Erbitux, 5 mg/ml, solution for infusion, 20 ml, 1 pc.

Pharmacological properties of the drug Erbitux™

Cetuximab is a chimeric monoclonal IgGl antibody directed against the epidermal growth factor receptor (EGFR). EGFR signaling pathways control cell survival, cell cycle progression, angiogenesis, cell migration, and cell invasion/metastasis. Cetuximab binds to EGFR with an affinity approximately 5-10 times greater than that of endogenous ligands. Cetuximab blocks the binding of endogenous EGFR ligands, which leads to inhibition of receptor functions. It further induces EGFR internalization, which may lead to negative regulation of the receptor. Cetuximab also sensitizes cytotoxic immune effector cells to EGFR-expressing tumor cells (antibody-dependent cell-mediated cytotoxicity (ADC)). Pharmacodynamic effects In in vitro and in vivo , cetuximab inhibits the proliferation and induces apoptosis of human tumor cells that express EGFR . In vitro , cetuximab inhibits the production of angiogenic factors in tumor cells and blocks the migration of endothelial cells. In vivo , cetuximab inhibits the production of angiogenic factors in tumor cells and reduces the activity of neovascularization and tumor metastasis. Immunogenicity The appearance of antichimeric antibodies in humans (ACHA) is the result of the action of a class of chimeric antibodies. Current data on the production of CHAHA are limited. In general, the measured titers of NAT are found in 4.9% of observed patients with frequencies ranging from 0% to 8.5% in experiments with similar indications. To date, there is no clear data on the neutralizing effect of CHA on cetuximab. The appearance of CAC does not correlate with the development of a hypersensitivity reaction or other undesirable effects of cetuximab. Pharmacokinetics The pharmacokinetics of cetuximab have been studied in clinical studies when administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy. IV infusions of cetuximab demonstrated dose-dependent pharmacokinetics when administered weekly at doses ranging from 5 to 500 mg/m2 body surface area. When cetuximab was administered at an initial dose of 400 mg/m2 body surface area, the mean volume of distribution was approximately equivalent to the vascular site (2.9 L/m2, range 1.5–6.2 L/m2). The mean maximum concentration (± standard deviation) was 185 + 55 μg/ml. The average clearance was respectively 0.022 l/g/m2 per body surface area. The half-life of cetuximab is long, varying between 70 and 100 hours at the indicated dose. Serum concentrations of cetuximab reached stable values ​​after 3 weeks of monotherapeutic use of the drug. The mean maximum concentration was 155.8 μg/ml after 3 weeks and 151.6 μg/ml after 8 weeks, while the corresponding mean trough concentrations were 41.3 and 55.4 μg/ml, respectively. In studies of the combined administration of cetuximab with irinotecan, the mean reduction in concentration was 50 mcg/ml after 12 weeks and 49.4 mcg/ml after 36 weeks. Several pathways for antibody metabolism have been described. All of these pathways involve the biodegradation of antibodies to smaller molecules, i.e. low molecular weight peptides and amino acids. Pharmacokinetics in different patient groups A pooled analysis of all clinical studies showed that the pharmacokinetic characteristics of cetuximab do not depend on the race, gender, age and state of renal and hepatic function of the patient. At this time, only patients with an adequate level of kidney and liver function took part in the studies (serum creatinine level was no more than 1.5 times, transaminases - 5 times and bilirubin - 1.5 times higher than the upper limit of normal). Preclinical Safety Data In studies examining chronic toxicity in Cynomolgus monkeys at clinically significant levels, cutaneous toxicity was the main event reported. Cetuximab caused severe toxic skin and fatal complications in monkeys at concentrations 17 times higher than in humans using standard treatment regimens. Preclinical data on genotoxicity and local tolerance obtained from accidental administration of the drug by routes other than infusion do not indicate a threat to humans. There have been no practical animal studies to assess the carcinogenic potential of cetuximab, its effects on male and female reproductive function, or its teratogenic potential. Toxicological studies have also not been conducted with the simultaneous administration of cetuximaba and irinotecan. To date, there is no preclinical data on the effect of anti-EGFR antibodies on the wound healing process. Although in preclinical models of regenerating wounds, EGFR-selective tyrosine kinase inhibitors have been shown to increase the duration of wound healing.

Erbitux® – Merck Serono Cetuximab

Types of tumors » Medicines in this group »

Instructions for use of the drug Erbitux®

Erbitux® (Erbitux®). Brief instructions for medical use

INSTRUCTIONS for the use of the medicinal product for medical use ERBITUX® (ERBITUX®)

REGISTRATION NUMBER:

SR-002745/09.

TRADENAME:

Erbitux®.

INTERNATIONAL NON-PROPENTED NAME (INN):

cetuximab.

DOSAGE FORM:

solution for infusion.

COMPOUND:

1 ml of solution contains:

• active substance:
  cetuximab 5 mg;
• excipients:
  glycine 7.507 mg, polysorbate 80 0.1 mg, sodium chloride 5.844 mg, citric acid monohydrate 2.101 mg, sodium hydroxide 1M to pH 5.5, water for injection up to 1 ml.

DESCRIPTION:

Transparent or slightly opalescent, colorless to light yellow solution.

PHARMACOTHERAPEUTIC GROUP:

antitumor agent, monoclonal antibodies.

ATX code:

L01ХС06.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Erbitux® is a chimeric IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR).

EGFR signaling pathways are involved in the control of cell survival, cell cycle progression, angiogenesis, cell migration and cell invasion/metastasis.

Erbitux® binds to EGFR with an affinity that is approximately 5-10 times higher than that characteristic of endogenous ligands. Erbitux® blocks the binding of endogenous EGFR ligands, which leads to inhibition of receptor functions. It further induces EGFR internalization, which may lead to negative regulation of the receptor. Erbitux® also sensitizes cytotoxic immune effector cells against EGFR-expressing tumor cells. In in vitro and in vivo studies, Erbitux® inhibits the proliferation and induces apoptosis of human tumor cells expressing EGFR. In vitro, Erbitux® inhibits the production of angiogenic factors in tumor cells and blocks the migration of endothelial cells. In vivo, Erbitux® inhibits the production of angiogenic factors in tumor cells and reduces the activity of angiogenesis and tumor metastasis. Erbitux® does not bind to other receptors belonging to the HER family.

The proto-oncogene KRAS (Kirsten rat sarcoma viral oncogene 2 homolog) is a downstream central signal transducer for EGFR. In tumors, activation of KRAS EGFR leads to increased proliferation and production of pro-angiogenic factors.

KRAS is one of the most common activated oncogenes in cancer. Mutations of the KRAS gene occur in the active site (codons 12 and 13) as a result of activation of the KRAS protein, regardless of the EGFR signal.

In metastatic colorectal cancer, the KRAS mutation occurs in 30-50% of cases.

The appearance of anti-chimeric antibodies in humans (ACHA) is the result of exposure to a class of chimeric antibodies. Current data on AHA production are limited. Overall, measurable ACHA titers were detected in 3.4% of patients studied, with frequencies ranging from 0% to 9.6% in studies with similar indications. The appearance of AChAC is not correlated with the development of hypersensitivity reactions or any other undesirable effects of the drug Erbitux®.

Pharmacokinetics

Intravenous infusions of Erbitux® demonstrated dose-dependent pharmacokinetics when administered weekly in doses ranging from 5 to 500 mg/m2 body surface area.

When Erbitux® was administered at an initial dose of 400 mg/m2 body surface area, the mean volume of distribution was approximately equivalent to the area of ​​the vessels supplying the affected area (2.9 L/m2, range 1.5 to 6.2 L/m2). Average Cmax values ​​were in the range of 185±55 μg/ml. The average clearance corresponded to 0.022 l/h/m2 body surface area. Erbitux® has a long half-life, varying between 70 and 100 hours at the indicated dose.

