Cetuxim5 mg/ml

Established (FDA-approved) indications

• RAS wild-type, EGFR-expressing metastatic colorectal cancer (mCRC) (confirmed by an FDA-approved RAS mutation test), used:
  • in combination with FOLFIRI as first-line treatment;
  • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy;
  • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.
• BRAF V600E-mutant metastatic colorectal cancer: Cetuxim in combination with encorafenib, after prior therapy, in patients with a confirmed BRAF V600E mutation.
• Squamous cell carcinoma of the head and neck (SCCHN), used:
  • in combination with radiation therapy for locally or regionally advanced disease;
  • in combination with platinum-based chemotherapy plus fluorouracil for recurrent locoregional disease or metastatic disease;
  • as a single agent for disease that has recurred or progressed after platinum-based chemotherapy.

Important: Cetuxim is not indicated for colorectal cancer with RAS mutations (KRAS or NRAS) or when RAS mutation status is unknown, and RAS/BRAF testing must be performed before starting therapy for colorectal cancer. Cetuxim must be prescribed and administered only under the supervision of a qualified oncology specialist.

Each single-dose vial contains Cetuximab 2 mg/mL as a sterile, clear, colorless solution for intravenous infusion. Cetuximab is a chimeric human/murine IgG1 monoclonal antibody produced in mammalian cell culture. Available as 100 mg/50 mL and 200 mg/100 mL single-dose vials (does not contain preservative).

Cetuxim is a recombinant, chimeric (human/murine) IgG1 monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR, also known as HER1 or c-ErbB-1), which is overexpressed in many epithelial tumors, including certain colorectal cancers and head and neck cancers.

Cetuxim is given only by intravenous infusion under specialist oncology supervision, typically in combination with chemotherapy or radiation therapy, and is not a self-administered or general-practice medication.

Antineoplastic agent – Monoclonal antibody, Epidermal Growth Factor Receptor (EGFR) inhibitor. Cetuxim belongs to this class.

Mechanism of action

Cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR) with an affinity greater than that of endogenous ligands. This competitively blocks the binding of epidermal growth factor (EGF) and other ligands such as transforming growth factor-alpha, preventing receptor dimerization, autophosphorylation, and activation of downstream intracellular signaling (RAS/RAF/MAPK and PI3K/AKT pathways) that drive tumor cell proliferation, survival, invasion, and angiogenesis. Cetuximab also promotes internalization of EGFR and can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) directed at EGFR-expressing tumor cells.

Pharmacokinetics

Cetuximab exhibits non-linear, target-mediated pharmacokinetics. With the standard 400 mg/m² loading dose followed by weekly 250 mg/m² maintenance doses, steady-state concentrations are generally reached by the third weekly dose. The mean elimination half-life is approximately 70–100+ hours (multi-day). Cetuximab is eliminated primarily through cellular (Fc receptor-mediated and target-mediated) uptake and catabolism rather than hepatic or renal pathways, so formal hepatic/renal dose-adjustment studies have not been established as necessary.

• Cetuxim is supplied as a ready-to-use solution; it must not be shaken or diluted below the recommended concentration and should be administered using a low protein-binding 0.22-micron in-line filter.
• Administer via infusion pump, gravity drip, or syringe pump; do not give as an intravenous push or bolus.
• The initial dose should be infused over 120 minutes and subsequent weekly doses over 60 minutes, through a separate line, with the infusion line flushed with normal saline at the end.
• Patients must be observed for at least 1 hour after the infusion in a facility equipped to manage anaphylaxis and other serious infusion reactions; longer observation is required if an infusion reaction occurs.
• Cetuxim should be administered only under specialist oncology supervision; it is not intended for self-administration.

• Platinum-based chemotherapy and radiation therapy: concurrent use with radiotherapy (in head and neck cancer) or platinum-based regimens increases the risk of severe cardiopulmonary events and electrolyte disturbances; cardiopulmonary and electrolyte monitoring is required (see Precautions and Warnings).
• Irinotecan-based chemotherapy: combination with Cetuxim can increase the frequency and severity of diarrhea and hematologic toxicity; dose modification of irinotecan may be required per its own labeling.
• RAS/BRAF-mutant tumors with chemotherapy: use of Cetuxim in combination with certain chemotherapy regimens in patients with RAS-mutant colorectal tumors has been associated with worse outcomes; RAS/BRAF testing before use is required (see Indications).
• Cetuxim is a monoclonal antibody eliminated by proteolytic catabolism and has no known clinically significant cytochrome P450-mediated drug interactions.

Common adverse reactions

Serious adverse reactions

Serious and sometimes fatal infusion reactions, cardiopulmonary arrest/sudden death (particularly with concurrent radiotherapy in head and neck cancer), severe dermatologic toxicity with risk of infection, interstitial lung disease, and severe electrolyte depletion (hypomagnesemia, hypocalcemia, hypokalemia) can occur — see Precautions and Warnings for details.

