Erbitux


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cetuximab

Erbitux

Pharmacologic class: Epidermal growth factor receptor (EGFR) inhibitor

Therapeutic class: Antineoplastic

Pregnancy risk category C

FDA Box Warning

• Drug may cause severe infusion reactions. If severe reaction occurs, stop infusion immediately and discontinue therapy permanently.

• Cardiopulmonary arrest, sudden death, or both occurred in 2% of patients with squamous-cell carcinoma of head and neck who received drug plus radiation therapy and in 3% of patients with squamous-cell carcinoma of head and neck treated with European-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil. Monitor serum electrolyte levels closely during and after therapy.

Action

Binds to EGFR, competitively inhibiting binding of epidermal growth factor and other ligands and blocking phosphorylation and activation of receptor-associated kinases. These actions lead to cell growth inhibition, apoptosis induction, and decreased matrix metalloproteinases and vascular endothelial growth factor.

Availability

Solution for injection: 50-ml single-use vial containing 100 mg (2 mg/ml), 100-ml single-use vial containing 200 mg (2 mg/ml)

Indications and dosages

EGFR-expressing metastatic colorectal carcinoma, used alone in patients intolerant to irinotecan-based chemotherapy or in combination with irinotecan in patients refractory to irinotecan-based therapy

Adults: 400 mg/m2 initial loading dose given as 120-minute I.V. infusion followed by maintenance dose of 250 mg/m2 infused I.V. over 60 minutes

Locally or regionally advanced squamous-cell carcinoma of head and neck, in combination with radiation therapy

Adults: 400 mg/m2 as initial loading dose (first infusion) given as 120-minute I.V. infusion 1 week before initiation of radiation therapy. For recommended weekly maintenance dose (all other infusions), 250 mg/m2 infused I.V. over 60 minutes weekly for duration of radiation therapy (6 to 7 weeks) given 1 hour before radiation therapy.

Locally or regionally advanced squamous-cell carcinoma of head and neck in combination with platinum-based therapy plus 5-fluorouracil (5-FU)

Adults: Initially, 400 mg/m2 on day of initiation of platinum-based therapy with 5-FU as a 120-minute I.V. infusion. Complete cetuximab administration 1 hour before platinum-based therapy with 5-FU. For recommended subsequent weekly doses (all other infusions), 250 mg/m2 I.V. infusion over 60 minutes for duration of radiation therapy (6 to 7 weeks) or until disease progression or unacceptable toxicity occurs.

Recurrent or metastatic squamous-cell carcinoma of head and neck (used alone) in patients for whom platinum-based therapy has failed

Adults: Initially, 400-mg/m2 I.V. infusion followed by 250 mg/m2 I.V. weekly until disease progresses or unacceptable toxicity occurs

Off-label uses

• Cancers that overexpress EGFR

Dosage adjustment

• Mild to moderate infusion (Grade 1 or 2) reaction
• Severe acneiform rash
• Acute onset or worsening of pulmonary symptoms

Contraindications

None

Precautions

Use cautiously in:
• hypersensitivity to murine proteins or drug components
• dermatologic or pulmonary toxicities
• patients receiving concurrent radiation therapy and cisplatin
• patients receiving concurrent radiation therapy who have history of coronary artery disease, arrhythmias, and congestive heart failure
• pregnant or breastfeeding patients
• children (safety and efficacy not established).

Administration

• As ordered, premedicate with histamine1-antagonist (such as 50 mg diphenhydramine I.V.).
• Use low-protein-binding, 0.22 micrometer in-line filter placed as close to patient as possible.

Don't give by I.V. push or bolus.

Don't shake or dilute vial.
• Administer by I.V. infusion pump or syringe pump.
• Piggyback drug to patient's infusion line.
• Give initial dose over 2 hours at a rate of 10 mg/minute; give subsequent weekly doses over 1 hour. Maximum infusion rate shouldn't exceed 10 mg/minute.
• At end of infusion, flush I.V. lines with normal saline solution.

Be aware that 90% of infusion reactions occur with first infusion. Observe patient closely for 1 hour after infusion (or longer in patients who have experienced infusion reactions). Severe and life-threatening infusion reactions have occurred, including rapid-onset airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension.