Serum concentrations of the drug Erbitux® reached stable values ​​after three weeks of using the drug Erbitux® in monotherapy. The mean peak concentrations of Erbitux® were 155.8 mcg/mL at 3 weeks and 151.6 mcg/mL at 8 weeks, while the corresponding mean trough concentrations were 41.3 and 55.4 mcg/mL, respectively. In a study of the combination of Erbitux® with irinotecan, the mean reduction in concentrations corresponded to 50.0 mcg/ml after 12 weeks and 49.4 mcg/ml after 36 weeks.

Several pathways have been described that may contribute to antibody metabolism. All of these pathways involve the biodegradation of antibodies to smaller molecules, that is, small peptides or amino acids.

Pharmacokinetics in special populations

The pharmacokinetic characteristics of Erbitux® do not depend on race, gender, age, renal or liver function.

INDICATIONS FOR USE

• Metastatic colorectal cancer with EGFR expression and wild-type KRAS in combination with standard chemotherapy
• Monotherapy for metastatic colorectal cancer in case of ineffectiveness of previous chemotherapy containing irinotecan or oxaliplatin, as well as in case of intolerance to irinotecan
• Locally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy
• Recurrent or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy
• Monotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck when previous platinum-based chemotherapy has failed

CONTRAINDICATIONS

• Severe (grade 3 or 4) hypersensitivity to cetuximab
• Pregnancy
• Breastfeeding period
• Children's age (efficacy and safety of use have not been established)

CAREFULLY

: In case of impaired liver and/or kidney function (data on the use of the drug Erbitux® with bilirubin levels exceeding the upper limit of normal (ULN) by more than 1.5 times, transaminases by more than 5 times and serum creatinine by more than 1.5 exceeding ULN, currently not), suppression of bone marrow hematopoiesis, history of cardiopulmonary diseases, old age.

It is recommended to monitor serum electrolytes and correct electrolyte disturbances before starting therapy with Erbitux® and periodically during treatment due to the possible development of reversible hypocalcemia (due to diarrhea), hypomagnesemia, hypokalemia.

METHOD OF APPLICATION AND DOSES

Erbitux® is administered as an intravenous infusion at a rate of no more than 10 mg/min. Before infusion, premedication with antihistamines and prednisolone is necessary. For all indications, the drug is administered once a week at an initial dose of 400 mg/m2 of body surface (first infusion) as a 120-minute infusion and then at a dose of 250 mg/m2 of body surface as a 60-minute infusion.

Colorectal cancer

In patients with metastatic colorectal cancer, Erbitux® is used in combination with chemotherapy or as monotherapy. It is recommended that determination of KRAS mutation status be performed by an experienced laboratory using validation test methods. When using combination therapy, you should follow the recommendations for dose modification set out in the information about this drug.

The chemotherapy drug is administered no earlier than 1 hour after the end of the infusion of Erbitux®. It is recommended to continue therapy with Erbitux® until signs of disease progression appear.

Squamous cell carcinoma of the head and neck

When using Erbitux® in combination with radiation therapy, treatment with Erbitux® is recommended to begin 7 days before the start of radiation treatment and continue weekly administrations of the drug until the end of radiation therapy.

In patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, in combination with platinum-based chemotherapy, Erbitux® is used as maintenance therapy until signs of disease progression appear. Chemotherapy is prescribed no earlier than an hour after the end of the infusion of Erbitux®.

In patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck in whom chemotherapy has failed, Erbitux® is also used as monotherapy, with treatment continued until signs of disease progression appear.

Recommendations for adjusting the dosage regimen

If skin reactions of grade 3 toxicity develop according to the National Cancer Institute (NCI-CTC) classification, use of Erbitux® should be interrupted. Resumption of therapy is allowed only if the reaction resolves to grade 2.

If severe skin reactions occur for the first time, treatment can be resumed without changing the dose level.

In case of secondary or tertiary development of severe skin reactions, the use of Erbitux® must again be interrupted. Therapy can be resumed at a lower dose level (200 mg/m2 body surface after the second occurrence of the reaction and 150 mg/m2 after the third) if the reaction has resolved to grade 2.

If severe skin reactions develop for the fourth time or do not resolve to grade 2 during drug withdrawal, Erbitux® therapy should be discontinued.

Recommendations for the use of Erbitux®

Erbitux® is administered intravenously using an infusion pump, gravity drip system, or syringe pump.

A separate infusion system must be used for infusion. At the end of the infusion, the system should be flushed with sterile 0.9% sodium chloride solution.

Erbitux® is compatible with:

• polyethylene, ethyl vinyl acetate or polyvinyl chloride bags for infusion solutions,
• polyethylene, ethyl vinyl acetate, polyvinyl chloride, polyolefin or polyurethane infusion systems,
• polypropylene syringes for syringe pump.

Erbitux® cannot be mixed with other medicines.

Administration in a system with an infusion pump or gravity drip. Before administration, the required amount of the drug is transferred from the vials to a sterile container or bag for infusion solutions using a sterile syringe (minimum volume 50 ml). Using a gravity drip or infusion pump, set the infusion rate as recommended.

Administration in a syringe pump system. Before administration, the required amount of the drug is drawn from the vial into a sterile syringe. A syringe with a drug solution is installed in a syringe pump, then the infusion system is connected to the syringe. Set the infusion rate as directed and begin the infusion. Repeat the procedure until the calculated volume of the drug is completely infused.

The Erbitux® solution does not contain antibacterial preservatives or bacteriostatic components, and therefore, when handling it, the rules of asepsis should be strictly observed. It is recommended to use the drug as soon as possible after opening the bottle.

If the drug was not used immediately, the time and conditions for storing the ready-to-use drug before use depend on the user and, normally, should not exceed 24 hours at a temperature of +2...+8°C.

When used, the drug retains its chemical and biochemical properties for 48 hours at +25°C.

SIDE EFFECT

The main side effects of Erbitux® are skin reactions, observed in 80% of patients, hypomagnesemia - in 10% of patients, infusion reactions with moderate symptoms - in more than 10% of cases, infusion reactions with severe symptoms - in approximately 1% of cases.

The following adverse events noted when using the drug Erbitux® are distributed according to the frequency of occurrence according to the following gradation: very often (≥1/10), often (from ≥1/100 to <1/10) infrequently (from ≥1/10) 1000 to <1/100) rare (from ≥1/10000 to <1/1000) extremely rare (<1/10000).

From the nervous system

: often – headache.

From the organs of vision

: often – conjunctivitis, infrequently – blepharitis, keratitis.

From the respiratory system

: uncommon – pulmonary embolism.

From the digestive system

: often – diarrhea, nausea, vomiting.

From the skin and subcutaneous structures

: very often - skin reactions (acne-like rash and/or skin itching, dry skin, peeling, hypertrichosis, nail disorders (for example, paronychia). In 15%, skin reactions are severe, in isolated cases skin necrosis develops. Most skin reactions reactions develop in the first 3 weeks of treatment and usually go away without consequences after interruption of treatment, subject to recommendations for adjusting the dosage regimen); superinfections of skin lesions with an unknown frequency (violation of the integrity of the skin in some cases can lead to the development of superinfections, which can lead to the development of inflammation of the subcutaneous fatty tissue, erysipelas, or potentially fatal complications, such as staphylococcal epidermal necrolysis - Lyell's syndrome, or sepsis).

Metabolism and nutrition

: very often - hypomagnesemia, often - dehydration, hypocalcemia, anorexia with weight loss.

From the vascular system

: uncommon – deep vein thrombosis.

General violations and conditions for changing assignments

: very often - mild or moderate infusion reactions (mild or moderate fever, chills, dizziness, shortness of breath); mucositis, which can lead to nosebleeds; often - severe infusion reactions (usually develop during the first hour of the first infusion or several hours after the first or subsequent infusions, the main mechanism for the development of these reactions has not been established, perhaps some of them may be of an anaphylactoid/anaphylactic nature, including bronchospasm, urticaria , decrease or increase in blood pressure, loss of consciousness or shock), in rare cases - angina pectoris, myocardial infarction or cardiac arrest, apathy.

