Cetuximab – Erbitux®

Cetuximab - Erbitux®

Usual Diluents

Dilution Data

Storage/Stability:
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Increased particulate formation may occur at temperatures at or below 0° C. This product contains no preservatives. Preparations of Erbitux in infusion containers are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C. Discard any unused portion of the vial.

CLINICAL PHARMACOLOGY

Mechanism of Action
The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits 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 production. Signal transduction through the EGFR results in activation of wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent 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 the 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
Erbitux administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it appeared to plateau. The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m2.

Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 µg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (range 63–230 hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer.

Based on a population pharmacokinetic analysis, female patients with colorectal cancer had a 25% lower intrinsic clearance of cetuximab than male patients. Qualitatively similar, but smaller gender differences in cetuximab clearance were observed in patients with SCCHN. The gender differences in clearance do not necessitate any alteration of dosing because of a similar safety profile.

1. INDICATIONS AND USAGE

1.1 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. [See PACKAGE INSERT FOR Clinical Studies (14.1).]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See PACKAGE INSERT FOR  Clinical Studies (14.1).]

1.2  Colorectal Cancer
Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See PACKAGE INSERT FOR Clinical Studies (14.2) and Warnings and Precautions (5.7).]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See PACKAGE INSERT FOR Clinical Studies (14.2) and Warnings and Precautions (5.7).]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see PACKAGE INSERT FOR Clinical Studies (14.2) and Clinical Pharmacology (12.1).]

2. DOSAGE AND ADMINISTRATION

2.1 Squamous Cell Carcinoma of the Head and Neck

Erbitux in combination with radiation therapy:
The recommended initial dose is 400 mg/m2 administered one week prior to initiation of a course of radiation therapy as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min).
The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) for the duration of radiation therapy (6–7 weeks). Complete Erbitux administration 1 hour prior to radiation therapy.

Erbitux monotherapy:
The recommended initial dose is 400 mg/m2 administered as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min).
The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity.

2.2 Colorectal Cancer
The recommended initial dose, either as monotherapy or in combination with irinotecan, is 400 mg/m2 administered as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min).
The recommended subsequent weekly dose, either as monotherapy or in combination with irinotecan, is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity.

2.3 Recommended Premedication
Premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) intravenously 30–60 minutes prior to the first dose; premedication should be administered for subsequent Erbitux doses based upon clinical judgment and presence/severity of prior infusion reactions.

2.4 Dose Modifications
Infusion Reactions
Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC Grades 3–4 infusion reactions.

Immediately and permanently discontinue Erbitux for serious infusion reactions requiring medical intervention and/or hospitalization. [See PACKAGE INSERT FOR Warnings and Precautions (5.1).]

Dermatologic Toxicity
Recommended dose modifications for severe (NCI CTC Grade 3 or 4) acneform rash are specified in Table 1. [See PACKAGE INSERT FOR Warnings and Precautions (5.4).]

Table 1: Erbitux Dose Modification Guidelines for Rash

2.5 Preparation for Administration
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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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.

3. DOSAGE FORMS AND STRENGTHS
100 mg/50 mL, single-use vial

200 mg/100 mL, single-use vial

4. CONTRAINDICATIONS
None.

HOW SUPPLIED/STORAGE AND HANDLING
Erbitux® (cetuximab) is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, single-use vial or as a 200 mg/100 mL, single-use vial as a sterile, preservative-free, injectable liquid.

NDC 66733-948-23 100 mg/50 mL, single-use vial, individually packaged in a carton
NDC 66733-958-23 200 mg/100 mL, single-use vial, individually packaged in a carton

Storage/Stability:
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Increased particulate formation may occur at temperatures at or below 0° C. This product contains no preservatives. Preparations of Erbitux in infusion containers are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C. Discard any unused portion of the vial.

Erbitux® is a registered trademark of ImClone Systems Incorporated.
Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876
Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543
Copyright© 2010 ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved