Cetuximab (Monograph)
Brand name: Erbitux
Drug class: Antineoplastic Agents
- Epidermal Growth Factor Receptor (EGFR) Inhibitors
VA class: AN900
Chemical name: Disulfide with human-mouse monoclonal C225 κ-chain anti-(human epidermal growth factor receptor) (human-mouse monoclonal C225 γ1-chain) immunoglobulin G1 dimer
CAS number: 205923-56-4
Warning
- Infusion-related Effects
-
Severe infusion-related effects (rarely fatal) reported in about 3% of patients.
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If severe infusion-related effects occur, discontinue cetuximab immediately and permanently. (See Infusion-related Effects under Cautions.)
- Cardiopulmonary Arrest
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Cardiopulmonary arrest and/or sudden death reported in 2% of patients with squamous cell carcinoma of the head and neck receiving cetuximab in combination with radiation therapy. (See Cardiopulmonary Arrest under Cautions.)
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Closely monitor serum electrolytes (including magnesium, potassium, and calcium) during and after cetuximab therapy. (See Electrolyte Disorders under Cautions.)
Introduction
Antineoplastic agent; a recombinant chimeric (human-murine) monoclonal antibody that binds to epidermal growth factor receptors (EGFR).
Uses for Cetuximab
Colorectal Cancer
Used in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal cancer that is refractory to irinotecan-based chemotherapy. Indication for use in combination with irinotecan is based on objective response rates; currently no data demonstrating clinical benefit (e.g., improvement in disease-related symptoms, increased survival).
Used as a single agent for the treatment of EGFR-expressing metastatic colorectal cancer in patients with disease that has failed treatment with both irinotecan-based and oxaliplatin-based regimens.
Also used as a single agent for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant of irinotecan-based chemotherapy.
Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for EGFR inhibitors (e.g., cetuximab, panitumumab) in patients whose tumors had KRAS (also called K-ras) mutations in codon 12 or 13. ASCO and some clinicians recommend that all patients with metastatic colorectal cancer who are potential candidates for EGFR inhibitor therapy have their tumor tested for KRAS mutations in a Clinical Laboratory Improvement Amendments (CLIA)-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, use of cetuximab is not recommended.
Under investigation for use in combination with chemotherapy regimens (e.g., irinotecan/fluorouracil/leucovorin [FOLFIRI], oxaliplatin/fluorouracil/leucovorin [FOLFOX]) for the first-line† [off-label] treatment of metastatic colorectal cancer.
Head and Neck Cancer
Used in combination with radiation therapy for initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck, particularly in patients who cannot tolerate platinum-based chemotherapy with radiation therapy. Platinum-based chemotherapy with radiation therapy is current standard of care for treatment of advanced head and neck cancer.
Used as a single agent for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck when previous platinum-based chemotherapy has failed.
Under investigation for use in combination with other antineoplastic agents (e.g., cisplatin), with or without radiation therapy,† [off-label] for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.
Non-small Cell Lung Cancer (NSCLC)
Use in combination with chemotherapy as first-line therapy for advanced (stage IIIB [with malignant pleural effusion] or IV [metastatic]) NSCLC† [off-label] is not fully established because of equivocal evidence; additional studies needed to validate predictive tumor biomarkers and identify subgroups of patients with previously untreated advanced NSCLC who might derive clinical benefit (e.g., prolonged progression-free survival, prolonged overall survival, improved quality of life) from the addition of cetuximab to chemotherapy.
Cetuximab Dosage and Administration
General
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To minimize risk of infusion-related reactions, premedicate with an antihistamine (e.g., diphenhydramine hydrochloride 50 mg) IV 30–60 minutes prior to initial cetuximab dose. Administer antihistamine prior to subsequent doses as clinically indicated based on occurrence and severity of previous reactions.
Administration
IV Administration
Administer by IV infusion. Do not administer by rapid IV injection, such as IV push or bolus.
Solution should be clear and colorless and may contain small amounts of easily visible, white, amorphous particulates.
Do not shake vials.
Contains no preservative; discard any unused portion of vial.
Use infusion pump or syringe pump to administer.
Administer drug through a low-protein-binding 0.22-µm inline filter.