From the hepato-biliary system

: very often increased levels of AST, ALT, alkaline phosphatase.

OVERDOSE

Cases of overdose have not been described. There is currently limited experience with single doses greater than 400 mg/m2 body surface area or subsequent weekly doses greater than 250 mg/m2 body surface area.

INTERACTION WITH OTHER DRUGS AND OTHER FORMS OF INTERACTION

The use of Erbitux® in combination with fluorouracil infusion, compared with the use of fluorouracil alone, may cause an increase in the incidence of coronary ischemia and thrombosis, including myocardial infarction, as well as hand-foot syndrome.

When Erbitux® and irinotecan were co-administered, no changes in the pharmacokinetic parameters of both drugs were observed.

No other interaction studies have been conducted with Erbitux® in humans.

Due to the lack of compatibility studies, mixing Erbitux® with other medications is prohibited.

The use of Erbitux® in combination with platinum-based chemotherapy compared with the use of platinum-based chemotherapy increases the incidence of severe neutropenia, which may be accompanied by concomitant infectious complications such as febrile neutropenia, pneumonia or sepsis.

SPECIAL INSTRUCTIONS

Therapy with Erbitux® should be carried out under the supervision of a physician experienced in the use of anticancer drugs.

When administering the drug Erbitux®, infusion reactions usually develop during the first infusion or within 1 hour after the end of the drug administration, but they can occur after several hours, as well as with repeated administrations. The patient should be warned about the possibility of such delayed reactions and instructed to consult a doctor immediately after they occur.

If the patient experiences a mild or moderate infusion-related reaction, the infusion rate should be reduced. During subsequent infusions, the drug should also be administered at a reduced rate.

The development of severe symptoms of an infusion reaction requires immediate and permanent cessation of treatment with Erbitux® and may result in the need for emergency medical attention.

Particular attention should be paid to patients with a history of heart or lung disease.

Isolated cases of interstitial pulmonary disorders have been described for which no causal relationship with the use of the drug Erbitux® has been identified. If interstitial lung disorders develop during therapy with Erbitux®, treatment with the drug should be discontinued and appropriate therapy should be prescribed.

Breastfeeding during therapy with Erbitux® and for 2 months after taking the last dose of the drug is contraindicated.

If grade 3-4 skin reactions occur, the dose and mode of administration of Erbitux® should be adjusted in accordance with the above recommendations.

When using Erbitux® in combination with chemotherapy, you should carefully read the instructions for medical use of the chemotherapy drug.

To date, experience has been gained in using the drug only in patients with adequate levels of kidney and liver function (serum creatinine and bilirubin levels did not exceed the upper limit of normal by more than 1.5 times, and the level of transaminases by more than 5 times).

The use of cetuximab has also not been studied in patients with suppressed bone marrow hematopoiesis, i.e. with a hemoglobin level <9 g/dL, white blood cell count <3,000/μL, absolute neutrophil count <1500/μL, and platelet count <100,000/μL.

The safety and effectiveness of Erbitux® in children have not been studied.

During treatment with Erbitux®, as well as for at least 2 months after, it is necessary to use reliable methods of contraception.

When Erbitux® is used in combination with platinum-based chemotherapy, the frequency and severity of hypocalcemia may increase.

Patients receiving Erbitux® in combination with platinum-based chemotherapy are at high risk of severe neutropenia, which may be accompanied by associated infectious complications such as febrile neutropenia, pneumonia or sepsis. Careful monitoring is recommended in such patients, especially those with a history of skin lesions, mucositis, or diarrhea, which may precipitate infections.

No studies have been conducted on the effect of the drug on the ability to drive and control equipment. If the patient notices treatment-related symptoms that affect his ability to concentrate and react quickly, it is recommended to refrain from driving and performing potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Release form

Solution for infusion 5 mg/ml at 50 mg/10 ml, 100 mg/20 ml, 250 mg/50 ml, 500 mg/100 ml in a colorless glass bottle type I with a bromobutyl rubber stopper coated with Teflon; 1 bottle along with instructions for use in a cardboard box.

Storage conditions:

Store at 2-8°C. Do not freeze. Keep out of the reach of children.

Best before date:

3 years. Do not use after the expiration date.

Conditions for dispensing from pharmacies:

On prescription.

Manufacturer:

Merck KGaA, 64293 Damstadt, Frankfurterstrasse 250, Germany

Consumer complaints and information about adverse events should be sent to:

"Representative office of Ares Trading S.A." 125445, Moscow, st. Smolnaya, 24D, office of Merck LLC Tel. Fax E-mail:

Indications for use of the drug Erbitux™

• Metastatic colorectal cancer in combination with standard chemotherapy as first line of therapy;
• monotherapy for metastatic colorectal cancer in cases of ineffective previous use of chemotherapy containing irinotecan or oxaliplatin, as well as in cases of intolerance to irinotecan;
• local forms of squamous cancer of the head and neck in combination with radiation therapy as the first line of therapy;
• recurrent and/or metastatic squamous head and neck cancer in combination with platinum-based chemotherapy;
• monotherapy for recurrent and/or metastatic squamous head and neck cancer in cases of ineffective previous chemotherapy.

Use of the drug Erbitux™

It is recommended that EGFR expression analysis be performed by an experienced laboratory using valid testing methods. Erbitux should be prescribed under the supervision of a physician experienced in the use of antineoplastic drugs. During the infusion and for at least 1 hour after it, it is necessary to strictly monitor the patient's condition. The ability to use resuscitative equipment should be guaranteed. Before the first infusion, patients should be premedicated with antihistamines. Similar premedication is recommended before each subsequent infusion. Erbitux is prescribed once a week. The first dose is 400 mg of cetuximab per m2 of body surface. Thereafter, the weekly dose is 250 mg/m2. For the first dose, the recommended infusion period is 120 minutes. For subsequent weekly doses, the recommended infusion duration is 60 minutes. The maximum infusion rate should not exceed 10 mg/min. Colorectal cancer For the treatment of metastatic colorectal cancer, Erbitux is used as monotherapy and also in combination with irinotecan. To determine the dose of irinotecan, when prescribed simultaneously, you need to refer to the information on this medicinal product. Typically, the same dose of irinotecan is used as was prescribed in the last cycles of the previous course of irinotecan-containing therapy. However, you should follow the dosage modification recommendations for irinotecan provided in the product information for this medicinal product. Irinotecan should not be administered earlier than 1 hour after the end of the cetuximab infusion. It is recommended to continue treatment with Erbitux until progression of the underlying disease is recorded. Erbitux is administered IV through a filtration line using an infusion pump, gravity drip system, or syringe pump. Squamous cancer of the skin of the head and neck The drug Erbitux is prescribed for the treatment of local forms of squamous cancer of the skin of the head and neck in combination with radiation therapy. It is recommended to prescribe Erbitux therapy one week before the start of radiotherapy and continue until the end of radiotherapy. When treating local forms of squamous cancer of the head and neck in combination with the drug Erbitux, up to 6 courses of platinum-based chemotherapy are prescribed until progression of the underlying disease is recorded. Chemotherapy is prescribed no earlier than 1 hour after completion of the Erbitux infusion. For the treatment of recurrent and/or metastatic squamous cancer of the head and skin, Erbitux is used as monotherapy. It is recommended to continue treatment with Erbitux until progression of the underlying disease is recorded. Instructions for use and handling of Erbitux can be administered using a gravity dropper, infusion pump, or syringe plunger. A separate infusion line must be used for infusion, and at the end of the infusion, the line must be flushed with sterile sodium chloride solution 9 mg/ml (0.9%) for injection. Erbitux 2 mg/ml is a colorless solution that may contain whitish amorphous particles of the drug. These particles do not affect the quality of the drug. However, the solution must be filtered through an internal line filter with a pore size of 0.2 µm or 0.22 µm during drug administration. Erbitux 2 mg/ml is compatible with:

• polyethylene, ethyl vinyl acetate or polyvinyl chloride bags;
• polyethylene, ethyl vinyl acetate or polyvinyl chloride, polybutadiene or polyurethane infusion sets; polyethersulfone, polyamide or polysulfone line filters.