Permanently reduce infusion rate by 50% if patient experiences mild or moderate infusion reaction. Immediately and permanently discontinue drug in patient who experiences severe (Grade 3 or 4) infusion reaction.
• Make sure appropriate medical resources for treatment of severe infusion reactions are available during infusion.
• Expect patients with colorectal cancer to undergo immunohistochemical testing for EGFR expression using DakoCytomation EGFR pharmDx test kit.
• Interrupt therapy if patient develops acute onset or worsening of pulmonary symptoms. Discontinue therapy if pneumonitis or lung infiltrates are confirmed.
• For first occurrence of severe acneiform rash, delay infusion 1 to 2 weeks; if condition improves, continue therapy at 250 mg/m2; if no improvement occurs, withdraw drug. For second occurrence, delay infusion 1 to 2 weeks; if condition improves, reduce dosage to 200 mg/m2; if no improvement occurs, withdraw drug. For third occurrence, delay infusion for 1 to 2 weeks; if condition improves, reduce dosage to 150 mg/m2; if no improvement occurs, withdraw drug. On fourth occurrence, withdraw drug.

Adverse reactions

CNS: headache, insomnia, depression, malaise, asthenia

CV: cardiopulmonary arrest

EENT: conjunctivitis

GI: abdominal pain, diarrhea, nausea, vomiting, constipation, stomatitis, dyspepsia, anorexia

GU: renal failure

Hematologic: leukopenia, anemia

Metabolic: dehydration, electrolyte abnormalities

Musculoskeletal: back pain

Respiratory: dyspnea, increased cough, interstitial lung disease, pulmonary embolus

Skin: acneiform rash, alopecia, skin disorder, nail disorder, pruritus

Other: weight loss, fever, pain, infection, peripheral edema, severe infusion reaction

Interactions

Drug-diagnostic tests.Calcium, magnesium: decreased

Drug-behaviors.Sun exposure: exacerbated skin reactions

Patient monitoring

• Watch for signs and symptoms of infusion reaction.
• Monitor patient for hypomagnesemia and hypocalcemia during therapy and for 8 weeks afterward.
• Closely monitor serum electrolytes (including serum magnesium, potassium, and calcium) during therapy and after combination drug and radiation therapy in patients with history of coronary artery disease, arrhythmias, and heart failure.
• Monitor patient with dermatologic toxicities for inflammatory or infectious sequelae.
• Watch for pulmonary toxicities in patient with history of interstitial pneumonitis or pulmonary fibrosis. Be prepared to interrupt or discontinue therapy and intervene appropriately.
• Monitor for potentially serious cardiotoxicity if patient is receiving drug in combination with radiation therapy and cisplatin.
• Stay alert for severe diarrhea and electrolyte depletion.

Patient teaching

Urge patient to immediately report rash, which may indicate skin toxicity.

Instruct patient to immediately report new or worsening respiratory or cardiovascular symptoms.
• Advise patient to use sunscreen and wear a hat when outdoors and to limit sun exposure, because sunlight can exacerbate skin reactions.
• Caution female with childbearing potential that drug may cause pregnancy loss or pose hazard to fetus.
• Advise female to discontinue breastfeeding during therapy and for 60 days after last dose.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the tests and behaviors mentioned above.

cetuximab

(se-tux-i-mab) ,

Erbitux

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: monoclonal antibodies
Pregnancy Category: C

Indications

Locally or regionally advanced squamous cell carcinoma of the head and neck with radiation.Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.Recurrent or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-fluorouracil.genetic implicationK-ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer in patients who have not responded to irinotecan and oxaliplatin or are intolerant to irinotecan.genetic implication In combination with irinotecan in patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer who have not responded to irinotecan alone.genetic implication First-line treatment of K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI).

Action

genetic implication Binds specifically to EGFR, thereby preventing the binding of endogenous epidermal growth factor (EGF). This prevents cell growth and differentiation processes. Combination with irinotecan enhances antitumor effects of irinotecan.

Therapeutic effects

Decreased tumor growth and spread.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.
Distribution: Unknown.
Metabolism and Excretion: Unknown.
Half-life: 97–114 hr.

Time/action profile

ROUTEONSETPEAKDURATION
IVunknownunknownunknown

Contraindications/Precautions

Contraindicated in: Hypersensitivity to cetuximab or murine (mouse) proteins;genetic implication K-Ras mutation-positive colorectal cancergenetic implication Patients with colorectal cancer whose tumors have KRAS mutations in codon 12 or 13 (not effective); Obstetric / Lactation: Pregnancy or lactation.
Use Cautiously in: Exposure to sunlight (may exacerbate dermatologic toxicity); Pediatric: Safety not established.

