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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    BOXED WARNING

    History of tick bites, infusion-related reactions, murine protein hypersensitivity, red meat hypersensitivity

    Cetuximab should be used with caution in patients with known murine protein hypersensitivity or hypersensitivity to any component of the product. Severe and fatal infusion-related reactions requiring medical intervention and immediate, permanent discontinuation of cetuximab therapy may occur and are characterized by the rapid onset of airway obstruction (e.g., acute bronchospasm, stridor, hoarseness), hypotension, and shock. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat hypersensitivity/allergy, or in the presence of IgE antibodies directed against galactose-alpha-1, 3-galactose (alpha-gal). Monitor patients for at least 1 hour after administration of cetuximab in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen); longer observation periods may be required in patients who have experienced an infusion reaction. Approximately 90% of severe infusion reactions occurred with the first infusion, despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion. Premedicate with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine) prior to the first dose or subsequent doses as deemed necessary. An interruption of the infusion and adjustments to the infusion rate are recommended if a mild to moderate infusion reaction occurs; severe infusion reactions necessitate immediate interruption and permanent discontinuation of therapy.

    Cardiac arrest, cardiac arrhythmias, cardiac disease, coronary artery disease, electrolyte imbalance, heart failure, hypocalcemia, hypokalemia, hypomagnesemia, radiation therapy, respiratory arrest

    Cardiac arrest, respiratory arrest, and/or sudden death have occurred in patients receiving cetuximab. Cautious use of cetuximab in combination with either radiation therapy or platinum-based therapy with 5-FU is warranted for head and neck cancer patients with a history of cardiac disease, specifically coronary artery disease, congestive heart failure, or cardiac arrhythmias. Although the etiology of these events is unknown, electrolyte imbalance may be a risk factor for serious cardiac events such as arrhythmia. Because the onset of electrolyte abnormalities may be days to months after the initiation of cetuximab therapy, closely monitor serum electrolytes for hypomagnesemia, hypocalcemia, and hypokalemia during treatment and for at least 8 weeks after completion of cetuximab therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-EGFR monoclonal antibody
    Used for EGFR-positive, Ras wild-type, metastatic colorectal cancer and locally advanced or metastatic head and neck cancer
    Can cause serious infusion reactions and cardiopulmonary arrest; dermatologic toxicities are common

    COMMON BRAND NAMES

    Erbitux

    HOW SUPPLIED

    Erbitux Intravenous Inj Sol: 1mL, 2mg

    DOSAGE & INDICATIONS

    For the treatment of KRAS wild-type metastatic colorectal cancer.
    NOTE: Cetuximab is not indicated for the treatment of RAS mutant colorectal cancer or when the results of RAS mutation tests are unknown. The absence of a RAS mutation should be confirmed by an FDA approved test prior to starting therapy.
    NOTE: The serine-threonine kinase BRAF is the principal effector of KRAS. The introduction of the mutant BRAF V600E allele may impair therapeutic response to EGFR inhibitors. Mutant BRAF may be present in wild-type KRAS.
    For the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) as a single agent after failure of both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based chemotherapy.
    NOTE: In the clinical trials, patients were required to have immunohistochemical evidence of positive EGFR expression from primary tumor or metastatic tumor site using the DakCytomation EGFR pharmDx test kit. Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. EGFR expression status should be determined by an FDA approved test prior to starting therapy.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 120 minutes (maximum infusion rate: 10 mg/minute) on day 1, followed by weekly infusions of 250 mg/m2 IV over 60 minutes (maximum infusion rate: 10 mg/minute) until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial of patients with previously treated, recurrent mCRC, cetuximab monotherapy (n = 287) significantly improved median overall survival compared with best supportive care (n = 285) (6.1 months vs. 4.6 months; HR 0.77; p = 0.0046); in the subset of patients with KRAS wild-type tumors (n = 245), cetuximab monotherapy also improved overall survival (8.6 months vs. 5 months; HR 0.63).

