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CETUXIMAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cetuximab is an epidermal growth factor receptor (EGFR) antagonist used to treat squamous cell carcinoma of the head and neck and metastatic colorectal cancer.

Specific Substances

    1) C-225
    2) Cetuximabum
    3) CAS 205923-56-4

Available Forms Sources

    A) FORMS
    1) Cetuximab is available in the US at a concentration of 2 mg/mL as a 100 mg/50 mL or as a 200 mg/100 mL, single-use vial as a sterile, preservative-free injectable liquid (Prod Info ERBITUX(R) intravenous injection, 2015).
    B) USES
    1) Cetuximab is indicated, in combination with radiation therapy, for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (Prod Info ERBITUX(R) intravenous injection, 2015).
    2) Cetuximab is indicated as monotherapy for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck following treatment failure of a platinum-based therapy (Prod Info ERBITUX(R) intravenous injection, 2015).
    3) Cetuximab is indicated as monotherapy for use in patients with epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer who have failed both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based regimens (Prod Info ERBITUX(R) intravenous injection, 2015).
    4) Cetuximab is approved in combination with irinotecan for use in patients with EGFR-expressing metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy (Prod Info ERBITUX(R) intravenous injection, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cetuximab is used as monotherapy or in combination with other agents for the treatment of squamous cell carcinoma of the head and neck and EGFR-expressing metastatic colorectal cancer.
    B) PHARMACOLOGY: Cetuximab is a murine-human chimeric monoclonal antibody directed against epidermal growth factor receptor (EGFR). Over-expression of 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 growth and survival of tumor cells that over-express the EGFR.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most commonly reported adverse effects following cetuximab therapy include acneform rash, asthenia, pain, headache, fever, hypomagnesemia, nausea, vomiting, constipation, abdominal pain, diarrhea, and weight loss. Interstitial lung disease and severe infusion-related reactions characterized by rapid onset of respiratory distress (bronchospasm, stridor, hoarseness), urticaria, hypotension, and cardiac arrest, have infrequently occurred following therapeutic administration of cetuximab.
    E) WITH POISONING/EXPOSURE
    1) There is no cetuximab overdose information available at the time of this review. No adverse events were reported in a patient after receiving 1000 mg/m(2) of cetuximab.
    0.2.20) REPRODUCTIVE
    A) Cetuximab is classified as FDA pregnancy category C. No studies examining the use of cetuximab during pregnancy are available at this time.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    D) Monitor CBC with differential and liver enzymes in symptomatic patients.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Obtain an ECG, and institute continuous cardiac monitoring.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Correct hypomagnesemia with oral or intravenous magnesium. Treat persistent diarrhea with antidiarrheals and treat nausea and/or vomiting with several antiemetics of different classes.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or lactated ringers through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hrs). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress.
    F) ANTIDOTE
    1) None.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors in patients who develop severe neutropenia or neutropenic sepsis. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) HYPERSENSITIVITY
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    I) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    J) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess their electrolytes and fluid balance. A baseline CBC with differential and platelet count should be obtained. Ongoing laboratory monitoring should be arranged until there is evidence of bone marrow recovery.
    3) ADMISSION CRITERIA: Patients with evidence of bone marrow suppression should be admitted. Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring as indicated, and daily monitoring of CBC with differential until bone marrow suppression is resolved. Patients should also be admitted for persistent profuse diarrhea, severe vomiting, dehydration and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    5) PATIENT-TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    L) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking this agent may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    M) PHARMACOKINETICS
    1) Vd: 2 to 3 L/m(2). Excretion: renal: Approximately 0.4 mL/hr/kg (200 and 400 mg/m(2) weekly). Elimination half-life: 112 hours (range 63 to 230 hours).
    N) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hepatotoxicity, hypomagnesemia, or myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. No adverse events were reported in a patient after receiving 1000 mg/m(2) of cetuximab.
    B) THERAPEUTIC DOSE: An initial loading dose of 400 mg/m(2) administered as a 120-minute IV infusion, followed by a weekly maintenance dose of 250 mg/m(2) infused over 60 minutes. The maximum infusion rate is 10 mL/min.

