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cetuximab
Cetuximab is a recombinant, human (IgG1)/mouse (Fv regions) chimeric monoclonal antibody which binds specifically to the epidermal growth factor receptors (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. This blocks phosphorylation and activation of receptor-associated kinases, which results in inhibition of cell growth, induction of apoptosis, and decreased vascular endothelial growth factor production.
EGFR is expressed in normal tissues such as skin, mucosa and kidney as well as in common epithelial tumours such as NSCLC, colorectal cancer and head and neck tumours. The EGFR signaling cascade results in RAS protein activation, which contributes to K-RAS wild-type tumour growth. Tumours with K-RAS mutations appear to be unaffected by EGFR inhibition (i.e., RAS proteins are active regardless of EGFR activation).
Cetuximab exhibits non-linear pharmacokinetics. AUC increased in a greater than dose-proportional manner as the dose increased from 20 to 200 mg/m2. Steady state is reached by the third weekly infusion.
| Cross blood brain barrier? | Unknown |
| PPB | No information found (unlikely) |
Cetuximab is metabolized and eliminated via the reticuloendothelial system.
| Active metabolites | No |
| Inactive metabolites | No |
Clearance decreases with increasing dose.
| Half-life | 112 hours (mean; 400mg/m2 dose followed by 250mg/m2 weekly) |
| Urine | No |
- Colorectal cancer
- Head and neck cancer
Refer to the product monograph for a full list and details of approved indications.
Other Uses:
- Skin cancer
Emetogenic Potential:
Extravasation Potential: None
The following table contains adverse effects reported mainly in patients with advanced CRC treated with cetuximab plus best supportive care, unless otherwise specified. Severe or life-threatening adverse effects from other studies or post-marketing are also included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Auditory | Hearing impaired (2%) | E D | |||
| Cardiovascular | Arrhythmia (2%) | E | |||
| Arterial thromboembolism (rare) | E | ||||
| Hypertension (3%) | E | ||||
| Hypotension (4%) | E | ||||
| Sudden death (2%) (head and neck only) | E | ||||
| Venous thromboembolism (3%) | E | ||||
| Dermatological | Alopecia (7%) | E | |||
| Hand-foot syndrome (4%) | E | ||||
| Hypertrichosis (4%) (with FOLFIRI) | E | ||||
| Nail disorder (28%) | E | ||||
| Paronychia (20%) (with FOLFIRI) | E | ||||
| Rash (95%) (acneiform; 18% severe) | E | ||||
| Stevens-Johnson syndrome (rare) | E | ||||
| Toxic epidermal necrolysis (rare) | E | ||||
| Gastrointestinal | Abdominal pain (59%) | E | |||
| Anorexia (68%) | E | ||||
| Ascites (6%) | E D | ||||
| Constipation (51%) | E | ||||
| Diarrhea (39%) | E | ||||
| Dry mouth (14%) | E | ||||
| Dysphagia (7%) | E | ||||
| Flatulence (4%) | E | ||||
| GI obstruction (6%) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (31%) | E | ||||
| Nausea, vomiting (61%) (5% severe) | E | ||||
| General | Fatigue (91%) (30% severe) | E | |||
| Flu-like symptoms (25%) | E | ||||
| Hematological | Hemorrhage (9%) (including GI) | E | |||
| Hepatobiliary | ↑ LFTs (11%) | E | |||
| Pancreatitis (rare) | E | ||||
| Hypersensitivity | Infusion related reaction (20%) (4% severe) | I | |||
| Immune | Antibody response (<5%) (anti-cetuximab antibody response) | D | |||
| Infection | Infection (40%) (9% severe) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (3%) (high or low K, Ca) | E | |||
| Hyperglycemia (9%) (with radiation) | D | ||||
| ↓ Mg (43%) (17% severe) | E D | ||||
| Musculoskeletal | Musculoskeletal pain (14%) | E | |||
| Nervous System | Dizziness (10%) | E | |||
| Dysgeusia (10%) | E | ||||
| Headache (38%) | E | ||||
| Insomnia (30%) | E | ||||
| Mood changes (17%) (including confusion) | E | ||||
| Neuropathy (49%) (1% severe) | E D | ||||
| Ophthalmic | Conjunctivitis (3%) | E | |||
| Eye disorders (9%) (including keratitis, dry eye) | E | ||||
| Renal | Creatinine increased (<1%; may be severe) | E | |||
| Respiratory | Cough, dyspnea (48%) (16% severe) | E | |||
| Pleural effusion (2%) | E | ||||
| Pneumonitis (<0.3%) | E | ||||
| Rhinitis (8%) | I E | ||||
| Urinary | Urinary symptoms (6%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for cetuximab include rash, fatigue, anorexia, nausea, vomiting, abdominal pain, constipation, neuropathy, cough, dyspnea, hypomagnesemia and infection.