When preparing the infusion, special care should be taken to maintain aseptic conditions. Erbitux must be prepared as follows: Filtration in line with an infusion pump or gravity drip: take a sterile syringe (minimum 50 ml) and put a needle on it. Take the required amount of cetuximab from the vial. Transfer cetuximab to a sterile container or bag in which a vacuum has been created. Repeat the procedure until the calculated volume is obtained. Place an appropriate in-line filter in the infusion line and moisten it with Erbitux before starting the infusion. Use a gravity drip or infusion pump for administration. Set and monitor rate of administration as directed. Filtration in line with a syringe pump: take a sterile syringe (minimum 50 ml) and put a needle on it. Take the required amount of cetuximab from the vial. Remove the needle and install the syringe into the syringe pump. Take the appropriate in-line filter and attach it to the infusion set. Attach the infusion line to the syringe. Set and monitor the infusion rate as directed and begin infusion after wetting the line with Erbitux. Repeat this procedure until the entire calculated volume is infused. Filters may become clogged during infusion. If it is obvious that the filter is clogged, it must be replaced. Chemical and biochemical stability in the use of Erbitux was demonstrated for 20 hours at a temperature of 25°C. Erbitux does not contain antibacterial preservatives or bacteriostatic components. From a microbiological point of view, this drug should be used immediately after opening the bottle. If the drug was not used immediately, the time and storage conditions of the ready-to-use drug depend on the user and, normally, should not exceed 24 hours at a temperature of 2–8 ° C, except in cases where the opening of the package (vial) is carried out in a controlled and stable aseptic conditions.

Erbitux, 5 mg/ml, solution for infusion, 20 ml, 1 pc.

Infusion.

Therapy with Erbitux® must be carried out under the supervision of a physician with experience in the use of antitumor drugs.

During the infusion and for at least 1 hour after its completion, careful monitoring of the patient's condition is necessary. Equipment for resuscitation measures must be prepared.

Before the first infusion, premedication with antihistamines and corticosteroids is necessary. Premedication is also recommended before all subsequent infusions.

For all indications, Erbitux® is administered once a week at an initial dose of 400 mg/m2 (first infusion) as a 120-minute infusion. All subsequent weekly infusions are carried out at a dose of 250 mg/m2 with a recommended infusion duration of 60 minutes. The maximum infusion rate should not exceed 10 mg/min.

Colorectal cancer

In patients with mCRC, Erbitux® is used in combination with chemotherapy or as monotherapy. Before using Erbitux® for the first time, the status of RAS gene mutations (KRAS)

and
NRAS)
.
This study should be performed in a laboratory experienced in performing such tests using validated methods for determining the mutation status of the KRAS
and
NRAS
in exons 2, 3 and 4.

When combining therapy, you should adhere to the recommendations for modifying the doses of co-prescribed chemotherapy drugs given in the instructions for their use. In any case, these drugs should not be administered earlier than 1 hour after the end of the Erbitux® infusion. It is recommended to continue therapy with Erbitux® until signs of disease progression appear.

Squamous cell carcinoma of the head and neck

In patients with locally advanced HNSCC, Erbitux® is used in conjunction with radiation therapy. It is recommended to start treatment with Erbitux® 7 days before the start of radiotherapy and continue it until the end of radiotherapy. In patients with recurrent and/or metastatic HNSCC, Erbitux® is used in combination with platinum-based chemotherapy. Erbitux® is used as maintenance therapy until signs of disease progression appear. Chemotherapy drugs should not be administered earlier than 1 hour after the end of the Erbitux® infusion.

In patients with recurrent and/or metastatic HNSCC in whom chemotherapy has failed, Erbitux® is used as monotherapy. It is recommended to continue therapy with Erbitux® until signs of disease progression appear.

Recommendations for adjusting the dosage regimen

If a skin reaction develops (grade 3 or 4 on the US National Cancer Institute toxicity scale), use of Erbitux® should be discontinued. Treatment may be resumed after the reaction has resolved to a level corresponding to grade 2. If a severe skin reaction occurs for the first time, treatment can be resumed at the previous dose.

If a severe skin reaction recurs, Erbitux® should again be temporarily discontinued. Treatment can only be resumed at a reduced dose (200 mg/m2 after the 2nd reaction and 150 mg2 after the 3rd reaction) after the reaction has resolved to a level corresponding to grade 2.

If a severe skin reaction occurs for the 4th time or does not resolve to a level corresponding to grade 2 during a break in treatment, further use of Erbitux® is contraindicated.

Recommendations for the preparation of infusion solution and methods of administration

Erbitux®, 5 mg/ml, is administered IV using an infusion pump, gravity drip system, or syringe pump. Erbitux® is compatible only with sterile 0.9% sodium chloride solution. The drug Erbitux® should not be mixed with other drugs. A separate infusion set should be used for infusion and the system should be flushed with sterile 0.9% sodium chloride injection at the end of the infusion.

Erbitux®, 5 mg/ml, compatible with:

— PE, ethyl vinyl acetate (EVA) or PVC bags for infusion solutions;

- PE, polyurethane (PU), EVA, PVC or polyolefin (PTP), infusion systems;

— polypropylene (PP) syringes for syringe pumps.

Care must be taken to ensure aseptic conditions when preparing the solution for infusion.

Erbitux®, 5 mg/ml, should be diluted as follows:

For administration in a system with an infusion pump or gravity drip system (in a sterile solution of 0.9% sodium chloride).

Take a bag with a sterile solution of 0.9% sodium chloride for infusion solutions of a suitable volume. Calculate the required volume of Erbitux®. Remove excess sodium chloride solution from the bag using a sterile syringe and a suitable needle. Take a suitable sterile syringe and attach the appropriate needle. Take the required volume of Erbitux® from the vial and transfer it to a bag for infusion solutions. Repeat this procedure until the calculated volume of the drug is reached. Connect the infusion system and fill it with diluted Erbitux® before starting the infusion. To administer the drug, use a gravity drip system or infusion pump. Set and monitor the infusion rate according to the recommendations described above.

For administration in a system with an infusion pump or gravity drip system (without dilution).

Calculate the required volume of Erbitux®. Take a suitable sterile syringe (volume of at least 50 ml) and attach the appropriate needle to it. Take the required volume of Erbitux® from the vial. Transfer the collected volume of Erbitux® into a sterile container or bag for infusion solutions. Repeat this procedure until the calculated volume of the drug is reached. Connect the infusion system and fill it with Erbitux® before starting the infusion. To administer the drug, use a gravity drip system or infusion pump. Set and monitor the infusion rate according to the recommendations described above.

For administration in a syringe pump system.

Calculate the required volume of Erbitux®. Take a suitable sterile syringe and attach the appropriate needle to it. Take the required volume of Erbitux® from the vial. Disconnect the needle and insert the syringe into the syringe pump. Connect the infusion system to the syringe, set and control the rate of administration in accordance with the recommendations. Before starting the infusion, fill the infusion system with Erbitux® or a sterile 0.9% sodium chloride solution. If necessary, repeat this procedure until the calculated volume is achieved.

The chemical and physical stability of Erbitux® during use has been demonstrated for 48 hours at 25°C when the solution is prepared as described above.

The drug Erbitux® does not contain antibacterial preservatives or bacteriostatic substances, therefore, when handling it and preparing the infusion, aseptic rules should be strictly observed. It is strongly recommended to use the drug immediately after opening the bottle. If the solution is not used immediately, the user is responsible for its storage and further use. The storage period should not exceed 24 hours at a temperature of 2–8 °C.

