protein-binding 0.22 micrometer in-line filter. Use 0.9% NaCl to flush line at the end of infusion.
For biweekly administration (unlabeled frequency and dose), the initial dose was infused over 120 minutes and subsequent doses infused over 60 minutes (Pfeiffer, 2007).
Administration: I.V. Detail
pH: 7-7.4; may contain a small amount of visible white, amorphous cetuximab particles
Monitoring Parameters
Vital signs during infusion and observe for at least 1 hour postinfusion. Patients developing dermatologic toxicities should be monitored for the development of complications. Periodic monitoring of serum magnesium, calcium, and potassium are recommended to continue over an interval consistent with the half-life (8 weeks); monitor closely (during and after treatment) for cetuximab plus radiation therapy. KRAS genotyping of tumor tissue in patients with colorectal cancer.
Patient Education
Do not take any new prescription, OTC medications, or herbal products during therapy unless approved by prescriber. This medication can only be administered by infusion and you will be closely monitored during each infusion. Report immediately unusual chest tightness; difficulty breathing or swallowing; itching or skin rash; back pain or acute headache; or redness, swelling, or pain at infusion site. Maintain adequate nutrition (small, frequent meals) and hydration unless instructed to restrict fluid intake. You may experience feelings of weakness or fatigue (adequate rest is important); nausea, vomiting, or loss of appetite (small, frequent meals, sucking lozenges, or chewing gum may help); diarrhea; headache or back pain (consult prescriber for appropriate analgesic); skin rash or dryness (avoid sunlight, use protective clothing, use only mild soap, and consult prescriber for approved lotion); or loss of hair or nail disorder (may grow back after therapy). Report immediately chest pain, irregular heart beat, or palpitations; difficulty breathing; persistent gastrointestinal disturbances (pain, constipation, diarrhea, vomiting); CNS changes (depression or insomnia); skin rash, dryness, or cracking; any signs of infection; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed during therapy or for 60 days following completion.
Additional Information
Oncology Comment: EGFR expression is detected in nearly all patients with head and neck cancer; laboratory evidence of EGFR expression is not necessary for head and neck cancers.
The National Comprehensive Cancer Network® (NCCN) guidelines for colon cancer (v.2.2009) and the American Society of Clinical Oncology (ASCO) provisional clinical opinion (Allegra, 2009) recommend genotyping tumor tissue for KRAS mutation in all patients with metastatic colorectal cancer (genotyping may be done on archived specimens). Patients with known codon 12 or 13 KRAS gene mutations are unlikely to respond to EGFR inhibitors and should not receive cetuximab. Favorable progression-free survival and overall survival has been demonstrated with cetuximab in patients with KRAS wild-type (Karapetis, 2008; Van Cutsem, 2008). Because EGFR testing in colorectal tumors does not correlate with response, the NCCN guidelines do not recommend routine EGFR testing in colorectal cancer. Dermatologic toxicity with cetuximab is predictive for response; the presence of acneiform rash correlates with treatment response and prolonged survival (Cunningham, 2004).
The NCCN Non-Small Cell Lung cancer guidelines (v.2.2009) recommend cetuximab in combination with cisplatin and vinorelbine as a first-line therapy option in patients with advanced (stage IIIB or IV disease), with EGFR expression and a performance status of 0-2.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause malaise, insomnia, or depression
Mental Health: Effects on Psychiatric Treatment
Gastrointestinal side effects are common; these effects may be additive with concurrent use of SSRIs, acetylcholinesterase inhibitors, aripiprazole, or ziprasidone. May cause anemia and leukopenia; use caution with clozapine and carbamazepine.
Nursing: Physical Assessment/Monitoring
Use caution with pre-existing coronary or lung disease. Premedication with antihistamines is recommended. Patient must be monitored closely for adverse reactions (eg, airway obstruction, hives, hypotension) during and for 1 hour following infusion. Treatment for anaphylactic reactions should be available. In case of severe infusion reaction, treatment should be stopped and prescriber notified. Dosing adjustment or permanent discontinuation may be necessary in event of infusion reaction. Evaluate results of laboratory tests prior to and periodically during treatment. Assess therapeutic response and adverse reactions. Teach patient possible side effects/interventions and adverse symptoms to report (eg, skin reactions, cough, dyspnea, gastrointestinal upset, opportunistic infection).
