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Cetuximab

Pronunciation: se-TUX-i-mab
Class: Antineoplastic, Monoclonal antibody

Trade Names

Erbitux
- Injection, solution 2 mg/mL

Pharmacology

Competitively inhibits binding of epidermal growth factor (EGF) to receptors, which 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 production.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Steady-state peak and trough values range from 168 to 235 mcg/mL and 41 to 85 mcg/mL, respectively. AUC increases in a dose-proportional manner as the dose is increased from 20 to 200 mg/m 2 and appears to plateau at doses greater than 200 mg/m 2 .

Distribution

Vd is approximately 2 to 3 L/m 2 .

Elimination

Mean half-life is approximately 112 h. Clearance decreases from 0.08 to 0.02 L/h/m 2 as the dose is increased from 20 to 200 mg/m 2 and appears to plateau at doses greater than 200 mg/m 2 .

Special Populations

Children

In combination with irinotecan, Vd is 2 to 3 L/m 2 . AUC is 17.7 mg•h/mL in patients 1 to 12 y of age (younger age group) and 13.4 mg•h/mL in patients 13 to 18 y of age (adolescent age group). Mean half-life is 110 and 82 h in the younger age group and adolescent age group, respectively.

Indications and Usage

In combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck; as single-agent treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in patients in whom prior platinum-based therapy failed; in combination with platinum-based therapy with 5-fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck; in combination with irinotecan for the treatment of EGF receptor (EGFR)–expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy; as single-agent treatment of EGFR–expressing metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-based regimens and in patients who are intolerant to irinotecan-based regimens.

Contraindications

None well documented.

Dosage and Administration

Colorectal Cancer
Adults

IV As monotherapy or in combination with irinotecan, 400 mg/m 2 as an initial loading dose administered as a 120-min infusion (max rate of infusion, 10 mg/min). The weekly maintenance dose is 250 mg/m 2 infused over 60 min (max rate of infusion, 10 mg/min) until disease progression or unacceptable toxicity.

Squamous Cell Carcinoma of the Head and Neck
Adults

IV In combination with radiation therapy or in combination with platinum-based therapy with 5-fluorouracil, the recommended dose is 400 mg/m 2 as an initial dose given as a 120-min infusion (max infusion rate, 10 mg/min) 1 wk prior to initiation of a course of radiation therapy or on the day of initiation of platinum-based therapy with 5-fluorouracil, with cetuximab administration completed 1 hour prior to platinum-based therapy with 5-fluorouracil. The recommended weekly maintenance dose is 250 mg/m 2 infused over 60 min (max infusion rate, 10 mg/min) weekly for the duration of radiation therapy (6 to 7 wk) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-fluorouracil. Complete cetuximab administration 1 h prior to radiation therapy or platinum-based therapy with 5-fluorouracil. As a single agent, the recommended initial dose is 400 mg/m 2 followed by 250 mg/m 2 weekly (max infusion rate, 10 mg/min) until disease progression or unacceptable toxicity.

Dose Modification
Adults Dermatologic toxicity

IV If patient experiences severe acneiform rash, at first occurrence, delay infusion 1 to 2 wk and, if improvement occurs, continue at 250 mg/m 2 ; discontinue if no improvement. At second occurrence, delay infusion 1 to 2 wk and, if improvement occurs, reduce dose to 200 mg/m 2 ; discontinue if no improvement. At third occurrence, delay infusion 1 to 2 wk and, if improvement occurs, reduce dose to 150 mg/m 2 ; discontinue if no improvement. At fourth occurrence, discontinue.

Infusion reactions

IV Reduce the infusion rate by 50% in patients experiencing mild or moderate (grade 1 or 2) or nonserious grade 3 infusion reactions; permanently discontinue in patients experiencing severe infusion reactions requiring medical intervention and/or hospitalization.

General Advice

  • Follow institutional procedures for handling, administering, and disposing of anticancer drugs.
  • Premedicate patients with antihistamine (eg, diphenhydramine 50 mg IV) 30 to 60 min prior to first dose. Administer premedication for subsequent doses based on clinical judgment and presence/severity of prior infusion reaction.
  • Do not shake or dilute solution.
  • Do not mix with any other medications.
  • Do not administer if cloudy or discolored. A small amount of white amorphous particulates is normal.
  • For IV infusion only; do not administer as an IV bush or bolus.
  • Administer prescribed dose using syringe pump or infusion pump following manufacturer's recommendations.
  • Administer with use of low protein–binding 0.22-micrometer in-line filter placed as proximal to the patient as possible.
  • Observe patients for 1 h after administration.