Clinical Effects

Summary Of Exposure

    A) USES: Cetuximab is used as monotherapy or in combination with other agents for the treatment of squamous cell carcinoma of the head and neck and EGFR-expressing metastatic colorectal cancer.
    B) PHARMACOLOGY: Cetuximab is a murine-human chimeric monoclonal antibody directed against epidermal growth factor receptor (EGFR). Over-expression of 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 growth and survival of tumor cells that over-express the EGFR.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most commonly reported adverse effects following cetuximab therapy include acneform rash, asthenia, pain, headache, fever, hypomagnesemia, nausea, vomiting, constipation, abdominal pain, diarrhea, and weight loss. Interstitial lung disease and severe infusion-related reactions characterized by rapid onset of respiratory distress (bronchospasm, stridor, hoarseness), urticaria, hypotension, and cardiac arrest, have infrequently occurred following therapeutic administration of cetuximab.
    E) WITH POISONING/EXPOSURE
    1) There is no cetuximab overdose information available at the time of this review. No adverse events were reported in a patient after receiving 1000 mg/m(2) of cetuximab.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever with or without chills is relatively common during or after infusion of cetuximab (approximately 15% of patients) (Etessami & Bourhis, 2000a; Robert et al, 2001; Baselga et al, 2000a).
    2) In a randomized, multicenter, controlled trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 29% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 13% of patients receiving radiation alone (n=212) experienced fever (Prod Info ERBITUX(R) IV injection, 2007a).
    3) Fever occurred in 30% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 18% of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLEPHARITIS - Blepharitis has been reported in patients receiving cetuximab in clinical trials (Prod Info ERBITUX(R) IV injection, 2007a).
    a) CASE REPORTS - Two patients with metastatic colorectal cancer developed blepharitis and conjunctivitis after receiving 15 to 17 doses of cetuximab. The physical examination of the first patient showed erythema of the left inferior lid margin and palpebral conjunctivae and crusty scaling of the superior lashes bilaterally. No scleral injection or purulent discharge were observed. The physical examination of the second patient showed right scleral injection with increased lacrimation and erythema of the superior and inferior right palpebral conjunctivae. Following the discontinuation of cetuximab and treatment with gentamicin, ocular symptoms resolved completely (Dranko et al, 2006).
    2) CICATRICIAL ECTROPION - A 49-year-old man with metastatic colon cancer receiving irinotecan and 5-fluorouracil developed periocular skin toxicity, madarosis, and cicatricial ectropion after the addition of weekly cetuximab. The patient reported epiphora, bilateral eyelid and periorbital skin irritation, which began one week after starting cetuximab. Initially, the patient was treated with topical steroid drops and ointment with no effect. Symptoms progressed to crusting and bleeding of the eyelid skin and loss of eyelashes. After 4 cetuximab infusions, an ocular exam revealed bilateral cicatricial ectropion of the lower eyelid margins, tight skin on the eyelids and cheeks, everted lower puncta and high tear meniscus, and complete madarosis with inflammation of the eyelid margins; however, the patient had normal visual acuity, motility, and pupillary response. Erythromycin ointment applied nightly to both eyes, desonide ointment applied twice daily to both eyelids, and artificial tears were started and cetuximab was discontinued due to evidence of disease progression after the sixth scheduled dose. Six weeks after his last cetuximab dose, the patient had resolution of his ocular and skin symptoms but continued to have epiphora. Upon examination, the patient had bilateral patent puncta and high tear meniscus, suspicious for canalicular obstruction, which may have been caused by chronic 5-fluorouracil therapy. The patient deferred treatment for the persistent epiphora (Garibaldi & Adler, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 2% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (4/208) and 0% of patients receiving radiation alone (n=212) experienced cardiopulmonary arrest and/or sudden death. Three patients who died had a history of coronary artery disease (CAD) with one of these patients also having a history of dysrhythmia and another patient having a history of congestive heart failure (CHF). Additionally, one patient who died had no prior history of CAD. Fatal events occurred 27, 32, and 43 days after the last cetuximab dose (Prod Info ERBITUX(R) IV injection, 2007a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 26% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 19% of patients receiving radiation alone (n=212) experienced pharyngitis; of whom, 3% and 4%, respectively, experienced grades 3 and 4 pharyngitis (Prod Info ERBITUX(R) IV injection, 2007a).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported during or after infusion in some patients, with or without concurrent cisplatin; causality is uncertain (Baselga et al, 2000a).
    b) Dyspnea occurred in 48% (grades 3 and 4, 16%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 43% (grades 3 and 4, 12%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough occurred in 29% (grades 3 and 4, 2%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 19% (grades 3 and 4, 1%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    D) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) Pulmonary embolus has been reported in patients receiving cetuximab therapy (Prod Info ERBITUX(R) IV injection, 2007a).