Side effects of Erbitux™

Taking the drug can cause serious side effects, including death. They usually develop within an hour after the first dose of the drug. Symptoms may include the following: acute attacks of airway obstruction (bronchospasm, wheezing, hoarseness, difficulty speaking), as well as urticaria, hypotension or loss of consciousness, and sometimes sore throat, myocardial infarction or cardiac arrest. The side effects described in this section are specific to cetuximab. There is no evidence that irinotecan affects the safety profile of cetuximab and vice versa. When used in combination with irinotecan, side effects were supplemented by those that are expected when prescribing irinotecan (such as diarrhea 72%, nausea 55%, vomiting 41%, mucositis, i.e. stomatitis 26%, fever 33%, leukopenia 25%, baldness 22%). Therefore, you should also read the information about the drug substance irinotecan. There were no clinically significant differences in side effects depending on gender. In combination with local radiation therapy of the head and neck, side effects characteristic of radiation therapy (stomatitis, radiation dermatitis, dysphagia, leukopenia, mainly lymphocytopenia) are additionally noted. In randomized clinical trials involving 424 patients, it was recorded that the occurrence of acute mucositis and radiation dermatitis, as well as adverse effects associated with radiation therapy, was observed slightly more often with the combined use of radiation therapy with Erbitux than in patients who received radiation therapy alone. Dyspnea may occur within a short period of time after cetuximab administration as part of a hypersensitivity reaction, but similar cases have also been described after several weeks of therapy, which is likely related to the underlying disease. The risk of severe and prolonged dyspnea exists for elderly patients with a reduced functional status of the respiratory system and a history of bronchopulmonary diseases. If a patient develops dyspnea during a course of cetuximab, it is recommended that testing be performed to identify signs of progressive lung disease. Individual cases of interstitial pulmonary diseases have been described, the connection of which with the use of cetuximab has not been established. A gradual decrease in serum magnesium levels has been observed, leading to severe hypomagnesemia in some patients. Other electrolytic abnormalities, mainly hypocalcemia and hypokalemia, of varying severity were also observed. Skin reactions If a patient experiences severe skin reactions (Grade 3; US National Cancer Institute - Common Toxicity Criteria, NCI-CTC), cetuximab should be discontinued. Resumption of therapy is allowed only if the response decreases to grade II. If severe skin reactions occur for the first time, treatment can be resumed without changing the dose level. With secondary or tertiary development of severe skin reactions, the use of cetuximab must again be interrupted. Therapy can be resumed at a lower dose level (200 mg/m2 of body surface after the second occurrence of the reaction and 150 mg/m2 after the third), if the reaction has decreased to grade II. If severe skin reactions develop for the fourth time or do not decrease to grade 2, cetuximab therapy should be permanently discontinued. To date, only patients with an adequate level of kidney and liver function have been studied (serum creatinine level is no more than 1.5 times, transaminases - 5 times and bilirubin - 1.5 times higher than the upper limit of normal). Cetuximab has not been studied in patients with one or more of the following hematologic abnormalities: hemoglobin ≤ 9 g/dL; leukocyte count ≤ 3000/mm3; absolute neutrophil count ≤ 1500/mm3; platelet count ≤ 100,000/mm3. Immune system disorders Common (1/100, ≤1/10) Approximately 5% of patients experienced hypersensitivity reactions while using cetuximab; approximately half of these reactions were severe. Mild to moderate reactions (grade 1 or 2) include symptoms such as fever, chills, nausea, skin rash, or dyspnea. Severe hypersensitivity reactions (grade 3 or 4) usually develop during the first infusion of cetuximab or within 1 hour after it. Their symptoms include rapid development of airway obstruction (bronchospasm, stridor, hoarseness, difficulty speaking), urticarial rash and/or hypotension. Eye disorders Common (1/10) The development of conjunctivitis can be expected in approximately 5% of patients. Respiratory, thoracic and mediastinal disorders Very common (1/10) Dyspnea is described in 25% of patients with the last stage of rectal and colon cancer. An increased incidence of dyspnea (sometimes severe) was observed in elderly patients, in patients with decreased functional status or a history of chronic bronchopulmonary diseases. Skin and subcutaneous tissue disorders Very common (1/10) Skin reactions may occur in more than 80% of patients; approximately 15% of reported reactions are severe. As a rule, these are reactions in the form of acne-like rashes and/or occasionally in the form of nail disorders (for example, paronychia). Most skin reactions develop during the first week of therapy. As a rule, they disappear over time without consequences after interruption of treatment, if the necessary correction of the dosage regimen is carried out. According to the NOR-ZKT, grade II skin reactions are characterized by rashes that occupy about 50% of the body surface, while grade III reactions occupy 50% or more of the body surface area.

Skin toxicity of EGFR blockers (based on clinical studies of cetuximab)

It was assumed that such a molecularly targeted mechanism of action would reduce the severity of associated toxicities, but it was not possible to make the therapy safer and more comfortable. It turned out that all targets blocked by new drugs perform a certain physiological role in normal cells and their blockade leads to previously unknown side effects. These adverse events may represent a serious clinical problem, necessitating dose reduction or even discontinuation of therapy. One of the most important modern areas of targeted therapy for malignant tumors is blockade of epidermal growth factor receptors (EGFR), which play a key role in signal transmission and stimulation of tumor cell proliferation. Several drugs of this class are registered for clinical use: monoclonal antibodies (MAbs) to the extracellular domain of the EGFR cetuximab (Erbitux) and panitumumab (Vectibix) and small molecules - tyrosine kinase inhibitors in the intracellular domain of the receptor erlotinib (Tartseva) and gefitinib (Iressa). The most common side effects of anti-EGFR drugs are specific skin reactions.

The most common is skin rash, which is more pronounced with the use of mAbs compared to tyrosine kinase inhibitors. Skin toxic reactions are very rarely life-threatening, but they can pose a serious problem for the patient and cause severe emotional distress. Knowledge of such features allows you to start symptomatic therapy in a timely manner and significantly reduce the severity of adverse events.

Cetuximab in the treatment of malignant tumors

Cetuximab (Erbitux, Germany) is the most widely studied drug from the group of EGFR blockers. It is effective for colorectal cancer, head and neck tumors. Studies are being conducted on the effectiveness of cetuximab in non-small cell lung cancer, cancer of the esophagus, stomach, pancreas, cervix, triple negative breast cancer, etc. The drug is a chimeric IgG1 mAb that specifically binds to the extracellular domain of the epidermal growth factor receptor (EGFR or HER1/ ErbB1). Cetuximab has approximately 10-fold greater affinity than the natural EGFR ligands (EGF and TGF-α).

The drug competitively inhibits the receptor and prevents ligand-induced phosphorylation in the tyrosine kinase domain of the receptor, blocking subsequent activation of the signaling cascade, which leads to the suppression of proliferation, invasion and metastasis, while stimulating apoptosis and increasing sensitivity to chemotherapy and radiation therapy [1]. In addition, the antibody-receptor complex undergoes endocytosis and intracellular degradation, resulting in a decrease in the density of EGFR on the cell surface. Another important mechanism of action of cetuximab is the induction of an antitumor effect through antibody-dependent cell-mediated cytotoxicity [2]. In addition to the implementation of immune mechanisms, a significant aspect of the use of cetuximab is the fact that the EGFR signaling cascade is closely linked to VEGF and angiogenesis processes through phosphatidylinositol 3-kinase (PI3-K), the protein serine/threonine kinase Akt and the molecular target of rapamycin in mammals (mTOR). Thus, one of the most important antitumor effects of cetuximab is the suppression of excessive production of VEGF by tumor cells, and hence neoangiogenesis [3].

Treatment of colorectal cancer

Cetuximab has been studied in first, second and third line therapy for metastatic colorectal cancer (mCRC) in a large number of randomized phase II–III trials and is an established option in patients without a KRAS mutation. It should be noted that in the first clinical studies of antibodies to EGFR in colorectal cancer, patients were included after immunohistochemical analysis of the tumor. The effectiveness of cetuximab (and panitumumab) was later shown to be independent of EGFR expression, and IHC testing is not currently required to prescribe drugs.