    For the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy.
    NOTE: In the clinical trials, patients were required to have immunohistochemical evidence of positive EGFR expression from primary tumor or metastatic tumor site using the DakCytomation EGFR pharmDx test kit. Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. EGFR expression status should be determined by an FDA approved test prior to starting therapy.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 120 minutes (maximum infusion rate: 10 mg/minute) on day 1, followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate: 10 mg/minute) until disease progression or unacceptable toxicity, in combination with irinotecan. Multiple dosage regimens of irinotecan have been studied in combination with cetuximab, including irinotecan 180 mg/m2 IV once every 3 weeks; irinotecan 125 mg/m2 IV once weekly for 4 weeks out of 6; and, irinotecan 350 mg/m2 IV once every 3 weeks. In a multicenter clinical trial of patients with recurrent mCRC (tumor specimens not available for KRAS testing), patients were treated with cetuximab alone (n = 111) or cetuximab plus irinotecan (n = 218); in the irinotecan arm, the irinotecan dose and schedule was the same as the patient had previously failed. Of these patients, approximately 2/3 had previously failed oxaliplatin treatment. The objective response rate was 23% for patients treated with cetuximab plus irinotecan, versus 11% for those who received cetuximab alone; the median duration of response was 5.7 months vs. 4.2 months, and the median time to progression was 4.1 months versus 1.5 months, respectively. Response rates to combination therapy and monotherapy were similar for irinotecan refractory patients and patients who had failed both irinotecan and oxaliplatin.

    For the first-line treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin).
    NOTE: In the clinical trials, patients were required to have immunohistochemical evidence of positive EGFR expression from primary tumor or metastatic tumor site using the DakCytomation EGFR pharmDx test kit. Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. EGFR expression status should be determined by an FDA approved test prior to starting therapy.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute), administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity in combination with the FOLFIRI regimen (irinotecan 180 mg/m2 IV over 30 to 90 minutes on day 1 followed by L-leucovorin 200 mg/m2 IV over 2 hours (or racemic leucovorin 400 mg/m2 IV), followed by 5-fluorouracil 400 mg/m2 IV given as a bolus then 2,400 mg/m2 as a 46-hour continuous IV infusion, repeated every 14 days. In a multicenter, randomized, open-label, phase III clinical trial of patients with mCRC, unselected for KRAS mutational status, first-line treatment with cetuximab plus FOLFIRI (n = 599) significantly improved the primary endpoint of median progression-free survival (PFS) compared with FOLFIRI alone (n = 599) (8.9 months vs. 8 months; HR = 0.851; p = 0.0479); the overall response rate was 46.9% vs. 38.7%, respectively. Median overall survival was 19.9 months in the cetuximab group compared with 18.6 months in patients treated with FOLFIRI alone. In a subgroup analysis of patients with known KRAS mutational status (KRAS negative, n = 666; KRAS positive, n = 397), the addition of cetuximab to FOLFIRI therapy significantly improved the median PFS (9.9 vs. 8.4 months; HR = 0.696; p = 0.0012) and overall survival (23.5 vs. 20 months; HR = 0.796; p = 0.0093) times only in patients with KRAS wild type disease.

    For the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC), in combination with mFOLFOX6 (leucovorin, oxaliplatin, 5-fluorouracil)†.
    NOTE: Response rates do not correlate with either the percentage of EGFR-positive cells or the intensity of EGFR expression.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute), administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity in combination with the mFOLFOX6 regimen (oxaliplatin 85 mg/m2 IV concurrently via y-site with leucovorin 400 mg/m2 IV over 2 hours, followed by 5-fluorouracil 400 mg/m2 IV given as a bolus and then 2,400 mg/m2 as a 46-hour continuous IV infusion, repeated every 14 days). First-line treatment with cetuximab plus modified FOLFOX (mFOLFOX) 4 or 6 significantly improved objective response rates (ORR) in patients with KRAS WT mCRC in two randomized clinical trials. The benefit to progression-free survival (PFS) was small to nonsignificant, and a benefit to overall survival (OS) was not demonstrated. Skin and gastrointestinal toxicities were increased in patients treated with cetuximab. Total exposure (AUC) to 5-FU was similar when administered as two 22-hour infusions of 600 mg/m2, as in FOLFOX4, or as a single 46-hour infusion of 2,400 mg/m2, as in mFOLFOX6 in a pharmacokinetic study.