    E) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Interstitial lung disease, including one fatality, was reported in less than 0.5% of patients receiving cetuximab in clinical trials (n=1570) (Prod Info ERBITUX(R) IV injection, 2007a).
    F) OBLITERATIVE BRONCHIOLITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 78-year-old man with metastatic colorectal cancer presented with cough and worsening breathlessness approximately 2 months after beginning chemotherapy with cetuximab and irinotecan. A chest examination revealed fine crackles and scattered squeaks, and a CT scan demonstrated bilateral patchy ground-glass changes, consistent with a diagnosis of bronchiolitis obliterans organizing pneumonia. Following cessation of cetuximab and administration of prednisone, the patient's signs and symptoms improved; however he died 4 months later from respiratory failure secondary to progressive lung metastases (Chua et al, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion was experienced by 15% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 9% of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years). Grades 3 or 4 neurologic events occurred in 6% of cetuximab treated patients and 2% of patients treated with BSC alone (Prod Info ERBITUX(R) IV injection, 2007a).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a multicenter, randomized trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 56% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 49% of patients receiving radiation alone (n=212) experienced asthenia; 4% of patients receiving cetuximab plus radiation (n=208) and 5% of patients receiving radiation alone (n=212) experienced asthenia (grades 3 and 4) (Prod Info ERBITUX(R) IV injection, 2007a).
    b) In clinical trials in patients receiving cetuximab plus irinotecan (n=354) for colorectal cancer, asthenia/malaise (any grade) occurred in 73% of patients; severe asthenia/malaise (grades 3 and 4) occurred in 16% of patients (Prod Info ERBITUX(R) IV injection, 2007a).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia occurred in 30% (grades 3 and 4, 1%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 15% (grades 3 and 4, 1%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 19% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 8% of patients receiving radiation alone (n=212) experienced headache, with less than 1% in each group experiencing grades 3 and 4 headaches (Prod Info ERBITUX(R) IV injection, 2007a).
    b) Headache occurred in 33% (grades 3 and 4, 4%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 11% (grades 3 and 4, 0%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    E) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue occurred in 89% (grades 3 and 4, 33%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 76% (grades 3 and 4, 26%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain (any grade) occurred in 59% (grades 3 and 4, 14%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 52% (grades 3 and 4, 16%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 19% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 13% of patients receiving radiation alone (n=212) experienced diarrhea of any grade; of whom, 2% and 1%, respectively, experienced grades 3 and 4 diarrhea (Prod Info ERBITUX(R) IV injection, 2007a).
    b) Diarrhea (any grade) occurred in 39% (grades 3 and 4, 2%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 20% (grades 3 and 4, 1%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    c) In clinical trials in patients receiving cetuximab plus irinotecan (n=354) for colorectal cancer, diarrhea (any grade) occurred in 72% of patients with 22% of patients experiencing severe (grades 3 and 4) diarrhea (Prod Info ERBITUX(R) IV injection, 2007a).
    C) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 49% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 37% of patients receiving radiation alone (n=212) experienced nausea; 2% of patients in each treatment arm experienced grades 3 or 4 nausea (Prod Info ERBITUX(R) IV injection, 2007a).
    b) In clinical trials in patients receiving cetuximab plus irinotecan (n=354) for colorectal cancer, nausea occurred in 55% of patients (Prod Info ERBITUX(R) IV injection, 2007a).
    D) VOMITING
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 29% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 23% of patients receiving radiation alone (n=212) had emesis of any grade; of whom, 2% of cetuximab treated patients had grade 3 or 4 emesis compared with 4% of patients treated with radiation alone (Prod Info ERBITUX(R) IV injection, 2007a).
    b) Vomiting occurred in 37% (grades 3 and 4, 6%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 29% (grades 3 and 4, 6%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 46% (grades 3 and 4, 4%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 38% (grades 3 and 4, 5%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    F) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis (any grade) occurred in 25% (grades 3 and 4, 1%) of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 10% (grades 3 and 4, less than 1%) of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Mild elevations of transaminases and alkaline phosphatase have been reported occasionally following infusions (5% to 10% of patients), and do not appear to be dose-related (Robert et al, 2001; Baselga et al, 2000a; Etessami & Bourhis, 2000a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Mild thrombocytopenia has been reported in some head and neck cancer patients during cetuximab therapy (Robert et al, 2001), although causality is uncertain. In a further study in these patients, myelosuppression was not observed in relation to cetuximab infusion (Shin et al, 2001).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients receiving cetuximab plus irinotecan (n=354) for colorectal cancer, severe (grades 3 and 4) leukopenia occurred in 17% of patients (Prod Info ERBITUX(R) IV injection, 2007a).