As with all therapeutic proteins, there is potential for immunogenicity. However, there does not appear to be any relationship between the appearance of antibodies to cetuximab and the safety or antitumour activity of cetuximab.
Hypomagnesemia is severe in 17%. Magnesium supplementation may correct accompanied hypocalcemia, as parathyroid hormone release and its ability to mobilize calcium from the bone are impaired in the setting of hypomagnesemia. Electrolyte repletion was necessary in some patients, and intravenous replacement was required in severe cases. Monitoring during and after cetuximab treatment is recommended.
Severe infusion reactions occur in up to 3% of patients, may be fatal especially in patients with head and neck cancer receiving radiation, and can occur despite use of premedication. Although 90% occur with the first infusion, patients should be observed for at least 1-hour after each cetuximab infusion. Late-onset symptoms (i.e., several hours after infusion) have been reported with subsequent infusions. Severe infusion reactions require immediate discontinuation from further treatment. Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, vasopressors and oxygen should be available for use in the treatment of such reactions.
Anaphylactic reactions to cetuximab can occur in patients without previous cetuximab exposure. There is an increased risk for anaphylactic reactions in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-alpha-1,3-galactose which is present on cetuximab.
Interstitial lung disease (ILD) is rare but can be fatal. Onset is variable. Hold and investigate any acute onset or worsening respiratory symptoms. If a diagnosis of ILD is made, discontinue cetuximab and institute appropriate therapy.
Dermatologic toxicities, especially acneiform rash, are common and usually develop within the first two weeks of therapy. Complications including S. aureus sepsis and abscesses requiring incision and drainage can occur. If severe acneiform rash develops, modify the dose of subsequent cetuximab infusions. UV exposure can exacerbate any skin reaction that may occur. Patients should use sun protection while receiving cetuximab and for 2 months after treatment completion. Refer to the Canadian recommendations for the management of skin rash during EGFR-targeted monoclonal antibody treatment for GI malignancies (Melosky 2009).
Life-threatening mucocutaneous skin reactions, including Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TENS) have been reported.
Cetuximab given in combination with radiation results in incremental fatigue, fever, headache, chills, infection, pain, allergic reactions, hypotension, syncope, GI side effects, weight loss, hyperglycemia, abnormal LFTs, pain, rash and late radiation effects (skin, mucosa, salivary glands).
Cetuximab given in combination with FOLFIRI increased the risk of cardiac events and palmar-plantar erythrodysesthesia syndrome.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
RAS wild type status should be confirmed by validated test prior to starting treatment for mCRC.
Premedications (prophylaxis for infusion reaction):
- H1-receptor antagonist (e.g. diphenhydramine 50 mg IV) 30-60 minutes prior to the dose.
- Corticosteroid IV 30-60 minutes prior to the dose.
- Consider discontinuing pre-medications after the 2nd infusion based on clinical judgment and the presence/severity of IR.
Other Supportive Care:
- Patients should use sun protection while receiving cetuximab and for 2 months after treatment completion.
- Consider pre-emptive therapy for EGFR inhibitor-related skin toxicity; the following was shown to be of benefit with panitumumab treatment, starting the day before treatment and continued until week 6. (Lacouture et al, 2010):
- Skin moisturizer applied to the face, hands, feet, neck, back and chest in the morning
- Sunscreen to exposed areas (SPF > 15, UVA and UVB) before going outdoors
- Hydrocortisone 1% cream to the face, hands, feet, neck, back and chest at bedtime
- Doxycycline (or minocycline) PO
- Refer to the Canadian recommendations for the management of skin rash during EGFR-targeted monoclonal antibody treatment for GI malignancies. (Melosky et al, 2009)
The recommended dose of cetuximab in combination or as monotherapy is:
Loading dose:
Intravenous: 400 mg/m² single dose
(for head and neck cancer, give 1 week prior to radiation start date)
Maintenance dose:
Intravenous: 250 mg/m² Weekly
(for head and neck cancer complete infusion 1 hour prior to that day's radiation)
| Dose Level | Cetuximab Dose (mg/m² weekly) |
| 0 | 250 |
| -1 | 200 |
| -2 | 150 |
| -3 | Discontinue |
| Toxicity | Action | Next cycle |
Pneumonitis | Hold and investigate | Discontinue if confirmed. |
Keratitis | Hold and refer to ophthalmologist | Consider discontinuation. |
Dosage modification for skin toxicity:
Grade 3 or 4 Rash | Action | Outcome | Cetuximab Dose |
1st occurrence | Delay infusion | Improvement | Resume at same dose |
No improvement | Discontinue | ||
2nd occurrence | Delay infusion | Improvement | Resume at 1 dose level ↓ |
No improvement | Discontinue | ||
3rd occurrence | Delay infusion | Improvement | Resume at 1 dose level ↓ |
| No improvement | Discontinue | ||
4th occurrence | Discontinue | ||
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart: |
|
| 3 or 4 |
|
|
Population pharmacokinetics suggest no significant impact.