Pregnancy: Based on its mechanism of action (EGFR blockade), Cetuxim may cause fetal harm when administered to a pregnant woman. Cetuxim should be used during pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus; a physician must be consulted before use in pregnancy. Females of reproductive potential should use effective contraception during treatment and for at least 2 months after the last dose.

Lactation: It is not known whether Cetuxim is excreted in human milk. Because many antibodies are excreted in milk and the potential for serious adverse effects in a nursing infant is unknown, a decision should be made, in consultation with a physician, whether to discontinue breastfeeding or discontinue Cetuxim, taking into account the importance of treatment to the mother; breastfeeding is generally advised to be avoided during treatment and for at least 2 months after the final dose.

Boxed warnings

• Infusion reactions: Serious infusion reactions, including anaphylaxis, can occur with Cetuxim, most often with the first infusion, and can be fatal. Premedication with an antihistamine is required, and patients must be monitored during and for at least 1 hour after infusion in a setting equipped to manage anaphylaxis. Cetuxim must be permanently discontinued for severe (Grade 3–4) infusion reactions.
• Cardiopulmonary arrest: Cardiopulmonary arrest and sudden death have occurred in patients treated with Cetuxim, particularly in patients with head and neck cancer receiving concurrent radiation therapy. Cardiopulmonary monitoring during and after Cetuxim administration is required in this population, and electrolytes (magnesium, potassium, calcium) should be monitored closely.

Other warnings and precautions

• Dermatologic toxicity: Acneiform rash is very common and can be severe; dose modification protocols (interruption, delay, or discontinuation) apply for severe reactions, and secondary infection of affected skin can occur.
• Interstitial lung disease (ILD): Rare but can be severe and fatal; Cetuxim should be interrupted for acute onset of pulmonary symptoms and discontinued if ILD is confirmed.
• Electrolyte depletion: Hypomagnesemia is common and can be severe, sometimes occurring weeks after starting treatment; hypocalcemia and hypokalemia may accompany it. Monitor electrolytes before, during, and for at least 8 weeks after completing treatment, and replace as needed.
• RAS/BRAF mutation testing: RAS (KRAS/NRAS) mutation status must be tested before use in colorectal cancer, as Cetuxim is not effective (and may be harmful) in RAS-mutant tumors; BRAF status guides use of Cetuxim with encorafenib.
• Cetuxim must be prescribed and administered only by, or under the direct supervision of, a specialist experienced in oncology care in a facility equipped to manage severe reactions; it is not a general-practice or self-administered medication.

Doses of Cetuxim up to 700 mg/m² have been administered in clinical studies without reports of dose-limiting toxicity beyond the known adverse effect profile; there is no established specific antidote. In the event of a suspected overdose, the infusion should be stopped immediately, the patient should be monitored closely for signs of infusion reactions, cardiopulmonary compromise, or other toxicity, and supportive care should be provided. Patients or caregivers who suspect an overdose should seek immediate medical attention or contact emergency services.

Store Cetuxim vials refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake. Protect from direct light by keeping the vial in its original carton until time of use. Keep out of reach of children. Discard any unused portion per institutional pharmacy protocol.

• Renal impairment: No dedicated dose-adjustment studies exist; Cetuxim is not renally eliminated, so no specific adjustment is established.
• Hepatic impairment: No dedicated dose-adjustment studies exist; Cetuxim is not hepatically metabolized, so no specific adjustment is established.
• Elderly patients: No overall differences in safety or effectiveness have been observed between patients 65 years and older and younger patients, but age-related organ function and comorbidities should be considered.
• Pediatric patients: Safety and efficacy have not been established (see Pediatric Uses).
• Females of reproductive potential: Effective contraception is advised during and for at least 2 months after treatment (see Pregnancy and Lactation).

For metastatic colorectal cancer, Cetuxim is generally continued weekly until disease progression or unacceptable toxicity occurs. When used with radiation therapy for head and neck cancer, Cetuxim is given for the duration of the radiation course (typically 6–7 weeks). When used with platinum-based chemotherapy for recurrent or metastatic head and neck cancer, Cetuxim is continued as monotherapy maintenance after the chemotherapy phase until disease progression or unacceptable toxicity. The treating oncologist determines the exact duration based on response and tolerability.

Monoclonal antibodies; EGFR (Epidermal Growth Factor Receptor) inhibitors; Antineoplastic and immunomodulating agents

Cetuximab is a monoclonal antibody that binds the extracellular domain of EGFR, blocking ligand binding and downstream signaling that drives tumor cell growth, and can also trigger immune-mediated (antibody-dependent) destruction of EGFR-expressing tumor cells.

The safety and effectiveness of Cetuxim in pediatric patients have not been established. Cetuxim is not recommended for use in children outside of a clinical trial setting, and no weight- or age-based pediatric dosing has been established.