Mutations of the KRAS gene in codons 12–13 are detected in approximately 40% of cases of metastatic colon cancer [4]. In the presence of such a mutation, the KRAS protein (p21ras) is active independently of EGFR [5] and blockade of EGFR with mAbs (panitumumab or cetuximab) does not lead to blockade of downstream signaling pathways. Clinical studies have confirmed the significance of the KRAS gene mutation as a predictor of resistance to cetuximab and panitumumab. These drugs should only be used in patients without a KRAS mutation in the tumor (the so-called “wild” type according to the results of molecular genetic analysis).

In the first-line treatment of mCRC, cetuximab was studied in combination with an irinotecan-containing regimen in the CRYSTAL trial (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer). At baseline (at inclusion of patients, n = 1198), KRAS status was not assessed; later, KRAS status was assessed in 89% of patients, mutations were detected in 37% of cases. It was shown that in the subgroup with the “wild” type of KRAS (n = 666), the addition of cetuximab to chemotherapy according to the FOLFIRI regimen led to a significant improvement in all main assessed treatment outcomes [6–8]:

• increase in overall survival (OS) by 3.5 months. (median OS in the cetuximab group was 23.5 months, in the FOLFIRI only therapy group was 20.0 months, risk of death HR = 0.796; p = 0.0093);
• reduction in the risk of disease progression by 30.4% (median progression-free survival (PFS) was 9.9 months versus 8.4 months, HR = 0.696; p = 0.0012);
• increase in objective tumor response from 39.7% to 57.3% (odds ratio OR = 2.069; p

It should be noted that cetuximab is the only targeted drug today that, when added to modern first-line chemotherapy regimens, including 5-fluorouracil infusion, significantly increases the overall survival of patients with mCRC (in the subgroup without a KRAS mutation).

A very important feature of cetuximab is its high immediate effectiveness, which is assessed by the frequency of complete and partial regressions, which is very important for patients with potentially resectable liver metastases. Thus, according to the CRYSTAL study, in patients with isolated liver damage and wild-type KRAS, the effectiveness of the cetuximab + FOLFIRI regimen reaches 77%. Similar results were obtained in the CELIM study, in which 109 patients with colon cancer liver metastases received neoadjuvant chemotherapy with cetuximab + FOLFOX6 or cetuximab + FOLFIRI. In the group without the KRAS mutation, 70% of complete and partial regressions were registered, and the R0 rate of resections in patients with initially unresectable metastases reached 34% [9].

The OPUS study assessed the effectiveness of FOLFOX4 +/- cetuximab regimens also in the first line of mCRC treatment. It was shown that in patients without the KRAS mutation, the use of cetuximab was accompanied by a significant reduction in the risk of disease progression (HR = 0.57; p = 0.0163) and an increase in the overall effectiveness of treatment (regression rate was 61% versus 37%; OR = 2.54; p = 0.011) compared with FOLFOX4 chemotherapy alone [10]. In intensively pretreated patients without a KRAS mutation, cetuximab monotherapy, compared with best supportive care, significantly prolonged overall survival (median OS 9.5 months vs 4.8 months, HR = 0.55; 95% confidence interval (CI) ) 0.41–0.74; p

Interesting data on the effectiveness of cetuximab depending on the type of KRAS mutation were presented at the ASCO 2011 annual congress. For the first time, it was shown that in patients with the KRAS G13D mutation, anti-EGFR therapy can also be effective [12], however, this fact requires additional analysis and discussion.

Therapy for squamous cell carcinoma of the head and neck

To date, cetuximab is the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma. Results from a multicenter phase III clinical trial reported by JA Bonner et al showed that the addition of cetuximab to radiation therapy for locally advanced cancer of the oropharynx, hypopharynx, and larynx significantly improved locoregional disease control, progression-free survival, and overall survival compared with radiation alone. therapy [13]. Long-term follow-up confirmed the long-term effect of the drug: 5-year overall survival was 45.6% in the cetuximab + radiation therapy group compared to 36.4% in the radiation therapy only group, median OS was 49.0 months. versus 29.3 months. (HR = 0.73; 95% CI 0.56–0.95; p = 0.018) [14].

The effectiveness of cetuximab in combination with platinum-containing chemotherapy in the first-line treatment of recurrent and metastatic head and neck cancer was studied by JB Vermorken et al. [15]. Patients in the control group (n = 220) received cisplatin 100 mg/m2 (or carboplatin AUC5) on day 1 plus 5-fluorouracil 1000 mg/m2 on days 1–4 every 3 weeks for a maximum of 6 cycles. in the experimental group, cetuximab was additionally used: the first dose was 400 mg/m2, then 250 mg/m2 once a week, the maximum number of cycles was 6. It was shown that the addition of cetuximab significantly increased the median overall survival from 7.4 to 10, 1 month (HR = 0.8; 95% CI 0.64–0.99; p = 0.04) and median progression-free survival from 3.3 to 5.6 months. (HR = 0.54; p = 0.001), as well as the objective response rate from 20% to 36% (p

Skin toxic effects of cetuximab

A specific side effect of all EGFR inhibitors is skin toxicity, and when using mAbs its frequency is higher and reaches 90% compared to treatment with tyrosine kinase inhibitors (about 60%) [19, 20]. The pathogenesis of the development of skin toxicity is well studied and is associated with high expression of EGFR on normal epidermal cells and follicular keratinocytes, as well as on epithelial cells of the sebaceous and eccrine glands, antigen-presenting dendritic cells and various connective tissue cells [21]. EGFR plays an important role in the normal development and physiology of epidermal cells and the upper layers of the hair follicle, and its inhibition leads to suppression of growth and premature maturation of basal keratinocytes, leukocyte infiltration, apoptosis and cell death and is accompanied by a decrease in epidermal thickness (Fig. 1) [22– 25]. It should be noted that the pathogenesis of true acne and the rash associated with anti-EGFR therapy is different, so most researchers, when describing the latter, advise using the term “acne-like” rather than “acne” [26]. In general, several groups of dermatological reactions associated with EGFR inhibition are described [21, 27, 28]:

• skin: acne-like rash, dryness, cracks, eczema, itching, photosensitivity, hyperpigmentation;
• mucous membranes: dry mouth and mucositis;
• nails: paronychia;
• hair: trichomegaly and hypertrichosis.

It has been shown that the severity of side effects from the external integument changes during therapy with anti-EGFR mAbs (Fig. 2).

Clinical manifestations and methods of combating skin toxic effects of therapy Acneiform dermatitis and acne-like rash

Skin rash is the most common adverse event associated with cetuximab. Thus, in mCRC, rash of any degree was observed in 81% of patients receiving cetuximab in combination with irinotecan, and in 83% of patients receiving cetuximab monotherapy. Moreover, grade 3–4 severity was recorded in 13% and 9% of patients, respectively [29]. In squamous cell carcinoma of the head and neck, grade 3 skin reactions were observed in 9% of patients receiving cetuximab in combination with platinum derivatives and 5-fluorouracil [30].

The meta-analysis, which assessed the incidence of cutaneous toxicities during cetuximab therapy, included 16 clinical studies involving 2037 patients [52]. Various types of skin toxicity of all grades were recorded in 88.2% of cases (95% CI 84.8–91.0%), high grade - in 11.3% (95% CI 8.8–14.3). Skin rash of all degrees of severity was observed in 81.6% of patients (95% CI 75.4–86.6%), severe severity – in 6.5% (95% CI 4.1–10.0%). Interestingly, in colorectal cancer, severe manifestations of skin rash were observed significantly more often than in tumors of other locations (12.6% vs. 6.6%; HR = 1.9; 95% CI 1.0–3.6; p = 0.049 ).