Adverse Reactions/Side Effects

Most adverse reactions reflect combination therapy with irinotecan

Central nervous system

  • malaise (most frequent)
  • depression
  • headache
  • insomnia

Ear, Eye, Nose, Throat

  • conjunctivitis
  • ulcerative keratitis

Respiratory

  • cough
  • dyspnea
  • interstitial lung disease

Cardiovascular

  • cardiopulmonary arrest (life-threatening)
  • pulmonary embolism (life-threatening)
  • sudden cardiac death (life-threatening)

Gastrointestinal

  • abdominal pain (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • nausea (most frequent)
  • vomiting (most frequent)
  • anorexia
  • stomatitis

Genitourinary

  • renal failure

Dermatologic

  • acneform dermatitis (most frequent)
  • hypertrichosis
  • nail disorder
  • pruritus
  • skin desquamation
  • skin infection

Fluid and Electrolyte

  • dehydration
  • hypomagnesemia
  • peripheral edema

Hematologic

  • anemia
  • leukopenia

Musculoskeletal

  • back pain

Metabolic

  • weight loss

Miscellaneous

  • infusion reactions (life-threatening)
  • fever (most frequent)
  • desquamation of mucosal epithelium

Interactions

Drug-Drug interaction

None noted.

Route/Dosage

Head & Neck Cancer with Radiation or in Combination with Platinum-Based Therapy with 5-Fluorouracil

Intravenous (Adults) 400 mg/m2 administered 1 wk prior to initiation of radiation therapy or on the day of initiation of platinum-based therapy with 5-fluorouracil (complete infusion 1 hr to prior to starting platinum-based therapy with 5-fluorouracil), followed by weekly maintenance doses of 250 mg/m2 for the duration of radiation therapy or until disease progression or unacceptable toxicity with platinum-based therapy with 5-fluorouracil (complete infusion 1 hr prior to radiation therapy or platinum-based therapy with 5-fluorouracil). Dose modification recommended for dermatologic toxicity.

Head and Neck Cancer Monotherapy

Intravenous (Adults) 400 mg/m2 initial loading dose, followed by weekly maintenance doses of 250 mg/m2 until disease progression or unacceptable toxicity; dose modification recommended for dermatologic toxicity.

Colorectal Cancer

Intravenous (Adults) 400 mg/m2 initial loading dose, followed by weekly maintenance doses of 250 mg/m2 until disease progression or unacceptable toxicity; dose modification recommended for dermatologic toxicity.

Availability

Solution for injection: 2 mg/mL

Nursing implications

Nursing assessment

  • Assess for infusion reaction (rapid onset of airway obstruction [bronchospasm, stridor, hoarseness], urticaria, hypotension, loss of consciousness, myocardial infarction, cardiopulmonary arrest) for at least 1 hr following infusion. Longer observation periods may be required for those who experience infusion reactions. Most reactions occur during first dose, but may also occur in later doses. For severe reactions, immediately stop infusion and discontinue cetuximab permanently. Epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen should be available for reactions. Mild to moderate reactions (chills, fever, dyspnea) may be managed by slowing rate of infusion and administration of antihistamines.
  • Assess for onset or worsening of pulmonary symptoms. Interrupt therapy to determine nature of symptoms. If interstitial lung disease is confirmed, discontinue cetuximab and treat appropriately.
  • Assess for dermatologic toxicities (acneform rash, skin drying and fissuring, inflammatory and infectious sequelae [blepharitis, cheilitis, cellulitis, cyst]). Treat symptomatically. Acneform rash usually occurs within initial 2 wk of therapy and resolves following cessation, but may continue up to 28 days following therapy.
  • Lab Test Considerations: genetic implication Determine K-Ras mutation and EGFR-expression status using FDA-approved tests prior to initiating treatment. Only patients whose tumors are K-Ras mutation­negative (wild-type) should receive cetuximab.
  • Lab Test Considerations: May cause anemia and leukopenia.
    • Monitor serum electrolytes, especially serum magnesium, potassium, and calcium, closely during and periodically for at least 8 wk following infusion. May cause hypomagnesemia, hypocalcemia, and hypokalemia; may occur from days to months after initiation of therapy. May require electrolyte replacement. May lead to cardiopulmonary arrest and sudden death.