    b) Leukopenia has been reported in some head and neck cancer patients during cetuximab therapy (Robert et al, 2001), although causality is uncertain. In a further study in these patients, myelosuppression was not observed in relation to cetuximab infusion (Shin et al, 2001).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been reported in some head and neck cancer patients during cetuximab therapy (Robert et al, 2001), although causality is uncertain. In a further study in these patients, myelosuppression was not observed in relation to cetuximab infusion (Shin et al, 2001).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Dermatologic toxicities (eg, acneform rash, paronychial inflammation, skin drying and fissuring) and infectious sequelae (eg; Staphylococcus aureus sepsis, abscess formation, cellulitis, blepharitis, and cheilitis), and hypertrichosis have been reported in patients receiving cetuximab in clinical trials (Prod Info ERBITUX(R) IV injection, 2007a).
    B) ACNEIFORM ERUPTION
    1) WITH THERAPEUTIC USE
    a) Dermatologic toxicities (eg; desquamation, acneform rash) have been reported in patients receiving cetuximab. In clinical trials (n=1373), acneform rash (all grades) was reported in 76% to 88% of patients receiving cetuximab for colorectal cancer or squamous cell carcinoma of the head and neck. The severe acneform rash (grades 3 and 4) was reported in 1% to 17% of patients receiving cetuximab. The onset of acneform rash generally occurred within the first two weeks of cetuximab therapy and the majority of cases resolved following cessation of treatment. However, in almost half the cases, the acneform rash continued beyond 28 days following cetuximab cessation (Prod Info ERBITUX(R) IV injection, 2007a).
    b) The mechanism of skin reactions appears related to interference of the signal pathway of EGFR (Busam et al, 2001; Etessami & Bourhis, 2000a). Upregulation of the negative growth regulator p27(Kip1) has been observed in epidermal keratinocytes during cetuximab therapy (Busam et al, 2001). There is no evidence that rashes are due to infection.
    C) APPLICATION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 18% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 12% of patients receiving radiation alone (n=212) experienced application site reaction (Prod Info ERBITUX(R) IV injection, 2007a).
    D) NAIL CHANGES
    1) WITH THERAPEUTIC USE
    a) Nail changes occurred in 21% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 4% of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    E) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 16% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 4% of patients receiving radiation alone (n=212) experienced pruritus (Prod Info ERBITUX(R) IV injection, 2007a).
    b) Pruritus occurred in 40% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 8% of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    F) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) Dermatologic toxicities, including skin drying and fissuring, and infectious sequelae (eg, Staphylococcus aureus sepsis, abscess formation, cellulitis, cheilitis) have been reported in patients receiving cetuximab in clinical trials (Prod Info ERBITUX(R) IV injection, 2007a).
    b) Dry skin was experienced by 49% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus best supportive care (BSC) (n=288) and 11% of patients receiving BSC alone (n=274) in a multicenter, open-label, randomized, clinical trial in patients with epidermal growth factor receptor (EGFR)-expressing, previously treated, recurrent, metastatic colorectal cancer (n=562; median age, 63 years) (Prod Info ERBITUX(R) IV injection, 2007a).
    G) RADIATION DERMATITIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 86% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 90% of patients receiving radiation alone (n=212) experienced radiation dermatitis (any grade); of whom, 23% and 18%, respectively, experienced grades 3 and 4 radiation dermatitis (Prod Info ERBITUX(R) IV injection, 2007a).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) WEIGHT LOSS FINDING
    1) WITH THERAPEUTIC USE
    a) In a randomized, multicenter trial in patients with locally or regionally advanced squamous cell carcinoma of the head and neck (n=420; median age, 57 years), 84% of patients receiving cetuximab (400 mg/m(2) initially, then 250 mg/m(2) weekly) plus radiation (n=208) and 72% of patients receiving radiation alone (n=212) experienced weight loss; 11% of the cetuximab treated patients experienced grades 3 or 4 weight loss, compared with 7% of the patients treated with radiation alone (Prod Info ERBITUX(R) IV injection, 2007a).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity, including urticaria and anaphylactoid reactions, has occurred during infusions with relatively high frequency (4% to 8%) (Robert et al, 2001; Baselga et al, 2000a; Etessami & Bourhis, 2000a). The frequency of anaphylactoid reactions was about 2% in a series of 189 patients receiving the antibody alone or combination regimens (Etessami & Bourhis, 2000a). Some patients who experienced less severe (nonanaphylactoid) reactions have continued therapy with more prolonged infusions of cetuximab and premedication (eg, infusion of diphenhydramine 25 mg and dexamethasone 20 mg) (Shin et al, 2001; Robert et al, 2001).