    For the treatment of BRAF mutation-positive, RAS wild-type, metastatic colorectal cancer, in combination with irinotecan and vemurafenib†.
    Intravenous dosage
    Adults

    500 mg/m2 IV plus irinotecan (180 mg/m2 IV) on day 1, every 14 days, in combination with vemurafenib 960 mg by mouth twice daily, until disease progression or unacceptable toxicity. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 allele. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label phase 2 clinical trial, treatment with vemurafenib, cetuximab and irinotecan significantly improved the median progression-free survival (PFS) over treatment with cetuximab plus irinotecan, without vemurafenib (4.4 months vs. 2 months) in patients with BRAF V600E mutation-positive, RAS wild-type, metastatic colorectal cancer (mCRC) received treatment with cetuximab and irinotecan, with or without vemurafenib (a BRAF inhibitor). Approximately 50% of patients in the control arm crossed over to receive vemurafenib after progression; the rate of disease control was also significantly improved in the vemurafenib arm (67% vs. 22%).

    For the treatment of head and neck cancer.
    NOTE: Pretreatment assessment for evidence of EGFR expression is not required for patients with squamous cell cancer of the head and neck.
    For the first-line treatment of locally or regionally advanced squamous cell head and neck cancer, in combination with radiation therapy.
    NOTE: Progression-free survival was not improved when cetuximab was added to radiation therapy plus cisplatin for the treatment of locally advanced squamous cell head and neck cancer in a controlled study (n = 940); grade 3 and 4 toxicity and adverse reactions with fatal outcomes occurred more often in cetuximab-treated patients in this study.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 2 hours (maximum infusion rate: 10 mg/minute) as an initial loading dose 1 week prior to initiation of a course of radiation therapy, followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute) for the duration of radiation therapy (6 to 7 weeks). Complete cetuximab administration 1 hour before radiation therapy. In a randomized clinical trial of patients with locally or regionally advanced squamous cell head and neck cancer (n = 424), treatment with cetuximab plus radiation therapy significantly improved the median duration of locoregional control (24.4 months vs. 14.9 months) and overall survival (49 months vs. 29.3 months) compared with radiation therapy alone.

    For the treatment of recurrent or metastatic squamous cell cancer of the head and neck when prior platinum-based therapy has failed, as monotherapy.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 2 hours (maximum infusion rate: 10 mg/minute) on day 1 followed by weekly infusions of 250 mg/m2 IV over 60 minutes (maximum infusion rate: 10 mg/minute) until disease progression or unacceptable toxicity. In a multicenter, noncomparative trial of patients with recurrent or metastatic squamous cell head and neck cancer with progression within 30 days of platinum-based chemotherapy (n = 103), treatment with cetuximab resulted in an objective response rate of 13% for a median duration of 5.8 months.

    For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in combination with cisplatin†.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on day 1, followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute), in combination with cisplatin (100 mg/m2 IV on day 1), repeated every 4 weeks until disease progression or for 2 treatment cycles after the achievement of a complete response. In a phase 3 clinical trial of patients with recurrent or metastatic head and neck cancer (n = 117), neither progression-free survival (4.2 months vs. 2.7 months) nor overall survival (9.2 months vs. 8 months) were significantly improved with the addition of cetuximab; however the objective response rate was significantly improved (26% vs. 10%).

    For the first-line treatment of recurrent locoregional disease or metastatic squamous cell head and neck cancer, in combination with platinum-based chemotherapy and 5-fluorouracil (5-FU).
    Intravenous dosage
    Adults

    400 mg/m2 IV over 2 hours (maximum infusion rate: 10 mg/minute) as an initial loading dose on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute), administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity, in combination with up to 6 cycles of platinum-based chemotherapy plus 5-FU (cisplatin 100 mg/m2 IV or carboplatin AUC 5 IV on day 1, plus 5-FU 1,000 mg/m2 IV on days 1, 2, 3, and 4, repeated every 3 weeks). In a randomized, open-label clinical trial of patients with no prior therapy for recurrent locoregional disease or metastatic head and neck cancer (n = 442), the addition of cetuximab to platinum-based chemotherapy plus 5-FU significantly improved median overall survival (OS) (10.1 months vs. 7.4 months), median progression-free survival (PFS) (5.5 months vs. 3.3 months), and objective response rate (35.6% vs. 19.5%) compared with chemotherapy alone. In exploratory subgroup analyses by initial platinum therapy, the difference in median OS was 3.3 months for patients receiving cetuximab plus cisplatin/5-FU and 1.4 months for patients receiving cetuximab plus carboplatin/5-FU compared to platinum/5-FU alone; the difference in median PFS with the addition of cetuximab compared to chemotherapy alone was 2.1 months and 1.7 months, respectively.

