Erbitux included in United States Pharmacopeia-Drug Information (USP-DI) compendium:
[This will facilitate off-label sales in head-and-neck cancer, which is listed below as one of the indications where Erbitux (Cetuximab) is efficacious. Sorry, no URL link is available for this document.]
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USP-DI
Revised: 08/18/2005
Developed: 04/05/2004
CETUXIMAB Systemic
VA CLASSIFICATION (Primary): AN900
For a list of brand names for the articles in this monograph, refer to the General Index. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category: Antineoplastic; Monoclonal antibody.
Indications Accepted
Carcinoma, colorectal (treatment)—Cetuximab, used in combination with irinotecan, is indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. Cetuximab, used as a monotherapy, is also indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.
Malignant tumor of head and neck, relapsed/refractory (treatment) —Cetuximab has demonstrated activity as a single agent and in combination with radiotherapy or platinum-based chemotherapy in the treatment of head and neck cancer. Overall response rates and median survival ranged from 6% to 26% and 5.8 to 9.2 months, respectively. Cetuximab has a good safety profile with the most common associated adverse events being skin reactions (acne-like rash).
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—Recombinant, human/mouse chimeric monoclonal antibody produced in mammalian (murine myeloma) cell culture.
Molecular weight—Cetuximab: approximately 152 kilodaltons . pH—7.0 to 7.4
Mechanism of action/Effect:
Over expression of the epidermal growth factor receptor (EGFR) has been detected in many human cancers including those of the colon and rectum. Cetuximab specifically binds to EGFR blocking 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. Cetuximab inhibits growth and survival of tumor cells that over-express the EGFR.
Absorption: The area under the concentration time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 20 to 400 mg/m2.
Distribution: Volume of distribution (VolD)—2 to 3 L/m2
Half-life: Elimination—After the third dose; 114 hours (range 75–188)
Peak serum concentration:
Following 400 mg/m2 IV dose: 184 µg/mL (range: 92–327 µg/mL)
Following 250 mg/m2 IV dose: 140 µg/mL (range: 120–170 µg/mL)
Following 400 mg/m2 initial dose/250 mg/m2 weekly dose: 168 to 235 µg/mL.
Precautions to Consider
Carcinogenicity/Mutagenicity
Long term carcinogenicity studies in animals have not been done. No mutagenic or clastogenic potential was observed in the Salmonella-Escherichia coli (Ames) assay or in the in-vivo rat micronucleus test.
Pregnancy/Reproduction
Fertility—In a 39 week toxicity study in cynomolgus monkeys given doses of 0.4 to 4 times the human dose (based on total body surface area) results showed a tendency for impairment of menstrual cycling in female monkeys. The findings included higher incidences of irregularity or absence of cycles in comparison to control animals. There were no marked differences in serum testosterone levels, sperm counts, viability and motility of sperm in male monkeys treated with cetuximab compared to control monkeys. It is not known if cetuximab can impair fertility in humans.
Pregnancy—Adequate and well controlled studies in humans have not been done. However, human IgG1 is known to cross the placental barrier; therefore cetuximab has the potential to be transmitted from the mother to the fetus. EGFR has been implicated in the control of prenatal development and may be essential for the normal organogenesis, proliferation, and differentiation in the developing embryo. It is not known whether cetuximab can cause fetal harm when administered to a pregnant woman.
FDA Pregnancy Category C
Breast-feeding
It is not known whether cetuximab is distributed into human breast milk . However, human IgG1 is distributed into human milk, although the potential for absorption and consequent harm to the infant is unknown. It is recommended that women treated with cetuximab not breast-feed for 60 days following the last dose of cetuximab
Pediatrics
Safety and efficacy in pediatric patients have not been established .
Geriatrics
Appropriate studies performed to date have not demonstrated age-specificproblems that would limit the usefulness of cetuximab in the elderly.
Pharmacogenetics
In a population pharmacokinetic analysis female patients were found to have had a 25% lower intrinsic clearance of cetuximab than male patients.