Monitor patients for infusion reactions during and for 1 hour following each infusion. If infusion reaction requiring treatment occurs, monitor until event has resolved.
Dilution
Do not dilute solution.
Rate of Administration
Initial IV dose: Administer over 2 hours.
Subsequent weekly doses: Administer over 1 hour.
Infusion rate should not exceed 10 mg/minute.
Dosage
Adults
Colorectal Cancer
Cetuximab or Cetuximab/Irinotecan for EGFR-Expressing Metastatic Disease
IVInitial cetuximab dose of 400 mg/m2, followed by 250 mg/m2 once weekly until disease progression or unacceptable toxicity occurs.
Head and Neck Cancer
Cetuximab/Radiation Combination Therapy for Locally or Regionally Advanced Disease
IVInitial dose of 400 mg/m2 administered 1 week prior to initiation of first course of radiation therapy. Then, 250 mg/m2 once weekly for duration of radiation therapy (6–7 weeks); a median of 8 doses was administered in clinical studies. Cetuximab administration should be completed 1 hour prior to radiation therapy.
Monotherapy for Recurrent or Metastatic Disease
IVInitial dose of 400 mg/m2, followed by 250 mg/m2 once weekly until disease progression or unacceptable toxicity occurs.
Dosage Modification for Toxicity and Contraindications to Continued Therapy
Infusion-related Reactions
If grade 1 or 2 or nonserious grade 3 or 4 infusion-related reaction occurs, reduce infusion rate by 50%.
If serious infusion-related reaction (requiring medical intervention and/or hospitalization) occurs, discontinue therapy immediately and permanently.
Dermatologic Toxicity
If severe (grade 3 or 4) acneiform rash occurs, temporarily delay therapy; reduce subsequent doses or discontinue therapy depending on patient's response as follows:
Occurrence of Severe Acneiform Rash |
Intervention |
Outcome |
Cetuximab Dosage |
---|---|---|---|
First occurrence |
Delay infusion for 1–2 weeks |
Improvement |
Continue subsequent weekly dose of 250 mg/m2 |
No improvement |
Discontinue cetuximab |
||
Second occurrence |
Delay infusion for 1–2 weeks |
Improvement |
Reduce subsequent weekly dose to 200 mg/m2 |
No improvement |
Discontinue cetuximab |
||
Third occurrence |
Delay infusion for 1–2 weeks |
Improvement |
Reduce subsequent weekly dose to 150 mg/m2 |
No improvement |
Discontinue cetuximab |
||
Fourth occurrence |
Discontinue cetuximab |
Pulmonary Toxicity
If acute onset or worsening of pulmonary symptoms occurs, interrupt therapy. If interstitial lung disease is confirmed, permanently discontinue therapy.
Special Populations
No special population dosage recommendations at this time.
Cautions for Cetuximab
Contraindications
-
No known contraindications according to manufacturer.
Warnings/Precautions
Warnings
Infusion-related Effects
Potential for serious infusion-related effects (e.g., rapid airway obstruction [bronchospasm, stridor, hoarseness], hypotension, shock, loss of consciousness, MI, cardiac arrest). (See Infusion-related Effects in Boxed Warning.) Infusion-related effects are severe (grade 3 or 4) in 2–5% of patients; fatal in less than 1 in 1000 patients. Approximately 90% of severe reactions occur in association with initial cetuximab infusion despite premedication with antihistamines.
Monitor for signs of infusion reactions during and for 1 hour following each cetuximab infusion in a setting where resuscitation equipment and agents necessary to treat anaphylaxis are readily available. For patients experiencing infusion reactions requiring treatment, monitor until event has resolved.
If grade 1 or 2 or nonserious grade 3 or 4 infusion-related reaction occurs, reduce infusion rate by 50%.
If serious infusion-related effects occur, discontinue cetuximab immediately and permanently and initiate appropriate therapy (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, oxygen).
Cardiopulmonary Arrest
Cardiopulmonary arrest and/or sudden death reported in patients with or without CAD, arrhythmia, and/or CHF receiving cetuximab/radiation combination therapy for treatment of squamous cell carcinoma of the head and neck. (See Cardiopulmonary Arrest in Boxed Warning.)