    For the first-line treatment of advanced non-small cell lung cancer (NSCLC)† in combination with cisplatin and vinorelbine.
    Intravenous dosage
    Adults

    400 mg/m2 IV over 2 hours (maximum infusion rate: 10 mg/minute) the first week with subsequent weekly infusions of 250 mg/m2 IV over 60 minutes (maximum infusion rate: 10 mg/minute) until disease progression or unacceptable toxicity, in combination with up to 6 cycles of cisplatin (80 mg/m2 IV) on day 1 and vinorelbine (25 mg/m2 IV) on days 1 and 8 repeated every 21 days. In a phase 3 trial of 1,125 patients with advanced EGFR-detectable non-small cell lung cancer, the addition of cetuximab to the doublet cisplatin and vinorelbine significantly improved the primary end point overall survival (11.3 months vs. 10.1 months), response rate (36% vs. 29%), and time to treatment failure (4.2 months vs. 3.7 months). Patients who received cetuximab had a significantly higher incidence of febrile neutropenia (22% vs. 15%). A subgroup analysis of patients who developed a rash within the first 21 days of treatment, revealed a positive correlation between outcomes and the development of a first cycle rash. Multiple previous trials of EGFR-targeted tyrosine kinase inhibitors in combination with chemotherapy in the front-line treatment of patients with non-small cell lung cancer have generally shown no additional survival benefit with the addition of the tyrosine kinase inhibitor. Consideration should be given to the use of molecular markers to aid in patient selection as further information about this practice continues to become available.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Only administer in a hospital or clinic setting with full resuscitation equipment and under the supervision of a physician experienced with chemotherapy administration.
    Premedicate 30 to 60 minutes prior to the first dose or subsequent doses with an IV H1 antagonist (e.g., diphenhydramine 50 mg) as necessary.
    Do not shake or further dilute vial. Do not mix with other medications.
    Administer only as an IV infusion via a controlled rate IV infusion pump or syringe pump at a maximum rate of 10 mg/minute; do not administer as a bolus injection or as an intravenous push.
    Administer with low-protein binding 0.22 micrometer in-line filter.
    Following completion of infusion, monitor patients for at least one hour. Appropriate medical resources for the treatment of severe infusion reactions should be available during cetuximab infusion (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen). For individuals who experience infusion-related reactions, a prolonged observation period may be required to confirm resolution.

    STORAGE

    Erbitux:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Preparations of product in infusion containers are stable up to 12 hours at 36 to 46 degrees F and up to 8 hours at 68 to 77 degrees F
    - Reconstituted product is stable for up to 8 hours at room temperature (77 degrees F)
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    History of tick bites, infusion-related reactions, murine protein hypersensitivity, red meat hypersensitivity

    Cetuximab should be used with caution in patients with known murine protein hypersensitivity or hypersensitivity to any component of the product. Severe and fatal infusion-related reactions requiring medical intervention and immediate, permanent discontinuation of cetuximab therapy may occur and are characterized by the rapid onset of airway obstruction (e.g., acute bronchospasm, stridor, hoarseness), hypotension, and shock. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat hypersensitivity/allergy, or in the presence of IgE antibodies directed against galactose-alpha-1, 3-galactose (alpha-gal). Monitor patients for at least 1 hour after administration of cetuximab in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen); longer observation periods may be required in patients who have experienced an infusion reaction. Approximately 90% of severe infusion reactions occurred with the first infusion, despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion. Premedicate with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine) prior to the first dose or subsequent doses as deemed necessary. An interruption of the infusion and adjustments to the infusion rate are recommended if a mild to moderate infusion reaction occurs; severe infusion reactions necessitate immediate interruption and permanent discontinuation of therapy.

    Pneumonitis, pulmonary disease

    Use cetuximab with caution in patients with pre-existing pulmonary disease, as interstitial lung disease (ILD)/pneumonitis has been reported with cetuximab therapy, including one death. Monitor patients and interrupt cetuximab treatment for acute onset or worsening of pulmonary symptoms. Permanently discontinue cetuximab if a diagnosis of ILD is confirmed.

    Infection, sunlight (UV) exposure

    During clinical trials, cetuximab therapy was associated with dermatologic toxicities including acneiform rash as well as life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing. Subsequent to the development of severe dermatologic toxicities, complications including infection, S. aureus sepsis, and skin abscesses requiring incision and drainage have also been reported. Monitor patients for dermatologic toxicities and infectious sequelae; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. It is recommended that patients limit sunlight (UV) exposure by wearing sunscreen and hats while receiving cetuximab and for 2 months after the last dose, as UV exposure can exacerbate any skin reaction that may occur.

