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Cetuximab; Uses, Dosage, Side Effects, Interactions, Pregnanc

Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer. It is used to treat a certain type of cancer of the colon (large intestine) or rectum that has spread to other parts of the body. This medication is also used to treat head and neck cancer. Cetuximab works by slowing or stopping the growth of cancer cells. Cetuximab is an epidermal growth factor receptor binding FAB. Cetuximab is composed of the Fv (variable; antigen-binding) regions of the 225 murine EGFr monoclonal antibody specific for the N-terminal portion of human EGFr with human IgG1 heavy and kappa light chain constant (framework) regions.

Mechanism of Action of Cetuximab

Cetuximab binds to the epidermal growth factor receptor (EGFr) on both normal and tumor cells. EGFr is over-expressed in many colorectal cancers. Cetuximab competitively inhibits the binding of epidermal growth factor (EGF) and TGF alpha, thereby reducing their effects on cell growth and metastatic spread. Cetuximab is a monoclonal antibody that binds to and blocks the binding of ligands (e.g., epidermal growth factor and tissue growth factor-a) to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on the surface of normal and tumor cells. The binding of cetuximab to EGFR leads to internalization of the receptor preventing further activation and 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 (VEGF) production. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of cancer cells that over-express EGFR. No anti-tumor effects of cetuximab were noted in human tumor xerographs lacking EGFR expression. In addition, signal tranduction through the EGFR results in activation of wild-type RAS protein. In cells with activating RAS somatic mutations, the mutant RAS protein is continually active and appears independent of EGFR regulation. Cetuximab may make cancer cells more vulnerable to other cancer chemotherapy agents and radiation therapy. Preclinical trials have suggested synergy between cetuximab and irinotecan, gemcitabine, and doxorubicin. The addition of cetuximab to irinotecan or irinotecan/5-fluorouracil chemotherapy in animal studies increased anti-tumor effects compared to chemotherapy alone. The mechanism of this synergy has not been established. It is thought that the blockage of EGFR signaling, which alone may be cytotoxic in some cell lines, may increase the vulnerability of cells to the cytotoxic effects of chemotherapy that may have only have been slightly effective without EGFR blockade. Although considered a cytostatic agent, cetuximab can cause tumor regression when given as a single agent. In some cancers, such as colorectal cancer, cells can activate the EGFR receptor through autocrine or paracrine mechanisms. These autocrine and paracrine mechanisms are necessary for cells to survive in a less than hospitable microenvironment around the tumor with low pH and pO2 tension. These tumor cells may experience apoptosis when the autocrine and paracrine EGFR-activation is inhibited.

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Indications of Cetuximab

Squamous Cell Carcinoma
Colorectal Cancer
Head and Neck Cancer
Non-Small Cell Lung Cancer
Pancreatic Cancer
Metastatic Colorectal Cancers
Metastatic Squamous Cell Carcinoma of the Head and Neck
Advanced squamous cell carcinoma of the head and neck
Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy.
Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU.
Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.
K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by approved tests.
In combination with FOLFIRI for 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.

Contra-Indications of Cetuximab

Low amount of magnesium in the blood
Low amount of calcium in the blood
Low amount of potassium in the blood
Coronary artery disease
Abnormal heart rhythm
Chronic Heart Failure
Interstitial pneumonitis
Lung fibrosis
Skin infection due to a bacteria
Skin rash resembling acne
A Mother who is Producing Milk and Breastfeeding
Allergies to Cetuximab, Galactose-Alpha-1, 3-Galactose (Alpha-Gal)

Dosages of Cetuximab

Strengths: 2 mg/mL ; 1mL, 2mg

Adults

400 mg/m2 IV for the initial dose; 250 mg/m2 IV per week for subsequent doses.

Elderly

400 mg/m2 IV for the initial dose; 250 mg/m2 IV per week for subsequent doses.

Colorectal Cancer

Either as monotherapy or in combination with irinotecan or FOLFIRI (irinotecan, 5-fluorouracil, leucovorin):

Initial Dose: 400 mg/m2 administered as a 2 hour IV infusion (maximum infusion rate 10 mg /min)
Maintenance Dose: 250 mg/m2 infused over 1 hour (maximum infusion rate 10 mg/min) once a week

Squamous Cell Carcinoma

In combination with radiation therapy or in combination with platinum-based therapy with 5-FU:

Initial dose: 400 mg/m2 administered as a 2 hour IV infusion (maximum infusion rate 10 mg/min) 1 week prior to initiation of a course of radiation therapy or 1 hour before the initiation of platinum-based therapy with 5-FU
Maintenance dose: 250 mg/m2 infused over 1 hour (maximum infusion rate 10 mg/min) once a week for the duration of radiation therapy (6 to 7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU (complete the administration 1 hour prior to radiation therapy or platinum-based therapy with 5-FU)

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Monotherapy

Initial dose: 400 mg/m2 administered as a 2 hour IV infusion (maximum infusion rate 10 mg/min)
Maintenance dose: 250 mg/m2 administered as a 1 hour IV infusion (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity

Side Effects of Cetuximab

The most common

chest pain
certainly hair loss
headache
joint painPain
dizziness
nausea and vomiting
Severe stomach ache
epigastric pain,
diarrhoea,
anorexia,
flatulence,
headache,
dizziness,
fainting, fast or pounding heartbeats.

More common

Fast or irregular heartbeat
appetite loss
changes in nails
constipation
fatigue
fever
Back pain
dizziness
headache
increased cough
Acid or sour stomach
decreased appetite
Agitation
chest congestion
chest pain
cold sweats
confusion
decreased sexual ability or desire
stomach or abdominal cramps, gas, or pain
trouble sleeping

Less common

bleeding gums
blood in the urine or stools
chest pain
diarrhea
Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
difficulty in moving
muscle stiffness
redness of the face, neck, arms and occasionally, upper chest
lack or loss of strength
muscle spasm
difficult or labored breathing
dry mouth
headache
irritability
lack or loss of strength
loose stools
loss of interest or pleasure
muscle stiffness
night sweats
passing gas
stomach discomfort, upset, or pain
swollen joints
trouble concentrating
increased blood pressure

Drug Interactions of Cetuximab

Cetuximab may interact with following drugs, supplements & may decrease the efficacy of the drug

alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
“azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
beta-blockers (e.g., atenolol, propranolol, metoprolol)
barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, felodipine)
carbamazepine
chloroquine
corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
cyclosporine
dantrolene
“gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
losartan
macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
metronidazole
mirtazapine
modafinil
montelukast
norfloxacin
ondansetron
carbamazepine
phenytoin
progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
sildenafil
“statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
tadalafil
tetracycline
theophylline
tocilizumab
tolterodine
tramadol
other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
5-HT3 antagonists (e.g., granisetron, ondansetron)
tamsulosin
tapentadol
thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
tramadol
tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
trimethoprim
other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
tetracycline
tocilizumab
vandetanib
vemurafenib
vitamin C

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Pregnancy & Lactation of Cetuximab

FDA Pregnancy Category C

Pregnancy

It is not known whether cetuximab is secreted in human breast milk; however, IgG is secreted in human milk. The potential for absorption of cetuximab and harm to the infant after ingestion is unknown. It is advised that women avoid breastfeeding during cetuximab therapy and for 60 days after the last dose of cetuximab.

Lactation

It is not known if cetuximab passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Breastfeeding should be stopped while you are being treated with cetuximab and should not be restarted until at least 60 days after the last dose of medication. The safety and effectiveness of using this medication have not been established for children.