爱必妥(Erbitux)

【Function and Indications】
Erbitux (Cetuximab, Erbitux) is the first approved targeted monoclonal antibody for the treatment of metastatic colorectal cancer and a new biological targeted therapy for colorectal cancer.

【Model and Specification】
For intravenous injection, 100 mg per bottle (20 ml).

【Usage and Dosage】

It is recommended to test EGFR in an experienced laboratory according to a validated method; Cetuximab must be used under the guidance of a physician with experience in using anticancer drugs. During the medication process and within one hour after the end of the medication, the patient’s condition must be closely monitored and resuscitation equipment must be available.

Before the first infusion of this product, the patient must receive antihistamine treatment, and it is recommended that this treatment be given to the patient before each subsequent use of this product.

This product is administered once a week. The initial dose is 400 mg/㎡ body surface area, followed by 250 mg/㎡ body surface area per week.
For the first administration, the recommended infusion time is 120 minutes, and the infusion time for subsequent weekly administration is 60 minutes. The maximum infusion rate shall not exceed 5ml/min.

[Clinical Research]

A multicenter randomized phase II clinical controlled study evaluated the efficacy of this product in the treatment of metastatic colorectal cancer. Among the 329 subjects with EGF receptor overexpression, 206 were male, with an average age of 59 years (26-84 years), 58% were patients with colon cancer, and 40% were patients with rectal cancer, of which 63% were ineffective with oxaliplatin. In the study, patients were randomly divided into two groups, 218 in the combination group of this product and irinotecan, and 111 in the monotherapy group of this product. The initial dose of this product is 400mg per week, followed by 250mg per week, and the treatment endpoint is disease progression or the occurrence of intolerable adverse reactions. The dosage of irinotecan is 350mg/m2 every 3 weeks, 180mg/m2 every 2 weeks, or 125mg/m2 4 times in the 6th week. The results showed that the effective rates of the combination therapy group and the monotherapy group were 22.9% and 10.8%, respectively. The average duration of efficacy was 5.7 and 4.2 months in the combination therapy group and the monotherapy group, respectively; compared with the monotherapy group, the patients in the combination therapy group significantly delayed the progression of the disease.

Another multicenter single-group open clinical study evaluated the efficacy of this product combined with irinotecan in 138 patients with metastatic colorectal cancer with overexpression of EGF receptors. All patients had previously received irinotecan treatment, of which 74 still had overexpression of EGF receptors after treatment. The initial dose of this product is 400mg per week, followed by 250mg per week until the disease progresses or intolerable adverse reactions occur. The dosage of irinotecan is 350mg/m2 every 3 weeks, 180mg/m2 every 2 weeks, or 125mg/m2 4 times every 6 weeks. The total effective rate is 15%, and the average duration of efficacy is 6.5 months, while the effective rate of the irinotecan-ineffective group is 12%, and the average duration of efficacy is 6.7 months.

Another multicenter single-group open clinical study evaluated the efficacy of this product alone in 57 patients with metastatic colorectal cancer with overexpression of EGF receptors. All patients had previously received irinotecan treatment, and 28 of them still overexpressed EGF receptors after irinotecan treatment. After treatment with this product, the total effective rate was 9%, of which the effective rate of the irinotecan-ineffective group was 14%, and the average time to disease progression was 1.4 and 1.3 months, respectively. The average duration of efficacy of the two groups was 4.2 months.

[Precautions]

This product can often cause skin toxicity of varying degrees. Such patients should avoid light during medication. Mild to moderate skin toxicity does not require dose adjustment, and severe skin toxicity should be reduced as appropriate.

Studies have found that the drug clearance rate of female patients is 25% lower than that of male patients, but the efficacy and safety are similar, so there is no need to adjust the dose according to gender. Because this product can pass through the placental barrier, it may damage the fetus or affect the fertility of women, so pregnant women and women of childbearing age who do not take contraceptive measures should use it with caution. Because this product can be secreted through breast milk, it should be used with caution in lactating women. Before the safety of this product for pediatric patients is confirmed, it is contraindicated for children.

The incidence of severe infusion reactions is 3%, and the mortality rate is less than 0.1%. 90% of them occurred during the first use, characterized by sudden airway obstruction, urticaria and hypotension. Because some infusion reactions occur in the subsequent medication stage, the medication should be used under the supervision of a doctor. In case of mild to moderate infusion reaction, the infusion rate can be slowed down or antihistamines can be taken. If a severe infusion reaction occurs, the infusion should be stopped immediately, and adrenaline, glucocorticoids, antihistamines, bronchodilators and oxygen infusion should be given for treatment. Some patients should not use this product again. In addition, if acute pulmonary symptoms occur during the use of this product, it should be discontinued immediately to find out the cause. If it is indeed interstitial lung disease, it is prohibited and treated accordingly.

Medication Instructions

Operation Guide: Cetuximab can be administered by infusion pump, gravity drip or syringe pump, and a separate infusion tube must be used. When the infusion is about to end, the infusion tube must be flushed with 9 mg/mL (0.9%) sterile sodium chloride solution.