Reproductive

    3.20.1) SUMMARY
    A) Cetuximab is classified as FDA pregnancy category C. No studies examining the use of cetuximab during pregnancy are available at this time.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There is no data on the use of cetuximab in pregnant women. The effects, if any, on the developing fetus are unknown. Cetuximab is a recombinant monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR). The EGFR may participate in the control of prenatal development, and may be necessary for normal organogenesis, proliferation, and differentiation in the developing embryo. Cetuximab has the potential to be transmitted from the mother to the fetus (Prod Info ERBITUX(R) intravenous injection, 2015).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified cetuximab as FDA pregnancy category C (Prod Info ERBITUX(R) intravenous injection, 2015).
    2) Because cetuximab has the potential to cause fetal harm when administered to pregnant women, it should only be used if the potential benefit outweighs the potential risk to the fetus (Prod Info ERBITUX(R) intravenous injection, 2015).
    C) ANIMAL STUDIES
    1) Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at gestation day [GD] 49 after pregnant cynomolgus monkeys were treated weekly with cetuximab (0.4 to 4 times the recommended human dose, based on body surface area) during the period of organogenesis (gestation day [GD] 20 to 48). There were no fetal malformations or other teratogenic effects in offspring. However, following doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area), significant increases in embryolethality and abortions were observed (Prod Info ERBITUX(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) No reports describing the use of cetuximab during human lactation are available, and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known if cetuximab affects the quantity and composition of breast milk. Until more data are available, use caution when considering the use of cetuximab in lactating women. According to the manufacturer, cetuximab has a mean half-life of approximately 114 hours after multiple dosing. Women should discontinue nursing during treatment with cetuximab and for 60 days following the last dose (Prod Info ERBITUX(R) intravenous injection, 2015).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) In a toxicity study in cynomolgus monkeys given doses of 0.4 to 4 times the human dose (based on total body surface area), menstrual cycling was impaired 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 (Prod Info ERBITUX(R) intravenous injection, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Long term carcinogenicity studies in animals have not been conducted (Prod Info ERBITUX(R) IV injection, 2007).

Genotoxicity

    A) No mutagenic or clastogenic potential was observed in the Salmonella-Escherichia coli (Ames) assay or in the in-vivo rat micronucleus test (Prod Info ERBITUX(R) IV injection, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    D) Monitor CBC with differential and liver enzymes in symptomatic patients.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Obtain an ECG, and institute continuous cardiac monitoring.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with evidence of bone marrow suppression should be admitted. Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring as indicated, and daily monitoring of CBC with differential until bone marrow suppression is resolved. Patients should also be admitted for persistent profuse diarrhea, severe vomiting, dehydration and electrolyte abnormalities.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess their electrolytes and fluid balance. A baseline CBC with differential and platelet count should be obtained. Ongoing laboratory monitoring should be arranged until there is evidence of bone marrow recovery.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    D) Monitor CBC with differential and liver enzymes in symptomatic patients.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Obtain an ECG, and institute continuous cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. No adverse events were reported in a patient after receiving 1000 mg/m(2) of cetuximab.
    B) THERAPEUTIC DOSE: An initial loading dose of 400 mg/m(2) administered as a 120-minute IV infusion, followed by a weekly maintenance dose of 250 mg/m(2) infused over 60 minutes. The maximum infusion rate is 10 mL/min.

Therapeutic Dose

    7.2.1) ADULT
    A) An initial loading dose of 400 mg/m(2) administered as a 120-minute IV infusion, followed by a weekly maintenance dose of 250 mg/m(2) infused over 60 minutes. The maximum infusion rate is 10 mg/min (Prod Info ERBITUX(R) intravenous injection, 2012)
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in the pediatric or adolescent population. However, the pharmacokinetics of cetuximab with irinotecan was evaluated in 27 patients 1 to 12 years and in 19 patients 13 to 18 years with refractory solid tumors administered doses up to 250 mg/m(2) once-a week. No safety signals were identified (Prod Info ERBITUX(R) intravenous injection, 2012).

Maximum Tolerated Exposure

    A) A specific toxic dose of cetuximab has not been established. No adverse events were reported in a patient after receiving 1000 mg/m(2) of cetuximab (Prod Info ERBITUX(R) intravenous injection, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cetuximab is a murine-human chimeric monoclonal antibody directed against epidermal growth factor receptor (EGFR). Over-expression of 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 growth and survival of tumor cells that over-express the EGFR (Prod Info ERBITUX(R) IV injection, 2007).

Physicochemical

Physical Characteristics

    A) A sterile, clear, colorless liquid which may contain a small amount of easily visible, white, amorphous particulates (Prod Info ERBITUX(R) IV injection, 2008).

Ph

    A) 7 to 7.4 (Prod Info ERBITUX(R) IV injection, 2008)

Molecular Weight

    A) 152 kilodaltons (Prod Info ERBITUX(R) IV injection, 2008)

References

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