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist:
» Hypersensitivity to cetuximab, murine proteins, or any component of the product
(caution should be used when administering cetuximab)
» Fibrotic lung disease, pre-existing, or
(administration of cetuximab may exacerbate this disease)
» Radiation therapy
(incidence and severity of cutaneous reactions with combined modality therapy may be additive)
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance): Inflammation, development of or Infection, development of (patients developing dermatologic toxicities should be monitored for the development of inflammatory or infectious sequelae; may require a dose modification, in the case of severe acneform rash, or treatment with topical and/or oral antibiotics; topical corticosteroids are not recommended) Pulmonary symptoms, acute onset or worsening (cetuximab should be interrupted for a prompt investigation, if interstitial lung disease is confirmed cetuximab should be discontinued and the patient treated appropriately)
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)— not necessarily inclusive:
Immunogenicity-development of non-neutralizing antibodies occurred in approximately 5% of the patients during clinical studies. These antibodies did not impact the safety or antitumor activity of cetuximab.
Infusion Reactions-severe infusion reactions occurred with the administration of cetuximab in approximately 3% of patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions were associated with the first infusion. Severe infusion reactions are characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension) and require immediate interruption of the cetuximab infusion and permanent discontinuation from further treatment.
Those indicating need for medical attention
Incidence more frequent
Acneform rash (blemishes on the skin, pimples); anemia (pale skin; troubled breathing with exertion; unusual bleeding or bruising; unusual tiredness or weakness); dyspnea (shortness of breath ; difficult or labored breathing; tightness in chest; wheezing); fever; infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination); infusion reaction (dizziness; fever or chills; facial swelling; headache; nausea or vomiting; shortness of breath; skin rash, weakness), or peripheral edema (bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet, unusual weight gain or loss) Incidence less frequent
Dehydration (confusion; decreased urination; dizziness; dry mouth; fainting; increase in heart rate; lightheadedness; rapid breathing; sunken eyes; thirst; unusual tiredness or weakness; wrinkled skin); kidney failure; leukopenia (black, tarry stools; chest pain; chills; cough; fever; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness);
pulmonary embolism (anxiety; chest pain; cough; fainting; fast heartbeat; sudden shortness of breath or troubled breathing; dizziness or lightheadedness),
or sepsis (chills; confusion; dizziness; lightheadedness; fainting fast heartbeat; fever; rapid, shallow breathing) Incidence rare
Interstitial lung disease (cough; difficult breathing; fever; shortness of breath)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Abdominal pain (stomach pain); alopecia (hair loss, thinning of hair); anorexia (loss of appetite, weight loss); asthenia (lack or loss of strength); back pain; conjunctivitis (redness, pain, swelling of eye, eyelid, or inner lining of eyelid burning; dry or itching eyes; discharge; excessive tearing); cough increased; constipation (difficulty having a bowel movement (stool)); depression (discouragement; feeling sad or empty; irritability; lack of appetite; loss of interest or pleasure; tiredness; trouble concentrating; trouble sleeping); diarrhea; dyspepsia (acid or sour stomach; belching; heartburn; indigestion; stomach discomfort upset or pain); headache; insomnia (sleeplessness; trouble sleeping; unable to sleep); nail disorder (discoloration and swelling of fingernails or toenails); nausea; pain; pruritus (itching skin); stomatitis (swelling or inflammation of the mouth); vomiting, or weight loss
Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Treatment of overdose
Supportive care— There is no known specific antidote to cetuximab. Treatment is generally symptomatic and supportive. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cetuximab (Systemic). In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to cetuximab, murine proteins or any of its ingredients
Pregnancy—Human IgG1 crossed the placenta; therefore, cetuximab has the potential to be transmitted from the mother to the developing fetus.
Risk-benefit should be considered during pregnancy
Breast-feeding—Not recommended for 60 days following the last dose of cetuximab because of the risk of absorption and consequent harm to the infant
Pharmacogenetics—Female patients were found to have had a 25% lower intrinsic clearance of cetuximab than male patients.
Other medical problems, especially fibrotic lung disease, pre-existing
Proper use of this medication
» Proper injection technique
» Proper dosing
Discuss with physician
» Proper storage
Precautions while using this medication
» Importance of use of sunscreen, and hat and limiting sun exposure while receiving cetuximab.