Carefully consider use of cetuximab and radiation therapy for treatment of head and neck cancer in patients with a history of CAD, CHF, or arrhythmias. Closely monitor serum electrolytes, including magnesium, potassium, and calcium, during and following cetuximab therapy.
Serious cardiotoxicity requiring discontinuance of therapy also reported in patients with squamous cell carcinoma of the head and neck receiving cetuximab in combination with cisplatin and radiation therapy (see Use in Combination with Radiation Therapy and Cisplatin under Cautions).
Pulmonary Effects
Interstitial lung disease, interstitial pneumonitis (fatal in one case), and exacerbation of preexisting fibrotic lung disease reported.
If acute onset or exacerbation of pulmonary manifestations occurs, interrupt therapy. If interstitial lung disease is confirmed, permanently discontinue therapy.
Use in Combination with Radiation Therapy and Cisplatin
Safety of combination regimen consisting of cetuximab, radiation therapy, and cisplatin not established. Serious cardiotoxicity and death (secondary to pneumonia or unknown cause) reported in patients receiving this combination for treatment of locally advanced squamous cell carcinoma of the head and neck.
Electrolyte Disorders
Electrolyte abnormalities, including hypomagnesemia, hypocalcemia, and hypokalemia, have occurred. Hypomagnesemia reported in 55% of patients; severe (grade 3 or 4) in 6–17% of patients. Onset of hypomagnesemia and accompanying electrolyte abnormalities may occur from days to months following initiation of therapy. Manifestations of hypomagnesemia may include fatigue and hypocalcemia.
Monitor for hypomagnesemia, hypocalcemia, and hypokalemia during and for ≥8 weeks following completion of therapy. Replete electrolytes as necessary; IV replacement therapy indicated in severe cases.
Sensitivity Reactions
Dermatologic Effects
Acneiform rash reported in 76–88% of patients; severe in 1–17%. Generally appears within first 2 weeks of therapy and may resolve following discontinuance; however, may persist beyond 28 days.
Skin drying/fissuring, paronychial inflammation, infectious sequelae (e.g., abscess formation, blepharitis, conjunctivitis, keratitis, cheilitis, cellulitis, Staphylococcus aureus sepsis), and hypertrichosis reported. Fatal toxic epidermal necrolysis also reported.
Monitor for possible dermatologic effects and infectious complications. If severe acneiform rash occurs, reduce dosage or discontinue therapy. (See Dermatologic Toxicity under Dosage and Administration.)
Limit sun exposure. (See Advice to Patients.)
General Precautions
EGFR Expression and Response
In clinical trials for colorectal cancer, testing for evidence of EGFR expression was required. However, some authorities state that routine EGFR expression testing is not recommended in patients with colorectal cancer and that patients should not be included or excluded from cetuximab therapy based solely on EGFR test results.
Because expression of EGFR has been detected in nearly all head and neck cancers, EGFR testing was not required in these clinical trials.
Therapy Monitoring
Monitor for dermatologic toxicity and infectious sequelae.
Periodically monitor for hypomagnesemia and accompanying hypocalcemia and hypokalemia during and for ≥8 weeks following completion of therapy.
Immunologic Effects
Nonneutralizing anticetuximab antibodies detected in about 5% of patients. Incidence of antibody development not fully established, but there appears to be no effect on safety and efficacy of the drug.
Specific Populations
Pregnancy
Category C.
Lactation
Not known whether cetuximab is distributed into milk, but potential exists for distribution of IgG antibodies into milk. Discontinue nursing or the drug; if nursing is interrupted, do not resume for at least 60 days following last dose (due to long half-life). (See Half-life under Pharmacokinetics.)
Pediatric Use
Safety and efficacy not established in pediatric patients.
Geriatric Use
In patients receiving monotherapy or combination therapy for colorectal cancer, no overall differences in safety and efficacy relative to younger adults.
Insufficient experience in patients ≥65 years of age with head and neck cancer to determine whether they respond differently than younger adults.
Common Adverse Effects
Dermatologic effects (e.g., rash, pruritus, nail changes), headache, diarrhea, infection.