Population pharmacokinetics suggest no significant impact.
No dosage adjustment is required in colorectal cancer. No overall differences in safety or efficacy were observed in patients > 65 years of age compared to younger patients. Insufficient patients have been enrolled in head and neck studies to draw firm conclusions.
Females have lower cetuximab clearance, but dose modifications are not required.
The safety and efficacy of cetuximab in pediatric patients have not been studied.
- Do not shake or further dilute the solution.
- DO NOT administer as an IV push or bolus.
- Transfer undiluted solution into a compatible empty infusion container.
- Cetuximab is compatible with:
- glass,
- polyolefin, polyethylene, ethylene vinyl acetate (EVA), DEHP plasticized PVC, or PVC bags,
- polyethylene, EVA, PVC, polybutadiene or polymethane infusion sets, and
- polyethersulfone, polyamide or polysulfone in-line filters.
- If given with irinotecan, give cetuximab first.
- If given with radiation (for head and neck cancer), give cetuximab 1 week prior to radiation start date. For maintenance, complete cetuximab infusion 1 hour prior to that day's radiation.
- Administer the undiluted solution via a low protein binding 0.22-micrometer in-line filter, piggybacking to the patient’s infusion line.
- Infuse initial loading dose over 2 hours, and maintenance dose over 1 hour (maximum rate 10 mg/min). (May require infusion at slower rate in those who experienced infusion reactions).
- Prime administration line with drug solution before infusion. May use NS to flush line at the end of infusion.
- A 1-hour observation period is recommended following each cetuximab infusion. Longer observation periods may be required in those who experienced infusion reactions.
- Should not be mixed or diluted with other drugs.
- Store unopened vials at 2-8°C.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients with known hypersensitivity to this drug or any of its components
Other Warnings/Precautions:
- Cetuximab is not indicated for the treatment of colorectal cancer in patients with RAS mutations or RAS unknown status.
- Patients with a history of, or pre-existing keratitis, dry eyes or contact lens use
- Patients with poor performance status, or cardiopulmonary disease are at increased risk of severe hypersensitivity
- Cetuximab plus radiation therapy for head and neck cancer should be used with caution in patients who are over age 65, have poor performance status, known history of coronary artery disease, arrhythmias, congestive heart failure or receiving cardiotoxic agents as fatal events have been reported.
Other Drug Properties:
- Carcinogenicity: Unknown
Cetuximab has not been tested for carcinogenicity, but is not mutagenic or clastogenic.
Pregnancy and Lactation:
- Fetotoxicity: Yes
- Crosses placental barrier: Yes
(IgG molecules)
- Abortifacient effects: Yes
Cetuximab is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 6 months after the last dose.
- Excretion into breast milk: Probable
Breastfeeding is not recommended during cetuximab therapy and for at least 60 days after the last dose.
- Fertility effects: Unknown
No drug interactions of clinical significance have been reported. There is no evidence of any pharmacokinetic interaction between cetuximab and irinotecan.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Radiation | Additive mucocutaneous toxicity | Unknown | Caution; monitor for toxicity. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
Electrolytes, including serum magnesium, potassium and calcium | Baseline, weekly, and monthly for 2 months following completion of therapy |
CBC | Baseline and as clinically indicated |
Renal function | Baseline and as clinically indicated |
Clinical toxicity assessment for infusion reactions, skin, nail, cardiac, thromboembolism, GI, hypersensitivity, respiratory symptoms, fatigue and keratitis | At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Cetuximab and Radiation - Locally Advanced Squamous Cell Carcinoma of the Head and Neck
- Cetuximab with Irinotecan - Metastatic Colorectal, Small Bowel, or Appendiceal Cancer
- Cetuximab - In Combination with Encorafenib for Previously Treated Metastatic Colorectal Cancer
Lacouture, ME, Mitchell EP, Piperdi B et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 1351-7.
Melosky B, Burkes R, Rayson D, et al. Management of skin rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: Canadian recommendations. Current Oncology 2009; 16(10): 14-24.
Prescribing Information: Erbitux® (cetuximab). ImClone LLC, September, 2021.
Product Monograph: Erbitux® (cetuximab). Bristol Myers Squibb Canada, November 2016.
Product Monograph: Erbitux® (cetuximab). Eli Lilly Canada Inc, August 13, 2020.
Summary of Product Characteristics: Erbitux® (cetuximab). Merck Serono Ltd, May 2022.
Tran VL, Novell A, Tournier N, et al. Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab. J Control Release. 2020 Dec 10;328:304-312.
July 2023 Updated MOA/pharmacokinetics, indications, adverse effects, dosing, administration, special precautions, interactions, and monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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