    Cardiac arrest, cardiac arrhythmias, cardiac disease, coronary artery disease, electrolyte imbalance, heart failure, hypocalcemia, hypokalemia, hypomagnesemia, radiation therapy, respiratory arrest

    Cardiac arrest, respiratory arrest, and/or sudden death have occurred in patients receiving cetuximab. Cautious use of cetuximab in combination with either radiation therapy or platinum-based therapy with 5-FU is warranted for head and neck cancer patients with a history of cardiac disease, specifically coronary artery disease, congestive heart failure, or cardiac arrhythmias. Although the etiology of these events is unknown, electrolyte imbalance may be a risk factor for serious cardiac events such as arrhythmia. Because the onset of electrolyte abnormalities may be days to months after the initiation of cetuximab therapy, closely monitor serum electrolytes for hypomagnesemia, hypocalcemia, and hypokalemia during treatment and for at least 8 weeks after completion of cetuximab therapy.

    KRAS mutations

    Studies have demonstrated the benefit of cetuximab in KRAS wild-type metastatic colorectal cancer (mCRC) only; cetuximab is not effective and is not indicated for the treatment of RAS mutant mCRC (KRAS mutations or NRAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146)). Assess KRAS mutational status using FDA-approved tests prior to treating mCRC patients with cetuximab.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during cetuximab treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant women, cetuximab can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving cetuximab should be apprised of the potential hazard to the fetus. In an animal reproduction study, IV administration of cetuximab (1 to 4 times the recommended human dose based on BSA) to pregnant cynomolgus monkeys during organogenesis resulted in an increased incidence of embryolethality and abortion. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryofetal/postnatal survival and development. Reduction or elimination of embryofetal or maternal EGFR signaling can prevent implantation, can cause embryofetal loss during various stages of gestation through effects on placental development, and can cause developmental anomalies and early death in surviving fetuses. Disruption or depletion of EGFR in animal models results in impaired placental, lung, cardiac, skin, and neural development.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during cetuximab treatment. Cetuximab can cause loss of pregnancy if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 2 months after treatment with cetuximab. Females of reproductive potential should undergo pregnancy testing prior to initiation of cetuximab. Women who become pregnant while receiving cetuximab should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of cetuximab on human fertility, female infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from cetuximab, advise women to discontinue breast-feeding during treatment and for 2 months after the final dose. It is not known whether cetuximab is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    fatigue / Early / 0-31.0
    neutropenia / Delayed / 0-31.0
    diarrhea / Early / 2.0-22.0
    acneiform rash / Delayed / 1.0-18.0
    hypomagnesemia / Delayed / 5.0-17.0
    leukopenia / Delayed / 0-17.0
    dyspnea / Early / 0-16.0
    rash / Early / 5.0-16.0
    malaise / Early / 0-16.0
    asthenia / Delayed / 0-16.0
    infection / Delayed / 1.0-11.0
    weight loss / Delayed / 1.0-11.0
    hypokalemia / Delayed / 0-7.0
    nausea / Early / 2.0-6.0
    dehydration / Delayed / 5.0-6.0
    confusion / Early / 0-6.0
    infusion-related reactions / Rapid / 2.0-5.0
    vomiting / Early / 2.0-5.0
    anorexia / Delayed / 3.0-5.0
    hypocalcemia / Delayed / 0-4.0
    bone pain / Delayed / 0-4.0
    cardiac arrest / Early / 2.0-3.0
    fever / Early / 0-3.0
    pharyngitis / Delayed / 0-3.0
    constipation / Delayed / 0-3.0
    stomatitis / Delayed / 1.0-3.0
    arthralgia / Delayed / 0-3.0
    respiratory arrest / Rapid / 2.0-2.0
    cough / Delayed / 0-2.0
    pruritus / Rapid / 0-2.0
    acne vulgaris / Delayed / 0-2.0
    headache / Early / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    chills / Rapid / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    anxiety / Delayed / 1.0-1.0
    conjunctivitis / Delayed / 0-1.0
    heart failure / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    hypertensive crisis / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
    aseptic meningitis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    keratitis / Delayed / Incidence not known