Storage/Stability

Store unopened vials in refrigerator (36° to 46°F). Do not freeze. Preparations of cetuximab in infusion containers are stable for up to 8 h at 68° to 77°F or 12 h if refrigerated (36° to 46°F). Discard any unused solution.

Drug Interactions

None well documented.

Adverse Reactions

Adverse reaction percentages are for grades 1 to 4 toxicity with cetuximab monotherapy.

CNS

Fatigue (89%); headache (33%); insomnia (30%); confusion (15%); anxiety (14%); depression (13%).

Dermatologic

Rash/desquamation (89%); dry skin (49%); pruritus (40%); nail changes (21%).

Electrolytes

Hypomagnesemia (55%).

GI

Abdominal pain (59%); constipation (46%); diarrhea (39%); vomiting (37%); stomatitis (25%); dry mouth (11%).

Musculoskeletal

Bone pain (15%).

Respiratory

Dyspnea (48%); cough (29%).

Miscellaneous

Pain (51%); infection without neutropenia (35%); fever (30%); infusion reactions (20%); chills/rigors (13%).

Precautions

Warnings

Cardiopulmonary arrest

Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with cetuximab plus radiation therapy and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union–approved cetuximab in combination with platinum-based therapy with 5-fluorouracil.

Infusion reactions

Serious infusion reactions occurred in approximately 3% of patients in clinical trials, with fatal outcomes reported in fewer than 1 in 1,000 patients. Immediately interrupt and permanently discontinue infusion for serious infusion reactions.


Monitor

Closely monitor serum electrolytes, including serum calcium, magnesium, and potassium, during and for at least 8 wk after cetuximab therapy. Closely monitor patients during and for 1 h following each infusion for signs and symptoms of infusion reaction (eg, bronchospasm, hives, hoarseness, hypotension, stridor). If reactions are noted and are severe, immediately discontinue infusion and be prepared to treat appropriately (eg, bronchodilators, corticosteroids, epinephrine, IV antihistamines, oxygen). Monitor patients for dermatologic toxicities and infectious sequelae and initiate appropriate treatment if needed. Monitor patients for acute onset or worsening of existing pulmonary symptoms.


Pregnancy

Category C .

Lactation

Undetermined. Immunoglobulin G is excreted in human milk; therefore, cetuximab may also be excreted.

Children

Safety and efficacy not established.

Special Risk Patients

Exercise caution when using cetuximab in combination with radiation therapy or platinum-based therapy with 5-fluorouracil in patients with head and neck cancer with a history of coronary artery disease, CHF, or arrhythmias.

Combination therapy

Safety of cetuximab in combination with radiation therapy and cisplatin has not been established.

Dermatologic toxicity

Reactions, including acneiform rash, paronychial inflammation, infectious sequelae, hypertrichosis, and skin drying and fissuring, may occur. Rash usually appears within the first 2 wk and is usually resolved after stopping treatment, but in half of patients it continues beyond 28 days. Instruct patients to limit sun exposure to minimize any skin reactions.

Electrolyte abnormalities

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of cetuximab.

Immunogenicity

Antibodies to cetuximab may develop.

Pulmonary toxicity

Interstitial lung disease has been reported. Interrupt therapy for acute onset or worsening of pulmonary symptoms. Permanently discontinue cetuximab for confirmed interstitial lung disease.

Overdosage

Symptoms

No data available.

Patient Information

  • Advise patients, families, or caregivers that medication will be prepared and administered by their health care provider in a health care setting.
  • Review dosing schedule with patients, families, or caregivers.
  • Advise patients, families, or caregivers to immediately report any of the following to health care provider: acne-like rash, appetite loss, diarrhea, fever, chills, inflammation or infection, persistent nausea, persistent or worsening general body weakness or fatigue, skin drying or splitting, sores in mouth, unexplained shortness of breath or difficulty breathing, vomiting.
  • Advise patients to avoid unnecessary exposure to sunlight or tanning lamps and to use sunscreen and wear protective clothing to reduce risk of worsening any skin reactions during treatment and for at least 2 mo following the last dose of cetuximab.
  • Advise both men and women of childbearing potential to use adequate contraception during treatment and for 6 mo following the last dose of cetuximab.
  • Inform female patients that breast-feeding is not recommended during treatment and for 2 mo following the last dose.

Copyright © 2009 Wolters Kluwer Health.

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