Side/adverse effects
Signs of potential side effects, especially acneform rash, anemia, dehydration, dyspnea, fever, infection, infusion reaction, kidney failure, interstitial lung disease, leukopenia, peripheral edema, pulmonary embolism, and sepsis
General Dosing Information
Cetuximab is recommended for administration by intravenous infusion only. Rapid intravenous (push or bolus) administration is not recommended . It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving cetuximab as sunlight can exacerbate any skin reactions that may occur.
Treatment of adverse effects
It is recommended that medications for hypersensitivity reactions (e.g., epinephrine, intravenous antihistamines, bronchodilators, corticosteroids) and oxygen be readily available for each administration of cetuximab . Premedication with intravenous diphenhydramine may attenuate the hypersensitivity reaction and should be considered before each dose of cetuximab . If the patient experiences a mild or moderate infusion reaction, the infusion rate should be permanently reduced by 50%. If the patient experiences a severe infusion reaction, cetuximab should be immediately and permanently discontinued and patients should then receive appropriate medical care until the complete resolution of all signs and symptoms. A 1–hour observation period of the patient is recommended following the cetuximab infusion.
Parenteral Dosage Forms
CETUXIMAB FOR INJECTION
Usual Adult Dose:
Carcinoma, colorectal —
Single therapy or concomitant therapy with irinotecan : Intravenous infusion, 400 mg/m2 as an initial loading dose administered as a 120–minute IV infusion, then a weekly maintenance dose of 250 mg/m2 infused over 60 minutes. Patients with dermatologic toxicity occurrences:
• First occurrence: delay infusion 1 to 2 weeks, if improvement continue at 250 mg/m2; if no improvement discontinue therapy.
• Second occurrence: delay infusion 1 to 2 weeks, if improvement continue at 200 mg/m2; if no improvement discontinue therapy.
• Third occurrence: delay infusion 1 to 2 weeks, if improvement continue at 150 mg/m2; if no improvement discontinue therapy.
• Fourth occurrence: discontinue therapy
Usual Pediatric Dose:
Safety and efficacy have not been established .
Usual Geriatric Dose:
See Usual adult dose.
Strength(s) usually available:
U.S.—100 mg of cetuximab per 50-mL vial of sterile, preservative-free injectableliquid (Rx) [Erbitux (sodium chloride, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, water for injection)].
Packaging and storage:
Store between 2 and 8 _ C (36 and 46 _ F). DO NOT FREEZE.
Preparation of dosage form:
Do not shake or dilute contents of manufacturer supplied vial.
Infusion pump—
Each single use vial of cetuximab contains 50 mL of 2 mg/mL solution. The cetuximab solution should be clear and colorless and may contain as mall amount of visible white particulate. Draw up the volume from thevial using a sterile syringe attached to an appropriate needle (a vented spike or other appropriate transfer device may be used) and fill into a sterile evacuated container or bag such as glass containers, polyolefin bags, DEHP plasticized PVC bags, or PVC bags. Repeat until the calculated volume has been put into the container. Use a new needle for each vial. Cetuximab must be administered through a low protein binding 0.22 micrometer in-line filter. Affix the infusion line and prime it with cetuximab before starting the infusion. The maximum infusion rate should not exceed 5 mL/min. To flush the line at the end of infusion use 0.9% saline solution. Discard any unused portions of the cetuximab vials. See the manufacturer’s package insert for instructions.
Syringe pump—
Each single use vial of cetuximab contains 50 mL of 2 mg/mL solution. The cetuximab solution should be clear and colorless and may contain a small amount of visible white particulate. Draw up the volume from the vial using a sterile syringe attached to an appropriate needle and place the syringe into the syringe driver of a syringe pump and set the rate. Administered through a low protein binding 0.22 micrometer in-line filter rated for syringe pump use. Affix the infusion line and prime it with cetuximab before starting the infusion. Repeat until the calculated volume has been infused. Use a new needle and filter for each vial. The maximum infusion rate should not exceed 5 mL/min. To flush the line at the end of infusion use 0.9% saline solution. Discard any unused portions of the cetuximab vials. See the manufacturer’s package insert for instructions.
Cetuximab should be piggybacked to the patient’s infusion line.
Stability:
Preparations of cetuximab in infusion containers are stable for up to 12 hours at 2 to 8 _ C (36 to 46_ F) and up to 8 hours at controlled room temperature (20 to 25 _ C; 68 to 77 _ F).
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