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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.
Pronunciation
(se TUK see mab)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of EGFR-expressing metastatic colorectal cancer (as a single agent or in combination with irinotecan); treatment of squamous cell cancer of the head and neck (as a single agent for recurrent or metastatic disease after platinum-based chemotherapy failure; in combination with radiation therapy as initial treatment of locally or regionally advanced disease; in combination with platinum and fluorouracil-based chemotherapy as first-line treatment of locoregional or metastatic disease)
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
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. 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
According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. If breast-feeding is interrupted for cetuximab treatment, based on the half-life, breast-feeding should not be resumed for at least 60 days following the last cetuximab 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 reactions: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Cardiopulmonary arrest: [U.S. 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 caution with history of coronary artery disease, HF, 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. Monitor for dermatologic toxicity and corresponding infections. 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, ulcerative keratitis with decreased visual acuity) 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 (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: [U.S. Boxed Warning]: Serious infusion reactions have been reported in ~3% of patients; fatal outcome has been reported rarely; interrupt infusion promptly and permanently discontinue for serious infusion reactions. Reactions have included airway obstruction (bronchospasm, stridor, hoarseness), hypotension, loss of consciousness, shock, MI, and/or cardiac arrest. 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 pre-existing 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 (ILD): Has been reported; use with caution in patients with pre-existing lung disease. Interrupt treatment for acute onset or worsening of pulmonary symptoms. 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.
• 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: Safety has not been established when used in combination with radiation therapy and cisplatin; fatalities and serious cardiotoxicity, pneumonia or other adverse events have been observed.
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 studies with cetuximab monotherapy.
>10%:
Central nervous system: Fatigue (89%), pain (51%), headache (33%), fever (30%), insomnia (30%), confusion (15%), anxiety (14%), chills/rigors (13%), depression (13%)
Dermatologic: Acneiform rash (all studies: 76% to 88%; grades 3/4: 1% to 17%; onset: ≤14 days), rash (89%), dry skin (49%), pruritus (40%), nail changes (21%)
Endocrine & metabolic: Hypomagnesemia (all studies: 55%; grades 3/4: 6% to 17%)
Gastrointestinal: Abdominal pain (59%), constipation (46%), diarrhea (39%), vomiting (37%), stomatitis (25%), xerostomia (11%)
Neuromuscular & skeletal: Bone pain (15%)
Respiratory: Dyspnea (48%), cough (29%)
Miscellaneous: Infection (all studies: 13% to 35%), infusion reaction (all studies: 15% to 21%; grades 3/4: 2% to 5%; 90% of severe reactions occurred with first infusion)
1% to 10%:
Cardiovascular: Cardiopulmonary arrest (2%; with radiation therapy; 3% with platinum/fluorouracil-based chemotherapy)
Renal: Renal failure (all studies: 1%)
Miscellaneous: Sepsis (all studies: 1% to 4%)
<1%, postmarketing, and/or case reports (all studies): Abscess formation, arrhythmia, aseptic meningitis, blepharitis, bronchospasm, cardiac arrest, cellulitis, cheilitis, conjunctivitis, electrolyte abnormality, hoarseness, hypertrichosis, hypotension, interstitial lung disease (occurred between the fourth and eleventh doses), keratitis, leukopenia, loss of consciousness, MI, paronychial inflammation, pulmonary embolism, radiation dermatitis, shock, skin fissure, skin infection, stridor, ulcerative keratitis
Metabolism/Transport Effects
None known.
Drug Interactions
There are no known significant interactions.
Storage
Store unopened vials refrigerated 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 refrigerated 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 50 mg) 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 until disease progression or unacceptable toxicity
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 (squamous cell):
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). 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.
NSCLC (unlabeled use): Initial loading dose: 400 mg/m2, followed by maintenance dose: 250 mg/m2 weekly (Pirker, 2009)
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 (Colorectal Regimen)
Cetuximab + FOLFIRI (Colorectal)
Cetuximab-FOLFOX4
Cetuximab-Irinotecan (Colorectal)
Head and neck cancer:
Carboplatin-Cetuximab (Head and Neck Cancer)
Cetuximab-Carboplatin-Fluorouracil (Head and Neck Cancer)
Cetuximab-Cisplatin-Fluorouracil (Head and Neck Cancer)
Cisplatin-Cetuximab (Head and Neck Cancer)
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
This medication can only be administered by infusion and you will be closely monitored during each infusion. The first infusion takes longer to infuse. 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 and hydration, unless instructed to restrict fluid intake. Patient may experience feelings of weakness or fatigue, nausea, vomiting, loss of appetite, diarrhea, headache, back pain, acne from rash, skin dryness, or loss of hair or nails (may grow back after therapy). Report immediately chest pain, irregular heartbeat, or palpitations; difficulty breathing; persistent gastrointestinal disturbances (pain, constipation, diarrhea, vomiting); CNS changes (depression or insomnia); skin rash, dryness, or cracking; or any signs of infection. Instruct patients to avoid direct sunlight, including tanning booths. Wear sunscreen and protective clothing while receiving this medication and up to 2 months after treatment is complete.
Additional Information
Oncology Comment: The National Comprehensive Cancer Network® (NCCN) guidelines for colon cancer (v.2.2012) 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).
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 airway obstruction, hives, and 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 patient assessed. Dosing adjustment or permanent discontinuation may be necessary in event of infusion reaction. Instruct patient to report skin reactions, cough, dyspnea, gastrointestinal upset, and opportunistic infection. Monitor for skin reactions and signs of dermatologic toxicities. Monitor electrolytes up to 8 weeks after treatments.
Oncology: Emetic Potential
Minimal (<10%)
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): $575.99
200 mg/100 mL (100): $1061.94
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.
Feinstein TM, Gibson MK, and Argiris A, “Cetuximab-Induced Aseptic Meningitis,” Ann Oncol, 2009, 20(9):1609-10.
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.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Colon Cancer,” Version 2.2012. Available at http://www.nccn.org/professionals/physician_gls/PDF/colon.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 4133 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, Pereira JR, Szczesna A, et al, “Cetuximab Plus Chemotherapy in Patients With Advanced Non-Small-Cell Lung Cancer (FLEX): An Open-Label Randomised Phase III Trial,” Lancet, 2009, 373(9674):1525-31.
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):2 [abstract 2 from ASCO 2008 Annual Meeting].
Vermorken JB, Mesia R, Rivera F, et al, "Platinum-Based Chemotherapy Plus Cetuximab in Head and Neck Cancer," N Engl J Med, 2008, 359(11):1116-27.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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