Potential Nursing Diagnoses

Ineffective breathing pattern (Adverse Reactions)
Impaired skin integrity (Adverse Reactions)

Implementation

  • Premedicate with histamine1 antagonist (diphenhydramine 50 mg) 30–60 min prior to first dose; base subsequent administration on presence and severity of infusion reactions.
  • Administer through a low protein binding 0.22-micrometer in-line filter placed as proximal to patient as possible. Solution should be clear and colorless and may contain a small amount of white amorphous cetuximab particles. Do not shake or dilute.
    • Can be administered via infusion pump or syringe pump. Cetuximab should be piggybacked to the patient's infusion line.
    • Observe patient for 1 hr following infusion.
  • Intravenous Administration
  • pH: 7.0–7.4.
  • Intermittent Infusion: For administration via infusion pump: Draw up volume of a vial using vented spike needle or other transfer device. Transfer to a sterile evacuated container or bag. Repeat with new needle for each vial until calculated volume is in container. Affix infusion line and prime with cetuximab before starting infusion.
    • For administration via syringe pump: Draw up volume of a vial using sterile syringe attached to an appropriate vented spike needle. Place syringe into syringe driver of a syringe pump and set rate. Connect infusion line and prime with cetuximab. Use a new needle and filter for each vial. Diluent: Do not dilute.Concentration: 2 mg/mL.
  • Rate: Administer over 2 hr at a rate not to exceed 10 mg/min. Use 0.9% NaCl to flush line at end of infusion.
    • Cetuximab infusion must be completed 1 hr prior to FOLFIRI (irinotecan, 5-fluoruracil, leucovorin) regimen. May infuse subsequent weekly infusions over 1 hr.

Patient/Family Teaching

  • Explain purpose of cetuximab and potential side effects to patient.
  • Advise patient to report dermatologic changes and signs and symptoms of infusion reactions (fever, chills, or breathing problems) promptly.
  • Caution patient to wear sunscreen and hats and limit sun exposure during therapy during and for 2 mo following last dose of cetuximab.
  • Advise both female and male patients to use adequate contraception during and for 6 mo following therapy and to avoid breast feeding during and for 2 mo following therapy.

Evaluation/Desired Outcomes

  • Decreased tumor growth and spread.

Erbitux

(ûr′bĭ-tŭks)
A trademark for the drug cetuximab.

Erbitux

a trademark for cetuximab.
References in periodicals archive ?
We are pleased that ERBITUX is now commercially available as a treatment option for colorectal cancer patients in Japan, where this type of cancer is the second most prevalent and afflicts nearly 100,000 individuals each year," said Joseph I.
New York), the biotech company controlled by billionaire Carl Icahn, said second-quarter profit fell 14% as sales declined for its only marketed product, the Erbitux cancer drug.
With this additional funding, the companies will seek to add numerous Phase II and Phase III clinical trials that will further explore the activity of ERBITUX in a wide variety of therapeutic settings.
A preliminary review of the data reveals that a greater proportion of patients randomized to the FOLFIRI-only arm went on to receive ERBITUX following the development of disease progression compared to patients randomized to FOLFIRI plus ERBITUX.
New York) fell last week after the biopharmaceutical company said its lung-cancer treatment candidate Erbitux failed to meet its primary goal in a late-stage lung cancer trial.
Known as BMS CA225-099, this study included more than 600 patients from the United States and Canada and was one of several clinical trials intended to establish the role of ERBITUX in the treatment of advanced NSCLC.
Erbitux has already obtained market authorization in Switzerland, the US, Mexico, Argentina, Chile, Iceland, Norway, the European Union, Peru, Australia, Croatia and Singapore for the use in combination with irinotecan in patients with EGFR-expressing metastatic colorectal cancer who have failed prior irinotecan therapy.
The first set of data from the EPIC trial demonstrated that progression-free survival and tumor shrinkage increased significantly when Erbitux was administered to this patient population.
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the commercialization of ERBITUX in Japan.
The sBLA submission is based on data from the randomized Phase 3 EXTREME (ERBITUX in first-line Treatment of REcurrent or MEtastatic head and neck cancer) study1 investigating the efficacy of ERBITUX in combination with platinum-based chemotherapy in the first-line treatment of patients with recurrent or metastatic SCCHN.
I think Erbitux may have reached a point now where it's finally worth it to Bristol to make an offer.
There can be no guarantee that the clinical development of the use of ERBITUX for the treatment of other tumor types will be successful.