Combination therapy with irinotecan in patients with advanced colorectal cancer: Acneiform rash, asthenia/malaise, diarrhea, nausea.
Monotherapy in patients with advanced colorectal cancer: Rash/desquamation, fatigue, abdominal pain, pain, dry skin, dyspnea, constipation.
In combination with radiation therapy in patients with head and neck cancer: Acneiform rash; radiation dermatitis; weight loss; asthenia; nausea; elevated ALT, AST, and alkaline phosphatase.
Drug Interactions
Specific Drugs and Therapies
Drug or Therapy |
Interaction |
Comments |
---|---|---|
Cisplatin |
Pharmacokinetic interaction unlikely Serious cardiotoxicity and death reported with concomitant use of cetuximab, cisplatin, and radiation |
|
Docetaxel |
Pharmacokinetic interaction unlikely |
|
Fluorouracil |
Pharmacokinetic interaction unlikely |
|
Irinotecan |
Pharmacokinetic interaction unlikely |
|
Radiation therapy |
Increased risk of cardiopulmonary arrest, sudden death, and/or adverse dermatologic effects (e.g., acneiform rash) Increased risk of late radiation toxicities |
Use concomitantly with caution in patients with history or clinical evidence of CAD, CHF, or arrhythmias (see Cardiopulmonary Arrest under Cautions) |
Cetuximab Pharmacokinetics
Pharmacokinetics similar between patients with squamous cell carcinoma of the head and neck and those with colorectal cancer.
Elimination
Elimination Route
Systemic clearance believed to be through internalization of cetuximab-EGFR complex on hepatocytes and skin.
Half-life
112 hours following multiple dosing.
Special Populations
Clearance increases with increasing body surface area.
Decreased clearance observed in women. No effect on safety profile; effect on efficacy not elucidated.
Stability
Storage
Parenteral
Injection
2–8°C. Do not freeze.
Preparations in infusion containers are chemically and physically stable for up to 8 hours at 20–25°C or up to 12 hours at 2–8°C. Discard any unused portion after 8 hours (if stored at 20–25°C) or after 12 hours (if stored at 2–8°C).
Actions
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Antineoplastic agent; a recombinant chimeric (human-murine) monoclonal antibody containing human framework regions and murine Fv regions.
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Mechanism of antineoplastic effects in vivo unknown. However, cetuximab binds specifically to EGFR (HER1, c-ERbB-1) on both normal and tumor cells and competitively blocks cellular action of EGF and other ligands (e.g., transforming growth factor [TGF]-α). Binding to EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis (programmed cell death), and decreased matrix metalloproteinase and vascular endothelial growth factor production.
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Signal transduction through EGFR leads to activation of the wild-type (nonmutated) KRAS gene. However, the presence of an activating somatic mutation of the KRAS gene (mutated KRAS) in a cancer cell can lead to dysregulation of signaling pathways and resistance to EGFR inhibitor therapy (e.g., cetuximab, panitumumab).
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Can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain tumor types in vitro.
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Inhibits growth and survival of animal tumor cells that express EGFR.
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In xenograft models for human tumors in mice, addition of cetuximab to radiation therapy, irinotecan, or irinotecan/fluorouracil regimen resulted in increased antitumor effect compared with radiation therapy or chemotherapy alone.
Advice to Patients
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Risk of infusion-related effects and adverse cardiopulmonary, pulmonary, and dermatologic effects. Advise patients to report signs and symptoms of infusion reactions (e.g., fever, chills, difficulty breathing).
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Importance of advising patients to use sunscreen and hats and limit sun exposure during and for 2 months following the last dose of cetuximab to avoid exacerbation of adverse dermatologic effects.
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Necessity of advising men and women to use an effective method of contraception during and for 6 months following the last dose of cetuximab. Advise pregnant women of risk to fetus and/or potential risk for loss of pregnancy.
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Advise women to avoid breast-feeding during and for 60 days following the last dose of cetuximab.
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Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., arrhythmias, CAD, CHF).
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Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Parenteral |
Injection, for IV infusion only |
2 mg/mL (100 and 200 mg) |
Erbitux |
Bristol-Myers Squibb |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 28, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
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