This product is a colorless solution and may contain white visible amorphous particles related to the product. These particles will not affect the quality of the product. However, this product must be filtered with a 0.2 um or 0.22 um micropore filter during administration.

This product can be used with the following items: polyethylene, ethyl vinyl acetate or polyvinyl chloride plastic bags; polyethylene, ethyl vinyl acetate, polyvinyl chloride, polybutadiene or polyurethane infusion sets; polyethersulfone, polyamide or polysulfone series filters.

Aseptic operation must be ensured during the preparation of infusion.

This product must be prepared according to the following requirements:

Filter in series with an infusion pump or gravity drip: Take an appropriate sterile syringe (minimum 50 mL) and install a matching needle. Draw the required volume of cetuximab from the vial, transfer it to a vacuum container or plastic bag, and repeat the operation until the required volume is reached. Connect the above filter in series on the infusion tube, inject the product into the filter before dripping, and then start the drug administration. The drip rate is set and controlled as described above.

Filter in series with syringe pump: Take an appropriate sterile syringe (minimum 50 mL) and attach a matching needle, draw the required volume of cetuximab from the vial, remove the needle and put the syringe into the syringe pump, connect the above filter in series to the syringe pump, and inject the product into the filter before dripping, and then start the drug administration. The drip rate is set and controlled as described above. Repeat this operation until the required volume is reached.

During the drip, the filter may occasionally become clogged. If clogged, the filter must be replaced.

[Adverse Reactions and Contraindications]

The safety of cetuximab will not be affected by irinotecan, and vice versa. When used in combination with irinotecan, some other adverse reactions of this product are known adverse reactions of irinotecan (including diarrhea 72%, nausea 55%, vomiting 41%, mucositis such as stomatitis 26%, fever 33%, leukopenia 25%, and alopecia 22%). Therefore, please also refer to the instructions for use of irinotecan.

No gender differences were observed clinically for this product.

Immune system disorders: Common (]1/100, [1/10) – About 5% of patients experience hypersensitivity reactions when receiving cetuximab treatment; about half of these reactions are severe.

Mild to moderate (grade 1 or 2; National Cancer Center – Common Toxicity Criteria, NCI-CTC) reactions include symptoms such as fever, chills, nausea, rash, and dyspnea. Severe hypersensitivity reactions (grade 3 or 4) often occur during the initial infusion or within 1 hour after the end of the initial infusion, with symptoms including acute airway obstruction (such as bronchospasm, wheezing, hoarseness, difficulty speaking), urticaria, and/or hypotension.

For clinical management of the above adverse reactions, please refer to “Precautions”.

Eye diseases: Common (]1/100, [1/10) – About 5% of patients experience conjunctivitis.

Respiratory, chest and mediastinal disorders: common (1/10) – 25% of patients with terminal colorectal cancer have been reported to have dyspnea. The incidence of dyspnea is higher in elderly patients, those with low physical condition or patients with lung diseases, and the symptoms are sometimes severe (see “Precautions”).

Skin and subcutaneous tissue disorders: common (1/10) – More than 80% of patients may have skin reactions, of which about 15% have severe symptoms. The main symptoms are acne-like rashes, followed by nail diseases (such as onychomycosis). Most of these adverse reactions occur within the first week of treatment. Usually, the above symptoms can disappear on their own after interruption of treatment without sequelae. Treatment can then be continued according to the recommended adjusted dose (see “Precautions”). According to NCI-CTC, grade 2 skin reactions are rashes on 50% of the body surface, and grade 3 are rashes on more than or equal to 50% of the body surface.

Metabolic and nutritional disorders: Hypomagnesemia has been reported.

[Contraindications]

This product is contraindicated in patients with known severe hypersensitivity reactions (grade 3 or 4) to cetuximab.

For contraindications of irinotecan, please refer to its instructions for use.

[Pregnant women use]

EGFR is involved in fetal development. Existing studies have found that other IgG1 antibodies can pass through the placental barrier. Therefore, although no animal studies related to cetuximab have been conducted, and there is no sufficient data on the use of this product by pregnant or lactating women, it is still strongly recommended that pregnant women receive this product only when the benefits they may obtain outweigh the potential risks to the fetus.

Because it is unknown whether cetuximab will be secreted into breast milk, lactating women are advised not to breastfeed during treatment with this product and within 1 month after the last dose.

[Children use]

There is no safety and efficacy data on the use of cetuximab in pediatric patients.

[Drug interactions]

Irinotecan does not affect the safety of cetuximab, and vice versa. A formal drug interaction study showed that a single dose (350 mg/m2 body surface area) of irinotecan did not affect the pharmacokinetic properties of this product. Similarly, this product did not affect the pharmacokinetic properties of irinotecan.

Human studies on the interaction of this product with other drugs have not been conducted.

[Storage]

This product should be stored in a refrigerator (2-8°C), freezing is prohibited, and it should be used immediately after opening.

[Manufacturer]

Merck KGaA, Darmstadt