    Moderate

    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-15.0
    depression / Delayed / 0-14.0
    antibody formation / Delayed / 0-5.0
    angina / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    erythema / Early / Incidence not known
    skin erosion / Delayed / Incidence not known
    blepharitis / Early / Incidence not known

    Mild

    xerosis / Delayed / 14.0-57.0
    dyspepsia / Early / 14.0-16.0
    alopecia / Delayed / 0-12.0
    xerostomia / Early / 0-12.0
    dysgeusia / Early / 0-10.0
    diaphoresis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    syncope / Early / Incidence not known
    tremor / Early / Incidence not known
    hoarseness / Early / Incidence not known
    flushing / Rapid / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    hypertrichosis / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    telangiectasia / Delayed / Incidence not known
    cheilitis / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cisplatin: (Major) Cetuximab is not indicated for the treatment of squamous cell cancer of the head and neck (SCCHN) in combination with radiation and cisplatin due to the risk of increased serious adverse reactions. In a controlled study of patients with locally advanced SCCHN (n = 940), treatment with cetuximab in combination with radiation therapy and cisplatin increased the incidence of grade 3 and 4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Myocardial ischemia occurred in 2% of patients in the cetuximab arm compared with 0.9% in the control arm; adverse reactions with fatal outcome were reported in 4% in the cetuximab arm and 3% in the control arm. The addition of cetuximab to radiation and cisplatin did not improve progression free survival.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Tamoxifen: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during cetuximab treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant women, cetuximab can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving cetuximab should be apprised of the potential hazard to the fetus. In an animal reproduction study, IV administration of cetuximab (1 to 4 times the recommended human dose based on BSA) to pregnant cynomolgus monkeys during organogenesis resulted in an increased incidence of embryolethality and abortion. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryofetal/postnatal survival and development. Reduction or elimination of embryofetal or maternal EGFR signaling can prevent implantation, can cause embryofetal loss during various stages of gestation through effects on placental development, and can cause developmental anomalies and early death in surviving fetuses. Disruption or depletion of EGFR in animal models results in impaired placental, lung, cardiac, skin, and neural development.

    Counsel patients about the reproductive risk and contraception requirements during cetuximab treatment. Cetuximab can cause loss of pregnancy if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 2 months after treatment with cetuximab. Females of reproductive potential should undergo pregnancy testing prior to initiation of cetuximab. Women who become pregnant while receiving cetuximab should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of cetuximab on human fertility, female infertility has been observed in animal studies.

    MECHANISM OF ACTION

    Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). It is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions, and is produced in a mammalian (murine myeloma) cell culture. The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type 1 receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. It is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle, but is also detected in many human cancers including those of the head and neck, colon, and rectum.
     
    Cetuximab binds to EGFR on both normal and tumor cells, competitively inhibiting the binding of epidermal growth factor (EGF) and other ligands such as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR 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. Signal transduction through EGFR activates wild-type Ras proteins; however, in cells with activating Ras somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR regulation.
     
    In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express EGFR; no anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.

    PHARMACOKINETICS

    Cetuximab is administered as an IV infusion and exhibits nonlinear pharmacokinetics when administered both as monotherapy or in combination with chemotherapy. The volume of distribution (Vd) approximates the vascular space of 2 to 3 Liters/m2 and appears to be independent of dose. Steady-state is reached by the third weekly infusion when administered at the recommended dose regimen (400 mg/m2 initial dose, followed by 250 mg/m2 once weekly); the mean half-life was approximately 112 hours (range, 63 to 230 hours). Clearance of cetuximab decreased from 0.08 Liters/hour/m2 to 0.02 Liters/hour/m2 as the dose increased from 20 mg/m2 to 200 mg/m2.

    Intravenous Route

    The AUC increased in a greater than dose proportional manner as the dose increased from 20 mg/m2 to 200 mg/m2; at doses greater than 200 mg/m2, the AUC appeared to plateau. Mean peak (Cmax) concentrations across studies ranged from 168 mcg/mL to 235 mcg/mL, while mean trough (Cmin) concentrations ranged from 41 mcg/mL to 85 mcg/mL when administered at the recommended dose regimen (400 mg/m2 initial dose, followed by 250 mg/m2 once weekly). In a population pharmacokinetic analysis from two clinical trials, cetuximab had an approximately 22% (90% confidence interval, 6% to 38%) higher systemic exposure compared to EU-approved cetuximab.