Skin rash appears already at the beginning of therapy, at 2–4 weeks [31], and consists of multiple macules, papules or pustules without comedones, which are most often localized on the face, upper half of the torso and back, sometimes spreading to the extremities [21 , 29, 49–51]. In some cases, a rash is registered immediately after the first dose is administered and often serves as an unjustified reason for delaying the next administration of the drug or completely refusing treatment. It is important that over time, in most patients, skin reactions weaken, after skipping a drug dose or reducing its dose, they decrease significantly, and after discontinuation of cetuximab, as a rule, they disappear completely without any consequences (Fig. 2).

The international interdisciplinary consensus on the treatment of anti-EGFR therapy-associated skin toxicity recommends a distinction between three grades of skin adverse events: mild, moderate, and severe [32] (Table 1). According to the NCI CTC criteria, which are used in clinical trials, there are 4 grades of skin toxicity (4th, very severe, grade - exfoliating or ulcerative dermatitis). In routine practice, it is more convenient to use a three-grade classification, which is recommended by a group of German experts on the study of skin reactions associated with anti-EGFR therapy [21], as well as the Multinational Association of Supportive Care in Cancer (MASCC) [33].

In case of grade 1–2 skin toxicity of anti-EGFR therapy, it is recommended to continue therapy as standard; subsequently, the severity of the acne-like rash usually decreases. In the event of grade 3 adverse events (affecting more than 50% of the body surface), treatment is interrupted and resumed without reducing the dose of the drug when toxicity is reduced to grade 1-2. If a second episode of grade 3 skin toxicity occurs, treatment is suspended again, and the subsequent dose of the drug is reduced (Table 1).

Before starting therapy, it is important to warn the patient about simple preventive measures: avoid injuries, apply sunscreen with a protection level of at least 30 before going outside, avoid sun exposure, avoid makeup if possible, use mild detergents and moisturizers. It should also be noted that the dynamics of rash manifestations depend on the drug and its dose, but there is significant variability between patients. After stopping therapy, the rash disappears, and this may happen within a month. When a rash appears, the following are recommended as local treatment:

• local antibiotics (erythromycin, clindamycin, gentamicin gel, cream or lotion, metronidazole gel or cream 2 times a day);
• ointment with carbamide (urea), for example Keratolan;
• local corticosteroids (hydrocortisone, triamcinolone, etc.), usually in combination with local antibiotics, usually for a short time, in order to eliminate skin itching (with long-term use, corticosteroids can increase dry skin).

In addition, the manifestations of skin toxicity can be reduced with the help of creams containing vitamin K1 [34, 35], salt compresses (for 15 minutes 2-3 times a day), which help to quickly suppress the inflammatory process; Creams with menthol have a symptomatic effect.

Recently, publications have appeared on the possible effectiveness of the dermatotropic drug pimecrolimus, which is used to treat atopic dermatitis [36], but a randomized trial showed that the drug is ineffective against rash caused by cetuximab [37]. Drugs used to treat acne vulgaris or rosacea (retinoids, benzoyl peroxide, etc.) are not recommended for rash associated with anti-EGFR therapy [21], although they were effective in some patients. The use of alcohol-containing lotions is undesirable, as they can dry out the skin. It is necessary to carefully monitor the patient to prevent worsening of the xerosis. Systemic treatment:

• antibiotics (usually oral tetracyclines: doxycycline 100 mg 1-2 times a day, minocycline 100 mg 1 time a day for a long time, with the development of grade 3 toxicity, the dose of the antibiotic is increased for a short time; less commonly, cephalexin 250-500 mg 4 times is used per day or erythromycin 250–500 mg 4 times a day);
• antihistamines - to relieve itching;
• analgesics – for grade 3–4 toxicity, for example pregabalin (Lyrica);
• Systemic corticosteroids are usually prescribed for grade 4 (rarely for grade 3) because they can cause steroid acne.

If S. aureus superinfection is confirmed, therapy with cefuroxime or flucloxacillin should be initiated immediately.

Pruritis (skin itch), xerosis and eczema-like changes

For itchy skin and dry skin, water procedures are limited (no more than one short warm shower per day), soap is excluded, emollients and fatty creams are used, systemic use of antihistamines is recommended, and ointments with urea (urea) are prescribed locally. Erythema and desquamation, which can develop into eczema-like changes, require the use of topical corticosteroids; in grade 3, short-term systemic use of oral steroids is recommended.

Nail changes

Another common side effect of cetuximab is changes in the nails. In studies, these side effects were observed in 44 (12%) patients with advanced colorectal cancer receiving the drug in combination with irinotecan, and in 46 (16%) patients receiving cetuximab monotherapy. Nail changes manifested as inflammation of the paronychia with associated swelling of the lateral nail folds of the toes and fingers. The thumbs were most often affected [29], and the severity of most of these phenomena was mild or moderate (1st or 2nd).

The main role in preventing the development of paronychia is played by simple preventive measures: patients should be warned about the need to avoid cuticle injuries, avoid trimmed manicures and artificial nails, wear loose, comfortable shoes, avoid exposure to irritants and chemicals, do not soak your feet and hands in water, use cotton gloves, moisturizing creams and antiseptic solutions. It is advisable to use drying pastes containing antiseptics (for example, chlorhexidine), antifungals (for example, nystatin) and/or topical corticosteroids; in the case of pyogenic granuloma - silver nitrate.

For grade 2 paronychia (swelling of the nail fold or erythema with pain; associated with splitting and detachment of the nail plate), local therapy is indicated, and oral medications (antibiotics and antifungals) may be recommended. For grade 3 paronychia, surgery and/or intravenous antibiotics are indicated.

A. Scope et al. [37] assessed the possibility of preventing skin toxicity during cetuximab therapy. 48 patients took part in the randomized study: 24 patients received prophylactic minocycline and 24 received placebo; the retinoid tazarotene was prescribed topically to all patients on the right or left half of the face. Minocycline prophylaxis was started on the day of the first cetuximab administration and continued for 8 weeks. By the fourth week, grade 2 or higher skin toxicity was recorded in 20% of patients in the prophylactic group and in 50% of patients in the control group (p = 0.05); by the 8th week, the differences decreased slightly. Due to grade 3 rash, treatment was interrupted in 4 patients in the control group; all patients receiving minocycline completed the planned administrations. No clinical improvement has been reported from tazarotene applications (to date, the use of retinoids to combat rash during anti-EGFR therapy is not recommended).

A similar study on the prevention of skin toxicity was conducted in relation to another mAb against EGFR - panitumumab [38]. Preventive therapy started on the eve of the first injection of the drug, lasted for 6 weeks and consisted of daily use of moisturizer in the morning (face, neck, chest, back, arms, legs), sunscreen on exposed skin before going outside, 1% hydrocortisone cream before bedtime (face, neck, chest, back, arms, legs), as well as taking 100 mg of doxycycline orally 2 times a day.

In the control group, treatment began only after the appearance of the rash. It was shown that grade 2 or more skin toxicity was recorded 2 times less frequently during prophylaxis (29% versus 62%; HR = 0.3; 95% CI 0.1–0.6).

Relationship between skin toxicity and the effectiveness of anti-EGFR therapy

As mentioned earlier, acne-like rash is considered a specific side effect of cetuximab, which occurs in 50–100% of patients (grade 3 in 5–9%) [20]. Moreover, almost all clinical studies have shown a significant relationship between skin rash, its severity and the effectiveness of the drug [20, 39]. In the group of patients who developed grade 2 or higher rash during the first 28 days of treatment, there was a twofold increase in median overall survival (HR = 0.58; 95% CI 0.38–0.87; p = 0.002) [ 40].

