Dosage & Administration
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Erbitux Prescribing Information
Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions , Adverse Reactions ]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration ].
Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions ].
Squamous Cell Carcinoma of the Head and Neck (SCCHN)
ERBITUX® is indicated:
- in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).
- in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN.
- as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.
K-Ras Wild-type, EGFR-expressing Colorectal Cancer (CRC)
ERBITUX is indicated for the treatment of K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test [seeDosage and Administration ]:
- in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment,
- in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,
- as a single-agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.
Limitations of Use: ERBITUX is not indicated for treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown [see Warnings and Precautions ].
1.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
ERBITUX is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy [see Dosage and Administration ].
Patient Selection
Select patients with metastatic colorectal cancer (CRC) for treatment with ERBITUX based on the presence of:
- Ras wild-type, EGFR-expressing CRC [see Clinical Studies ], or
- BRAF V600E mutation-positive metastatic CRC [see Clinical Studies ]
Information on FDA-approved tests for the detection of K-Ras or BRAF V600E mutations in CRC in patients with metastatic CRC is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)
In combination with radiation therapy
- Initial dose: 400 mg/m2 administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.
- Subsequent doses: 250 mg/m2 administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).
- Complete ERBITUX administration 1 hour prior to radiation therapy.
As a single-agent or in combination with platinum-based therapy and fluorouracil
Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.
Weekly Dosage
- Initial dose: 400 mg/m2 administered as a 120-minute intravenous infusion
- Subsequent doses: 250 mg/m2 administered as a 60-minute infusion every week
Biweekly Dosage
- Initial and subsequent doses: 500 mg/m2 administered as a 120-minute intravenous infusion every 2 weeks
Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil. Continue treatment until disease progression or unacceptable toxicity.
Recommended Dosage for Colorectal Cancer (CRC)
As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)
Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.
Weekly Dosage
- Initial dose: 400 mg/m2 administered as a 120-minute intravenous infusion
- Subsequent doses: 250 mg/m2 administered as a 60-minute infusion every week
Biweekly Dosage
- Initial and subsequent doses: 500 mg/m2 administered as a 120-minute intravenous infusion every 2 weeks
Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.
In combination with encorafenib
- The recommended initial dose is 400 mg/m2 administered as a 120-minute intravenous infusion in combination with encorafenib.
- The recommended subsequent dosage is 250 mg/m2 weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.
Refer to the encorafenib prescribing information for recommended encorafenib dosage information.
Premedication
Premedicate with a histamine-1 (H1) receptor antagonist intravenously 30–60 minutes prior to the first dose or subsequent doses as deemed necessary [see Warnings and Precautions ].
Dosage Modifications for Adverse Reactions
Reduce, delay, or discontinue ERBITUX to manage adverse reactions as described in Table 1.
| Adverse Reaction | Severitya | Dosage Modification |
|---|---|---|
a National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0. | ||
| Infusion reactions [see Warnings and Precautions ] | Grade 1 or 2 | Reduce the infusion rate by 50%. |
| Grade 3 or 4 | Immediately and permanently, discontinue ERBITUX. | |
| Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease) [see Warnings and Precautions ] | 1st occurrence; Grade 3 or 4 | Delay infusion 1 to 2 weeks; if condition improves, continue at 250 mg/m2. If no improvement, discontinue ERBITUX. |
| 2nd occurrence; Grade 3 or 4 | Delay infusion 1 to 2 weeks; if condition improves, continue at 200 mg/m2. If no improvement, discontinue ERBITUX. | |
| 3rd occurrence; Grade 3 or 4 | Delay infusion 1 to 2 weeks; if condition improves, continue at 150 mg/m2. If no improvement, discontinue ERBITUX. | |
| 4th occurrence; Grade 3 or 4 | Discontinue ERBITUX. | |
| Pulmonary toxicity [see Warnings and Precautions ] | Acute onset or worsening pulmonary symptoms | Delay infusion 1 to 2 weeks; if condition improves, continue at the dose that was being administered at the time of occurrence. If no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue ERBITUX. |
Preparation for Administration
- The solution should be clear and colorless and may contain a small amount of easily visible, white, amorphous, cetuximab particulates. Do not shake or dilute.
- Visually inspect for foreign particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if solution is discolored, cloudy, or contains foreign particulate matter.
- Do not administer ERBITUX as an intravenous push or bolus.
- Administer via infusion pump or syringe pump. Do not exceed an infusion rate of 10 mg/min.
- Administer through a low protein binding 0.22-micrometer in-line filter.
Injection: 100 mg/50 mL (2 mg/mL) or 200 mg/100 mL (2 mg/mL) as a clear, colorless solution in a single-dose vial.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ], ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development (see Data). Human IgG is known to cross the placental barrier; therefore, cetuximab may be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.
Data
Animal Data
Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day [GD] 20-48) at dose levels 0.4 to 4 times the recommended dose of ERBITUX based on body surface area (BSA). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams on GD 49. While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA.
In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development), and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling.
Lactation
Risk Summary
There is no information regarding the presence of ERBITUX in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants from ERBITUX, advise women not to breastfeed during treatment with ERBITUX and for 2 months after the last dose of ERBITUX.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating ERBITUX [see Use in Specific Population ].
Contraception
Based on its mechanism of action, ERBITUX can cause harm to the fetus when administered to a pregnant woman [see Use in Specific Populations ].
Females
Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX.
Infertility
Females
Based on animal studies, ERBITUX may impair fertility in females of reproductive potential [see Nonclinical Toxicology ].
Pediatric Use
The safety and effectiveness of ERBITUX in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. ERBITUX was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetics of cetuximab between the two age groups were similar following a single dose of 75 mg/m2 and 150 mg/m2. The volume of the distribution appears to be independent of dose and approximates the vascular space of 2 L/m2 to 3 L/m2. Following a single dose of 250 mg/m2, the mean AUC0-inf (CV%) was 17.7 mg*h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg*h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (69 to 188 hours) in the younger group and 82 hours (55 to 117 hours) in the adolescent group.
Geriatric Use
Of the 1662 patients with advanced colorectal cancer who received ERBITUX with irinotecan, with FOLFIRI or as single-agent in six studies (BOND, IMCL-CP02-9923, IMCL-CP02-0141, IMCL-CP02-0144, CA225-025 and CRYSTAL), 35% of patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
Clinical studies of ERBITUX conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Of the 216 patients with BRAF V600E mutation positive metastatic CRC who received ERBITUX in combination with encorafenib 300 mg, once daily, 29% were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies ].
No overall differences in the safety or effectiveness of ERBITUX plus encorafenib were observed in elderly patients as compared to younger patients.
None.