Oncology: Emetic Potential
Low (10% to 30%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]:
Erbitux®: 2 mg/mL (50 mL, 100 mL)
Pricing: U.S. (www.drugstore.com)
Solution (Erbitux)
100 mg/50 mL (50): $570.01
References
Allegra CJ, Jessup JM, Somerfield MR, et al, “American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy, ” J Clin Oncol, 2009, 27(12):2091-6.
Baselga J, “The EGFR as a Target for Anticancer Therapy - Focus on Cetuximab,” Eur J Cancer, 2001, 37(Suppl 4):16-22.
Bonner JA, Harari PM, Giralt J, et al, “Radiotherapy Plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck,” N Engl J Med, 2006, 354(6):567-78.
Chung CH, Mirakhur B, Chan E, et al, “Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-alpha-1,3-galactose,” N Engl J Med, 2008, 358(11):1109-17
Cunningham D, Humblet Y, Siena S, et al, “Cetuximab Monotherapy and Cetuximab Plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer,” N Engl J Med, 2004, 351(4):337-45.
Jonker DJ, O'Callaghan CJ, Karapetis CS, et al, “Cetuximab for the Treatment of Colorectal Cancer,” N Engl J Med, 2007, 357(20):2040-8.
Karapetis CS, Khambata-Ford S, Jonker DJ, et al, “K-ras Mutations and Benefit From Cetuximab in Advanced Colorectal Cancer,” N Engl J Med, 2008, 359(17):1757-65.
Kies MS and Harari PM, “Cetuximab (Imclone/Merck/Bristol-Myers Squibb),” Curr Opin Investig Drugs, 2002, 3(7):1092-100.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Colon Cancer,” Version 2.2009. Accessible at http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer,” Version 2.2009. Accessible at http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.
O'Neil BH, Allen R, Spigel DR, et al, “High Incidence of Cetuximab-Related Infusion Reactions in Tennessee and North Carolina and the Association With Atopic History,” J Clin Oncol, 2007, 25(24):3644-8.
Pfeiffer P, Bjerregarrd JK, Qvortrup C, et al, “Simplification of Cetuximab (Cet) Administration: Double Dose Every Second Week as a 60 Minute Infusion,” J Clin Oncol, 2007, 25(18S):4133 [abstract from 2007 ASCO Annual Meeting Proceedings, Part I]
Pfeiffer P, Nielsen D, Bjerregaard J, et al, “Biweekly Cetuximab and Irinotecan as Third-Line Therapy in Patients With Advanced Colorectal Cancer After Failure to Irinotecan, Oxaliplatin and 5-Fluorouracil,” Ann Oncol, 2008, 19(6):1141-5.
Pirker R, Szczesna A, von Pawel J, et al, “FLEX: A Randomized, Multicenter, Phase III Study of Cetuximab in Combination With Cisplatin/Vinorelbine (CV) Versus CV Alone in the First-Line Treatment of Patients With Advanced Non-Small Cell Lung Cancer (NSCLC),”J Clin Oncol, 2008, 26(Supp) [abstract 3 from 2008 ASCO Annual Meeting].
Reynolds NA and Wagstaff AJ, “Cetuximab: In the Treatment of Metastatic Colorectal Cancer,” Drugs, 2004, 64(1):109-18.
Van Cutsem E, Lang, I, D'haens G, et al, “KRAS Status and Efficacy in the First-Line Treatment of Patients With Metastatic Colorectal Cancer (mCRC) Treated With FOLFIRI With or Without Cetuximab: The CRYSTAL Experience,” J Clin Oncol, 2008, 26(Supp) [abstract 2 from 2008 ASCO Annual Meeting].
International Brand Names
Lexi-Comp.com
Last full review/revision November 2009
Content last modified November 2009
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