INFUSION REACTIONS (SEE BOX WARNING: INFUSION REACTIONS, ADVERSE REACTIONS: INFUSION REACTIONS, AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
Severe infusion reactions occurred with the administration of ERBITUX in approximately 3% (20/774) of patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions were associated with the first infusion of ERBITUX despite the use of prophylactic antihistamines. These reactions were characterized by the rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions.
Severe infusion reactions require the immediate interruption of ERBITUX therapy and permanent discontinuation from further treatment. Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be available for use in the treatment of such reactions. Patients should be carefully observed until the complete resolution of all signs and symptoms.
In clinical trials, mild to moderate infusion reactions were managed by slowing the infusion rate of ERBITUX and by continued use of antihistamine medications (eg, diphenhydramine) in subsequent doses (see DOSAGE AND ADMINISTRATION: Dose Modifications).
Interstitial lung disease (ILD) was reported in 3 of 774 (<0.5%) patients with advanced colorectal cancer receiving ERBITUX. Interstitial pneumonitis with non-cardiogenic pulmonary edema resulting in death was reported in one case. Two patients had pre-existing fibrotic lung disease and experienced an acute exacerbation of their disease while receiving ERBITUX in combination with irinotecan. In the clinical investigational program, an additional case of interstitial pneumonitis was reported in a patient with head and neck cancer treated with ERBITUX and cisplatin. The onset of symptoms occurred between the fourth and eleventh doses of treatment in all reported cases.
In the event of acute onset or worsening pulmonary symptoms, ERBITUX therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, ERBITUX should be discontinued and the patient should be treated appropriately.
DERMATOLOGIC TOXICITY (SEE ADVERSE REACTIONS: DERMATOLOGIC TOXICITY AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
In cynomolgus monkeys, ERBITUX, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.
In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, and inflammatory and infectious sequelae (eg, blepharitis, cheilitis, cellulitis, cyst) were reported. In patients with advanced colorectal cancer, acneform rash was reported in 89% (686/774) of all treated patients, and was severe (Grade 3 or 4) in 11% (84/774) of these patients. Subsequent to the development of severe dermatologic toxicities, complications including S. aureus sepsis and abscesses requiring incision and drainage were reported.
Patients developing dermatologic toxicities while receiving ERBITUX should be monitored for the development of inflammatory or infectious sequelae, and appropriate treatment of these symptoms initiated. Dose modifications of any future ERBITUX infusions should be instituted in case of severe acneform rash (see DOSAGE AND ADMINISTRATION, Table 4). Treatment with topical and/or oral antibiotics should be considered; topical corticosteroids are not recommended.
ERBITUX therapy should be used with caution in patients with known hypersensitivity to Cetuximab, murine proteins, or any component of this product.
It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving ERBITUX as sunlight can exacerbate any skin reactions that may occur.
EGF RECEPTOR TESTING
Patients enrolled in the clinical studies were required to have immunohistochemical evidence of positive EGFR expression using the DakoCytomation EGFR pharmDx™ test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the DakoCytomation test kit package insert for full instructions on assay performance. (See CLINICAL STUDIES: EGFR Expression and Response.)
A drug interaction study was performed in which ERBITUX was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between ERBITUX and irinotecan.
As with all therapeutic proteins, there is potential for immunogenicity. Potential immunogenic responses to ERBITUX were assessed using either a double antigen radiometric assay or an enzyme-linked immunosorbant assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving ERBITUX has not been adequately determined. The incidence of antibodies to ERBITUX was measured by collecting and analyzing serum pre-study, prior to selected infusions and during treatment follow-up. Patients were considered evaluable if they had a negative pre-treatment sample and a post-treatment sample. Non-neutralizing anti-ERBITUX antibodies were detected in 5% (28 of 530) of evaluable patients. In patients positive for anti-ERBITUX antibody, the median time to onset was 44 days (range 8-281 days). Although the number of sero-positive patients is limited, there does not appear to be any relationship between the appearance of antibodies to ERBITUX and the safety or
antitumor activity of the molecule.
The observed incidence of anti-ERBITUX antibody responses may be influenced by the low sensitivity of available assays, inadequate to reliably detect lower antibody titers. Other factors which might influence the incidence of anti-ERBITUX antibody response include sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ERBITUX with the incidence of antibodies to other products may be misleading.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term animal studies have not been performed to test ERBITUX for carcinogenic potential. No mutagenic or clastogenic potential of ERBITUX was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. A 39-week toxicity study in cynomolgus monkeys receiving 0.4 to 4 times the human dose of ERBITUX (based on total body surface area) revealed a tendency for impairment of menstrual cycling in treated female monkeys, including increased incidences of irregularity or absence of cycles, when compared to control animals, and beginning from week 25 of treatment and continuing through the 6-week recovery period. Serum testosterone levels and analysis of sperm counts, viability, and motility were not remarkably different between ERBITUX-treated and control male monkeys. It is not known if ERBITUX can impair fertility in humans.
PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with ERBITUX. However, the EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. In addition, human IgG1 is known to cross the placental barrier; therefore, ERBITUX has the potential to be transmitted from the mother to the developing fetus. It is not known whether ERBITUX can cause fetal harm when administered to a pregnant woman or whether ERBITUX can affect reproductive capacity. There are no adequate and well-controlled studies of ERBITUX in pregnant women. ERBITUX should only be given to a pregnant woman, or any woman not employing adequate contraception if the potential benefit justifies the potential risk to the fetus. All patients should be counseled regarding the potential risk of ERBITUX treatment to the developing fetus prior to initiation of therapy. If the patient becomes pregnant while receiving this drug, she should be apprised
of the potential hazard to the fetus and/or the potential risk for loss of the pregnancy.
It is not known whether ERBITUX (Cetuximab) is secreted in human milk. Because human IgG1 is secreted in human milk, the potential for absorption and harm to the infant after ingestion is unknown. Based on the mean half-life of ERBITUX after multiple dosing of 114 hours [range 75-188 hours] (see CLINICAL PHARMACOLOGY: Human Pharmacokinetics), women should be advised to discontinue nursing during treatment with ERBITUX and for 60 days following the last dose of ERBITUX.
The safety and effectiveness of ERBITUX in pediatric patients have not been established.
Of the 774 patients who received ERBITUX with irinotecan or ERBITUX monotherapy in four advanced colorectal cancer studies, 253 patients (33%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.