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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

Medically reviewed by Drugs.com on Apr 18, 2023. Written by ASHP.

Warning

    Infusion-related Effects
  • Severe infusion-related effects (rarely fatal) reported in about 3% of patients.

  • If severe infusion-related effects occur, discontinue cetuximab immediately and permanently. (See Infusion-related Effects under Cautions.)

    Cardiopulmonary Arrest
  • 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.)

  • 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

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
IV

Initial 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
IV

Initial 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
IV

Initial 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:

Cetuximab Dosage Modification for Severe Acneiform Rash1

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

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

Advice to Patients

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.

Cetuximab (Recombinant)

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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