The EVEREST study assessed the relationship of rash with the effectiveness of cetuximab therapy and the effect of single dose escalation in patients without significant clinical manifestations of skin toxicity [41]. The program included 166 patients with mCRC who received chemotherapy in the irinotecan + cetuximab regimen in standard doses (first administration - 400 mg/m2, subsequent - 250 mg/m2 weekly). If grade 2 or higher skin toxicity developed, treatment was continued. Patients with grade 1 acne-like rash were randomized into 2 groups: patients in the first group received therapy as before (group A, n = 45), in the second, a single dose of cetuximab was gradually increased by 50 mg/m2 once every 2 weeks, to a maximum up to 500 mg/m2, until the development of grade 2 skin toxicity (group B, n = 44). Only partial regressions were registered, their frequency in group A (standard regimen, patients without significant manifestations of skin toxicity) was the smallest and amounted to 13%, in group B (dose escalation to toxic manifestations) - 30%, in patients with initial skin toxicity - 34 %. The correlation between cutaneous toxicity and the efficacy of cetuximab has been confirmed in other studies (Fig. 3) [31, 42–47].

Thus, the occurrence and severity of skin rash are a unique pharmacodynamic marker of the adequacy of the dose used and the effectiveness of treatment with EGFR inhibitors, as evidenced by data on the correlation of skin rash with the effectiveness of anti-EGFR therapy. Similar dose-dependent side effects are observed with all EGFR (HER1/ErbB1) inhibitors, including the ErbB1-specific mAbs cetuximab (Erbitux®) and panitumumab (Vectibix®), the ErbB1-specific tyrosine kinase inhibitors gefitinib (Iressa®) and erlotinib (Tarceva®), and also the ErbB1/ErbB2 inhibitor lapatinib (Tukerb®) and the ErbB1/ErbB2 + VEGFR inhibitor vandetanib (Zaktima®). No similar effect was observed with the ErbB2 inhibitor trastuzumab (Herceptin®).

In conclusion, it should be noted that, in general, targeted therapy has a significantly more favorable safety profile compared to treatment with traditional cytostatics, but the use of new drugs is associated with previously unknown side effects. The specific and most common adverse event with EGFR blockers is skin toxicity. It has been shown that skin rash of grade 2 or higher is associated with increased survival of patients and can serve as a kind of predictive pharmacodynamic marker of effectiveness, but worsens the quality of life of patients. Timely and adequate symptomatic treatment of toxic reactions is a key factor that improves the tolerability of antitumor treatment.

Special instructions for the use of Erbitux™

Hypersensitivity reactions If the patient has a mild or moderate hypersensitivity reaction (Grade I or II - National Cancer Institute - Common Toxicity Criteria, NCI-CTC), the infusion rate can be reduced. It is recommended to maintain a similar low infusion rate for all subsequent infusions. Severe hypersensitivity reactions (NCI-CTC grade III or IV) have been described in patients receiving cetuximab. As a rule, symptoms appeared during the first infusion and within 1 hour after its completion, but they could appear several hours later. The patient should be warned about the possibility of such late manifestation of symptoms and the need to consult a doctor if symptoms of hypersensitivity occur. If severe hypersensitivity reactions develop, immediately and permanently stop treatment with cetuximab; if necessary, the patient should receive emergency medical care. Until now, the use of the drug has been studied only in patients with adequate levels of kidney and liver function. The effect of cetuximab has not been studied in selected patients with previously diagnosed hematological disorders. There is no need to optimize the dose in elderly patients, but experience with the drug is limited in the group of people aged 75 years and older. Particular attention should be paid to patients with reduced functional reserve and a history of pulmonary-cardiac diseases. The safety and effectiveness of cetuximab in pediatric patients has not been studied. Data on the use of cetuximab in combination with radiation therapy for colorectal cancer are limited. Electrolytic disturbances A gradual decrease in serum magnesium levels has been observed, leading to severe hypomagnesemia in some patients. Hypomagnesemia is reversible when the drug is discontinued. Other electrolytic abnormalities, mainly hypocalcemia and hypokalemia, of varying severity were also observed. It is recommended to determine the level of electrolytes in the blood serum before starting treatment and during treatment. If necessary, electrolytic saturation is recommended. Combined treatment. If Erbitux is prescribed in combination with irinotecan, the above precautions should be taken into account. Pregnancy and lactation The epidermal growth factor receptor (EGFR) is involved in fetal development, and other IgGl antibodies have been found to cross the placental barrier. There are no data on the use of the drug during pregnancy and lactation. It is recommended to prescribe cetuximab during pregnancy only if the potential benefit outweighs the risk to the fetus. Women are not advised to breastfeed during treatment with cetuximab and for 1 month after the last dose because it is unknown whether cetuximab is excreted into breast milk. Effect on the ability to drive vehicles No studies have been conducted regarding the effect of the drug on the ability to drive vehicles. If the patient notices treatment-related symptoms that reduce his ability to concentrate and react quickly, it is recommended that he stop driving and driving until such effects disappear.

Description of the drug ERBITUX® (ERBITUX®)

Antitumor agent. It is a chimeric IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR).

EGFR signaling pathways are involved in the control of cell survival, cell cycle regulation, angiogenesis, cell migration and cell invasion/metastasis.

Cetuximab binds to EGFR with an affinity that is approximately 5-10 times greater than that of endogenous ligands. Blocks the binding of endogenous EGFR ligands, which leads to inhibition of receptor functions. It further induces EGFR internalization, which may lead to negative regulation of the receptor. Cetuximab also sensitizes cytotoxic immune effector cells against EGFR-expressing tumor cells. In in vitro and in vivo studies, cetuximab inhibits the proliferation and induces apoptosis of human tumor cells expressing EGFR. In vitro, cetuximab inhibits the production of angiogenic factors in tumor cells and blocks the migration of endothelial cells. In vivo, cetuximab inhibits the production of angiogenic factors in tumor cells and reduces the activity of angiogenesis and tumor metastasis.

Does not bind to other receptors belonging to the HER family.

The proto-oncogene KRAS (Kirsten rat sarcoma viral oncogene 2 homolog) is a downstream central signal transducer for EGFR. In tumors, activation of KRAS EGFR leads to increased proliferation and production of pro-angiogenic factors.

Oncogenic mutation of KRAS, resulting in its constitutive activity, is one of the most common oncogenic mutations in cancer. As a result of a mutation in the active site (codons 12 and 13), the KRAS protein is in an activated state and transmits a signal to proliferation into the nucleus, regardless of the EGFR signal.

In metastatic colorectal cancer, the KRAS mutation occurs in 30-50% of cases. The appearance of antichimeric antibodies in humans (ACHA) is the result of exposure to a class of chimeric antibodies. Current data on the mechanism of AChAC production are limited. Overall, measurable ACHA titers were detected in 3.4% of patients studied, with frequencies ranging from 0% to 9.6% in studies with similar indications. The appearance of AChAC is not correlated with the development of hypersensitivity reactions or any other undesirable effects of cetuximab.

Interactions of the drug Erbitux™

There is no evidence that irinotecan affects the safety profile of Erbitux and vice versa. Formal interaction studies have shown that the pharmacokinetic characteristics of cetuximab are not altered by co-administration of single doses of irinotecan (350 mg/m2 body surface area). Also, the pharmacokinetics of irinotecan did not change with simultaneous use of cetuximab. No other formal interaction studies have been conducted with cetuximab in humans. In the absence of data on compatibility studies, it is prohibited to mix this medicinal product with other drugs. It is necessary to use separate lines for parenteral infusion of the drug.

Storage conditions for Erbitux™

Store in the refrigerator at a temperature of 2–8 °C. Do not freeze. The stability of the drug Erbitux 2 mg/ml after opening the bottle was established - 20 hours at a temperature of 25 ° C. Erbitux does not contain antimicrobial preservatives or bacteriostatic agents. It is recommended to use the drug immediately after opening the bottle. If the drug is not used immediately after opening, storage for no more than 24 hours at a temperature of 2–8 °C is allowed (at the discretion of the consumer). Shelf life: 2 years.

List of pharmacies where you can buy Erbitux™:

• Moscow
• Saint Petersburg