Erbitux® (Erbitux®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceCetuximabCetuximab
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  • Erbitux®
    solution d / infusion 
    Merck KGaA     Germany
  • Erbitux®
    solution d / infusion 
    Merck KGaA     Germany
    • Dosage form: & nbspSolution for infusion.
    Composition:
    In 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 from a colorless to pale yellow solution.
    Pharmacotherapeutic group: Antitumor agent, antibodies monoclonal.
    ATX: & nbsp

    L.01.X.C.06   Cetuximab

    Pharmacodynamics:Cetuximab is a chimeric monoclonal antibody belonging to the IgGl immunoglobulin class specifically binding to the epidermal growth factor receptor (EGFR). EGFR signaling pathways are involved in the control of cell survival, cell cycle, angiogenesis, cell migration and cell invasion / metastasis. The affinity of cetuximab binding to EGFR is approximately 5 to 10 times higher than that of endogenous ligands, which results in blocking the function of the latter. Cetuximab induces the internalization of EGFR, which can lead to inhibition of receptor function. Cetuximab also sensitizes cytotoxic immune effector cells for EGFR expressing tumor cells (antibody-mediated cellular cytotoxicity, ADCC). Cetuximab does not bind to other receptors of the HER family. Protein, a product of RNA protoncogen (rat sarcoma) expression, plays a central role in the signal transmission from EGFR. In tumors characterized by activation of RAS genes by EGFR, there is an increase in proliferation, cell survival and production of proangiogenic factors.
    RAS is one of the most frequently activated families of oncogenes in human tumors. Mutations of RAS genes, particularly in exons 2, 3 and 4 of the KRAS and NRAS genes, lead to the constitutional activation of RAS proteins, independent of the EGFR signaling pathway.
    In experiments both in vitro and in vivo cetuximab inhibits proliferation and induces apoptosis of human tumor cells expressing EGFR. In vitro experiments cetuximab inhibits production factors angiogenesis by tumor cells and blocks the migration of endothelial cells. In vivo experiments cetuximab inhibits the expression of angiogenic factors by tumor cells and causes a decrease in tumor neovascularization and metastasis.
    Immunogenicity.
    The production of human anti-chimeric antibodies (AXAC) is the effect of monoclonal chimeric antibodies characteristic of this pharmacotherapeutic class. At present, data on AHAC products are limited. In general, measurable AHACH titers are found in 3.4% of patients enrolled; in the study of the drug when applied to the target reading, this value varies from 0% to 9.6%. Final data on the neutralizing effect of AHAC on cetuximab are not currently available. The AHAX products do not correlate with the frequency of hypersensitivity reactions, as well as any other undesirable effects of cetuximab.
    Pharmacokinetics:

    Intravenous infusions of cetuximab demonstrated dose-dependence parameters of the pharmacokinetics of cetuximab administered weekly at doses of 5 mg / m2 up to 500 mg / m2 body surface area. With the introduction of cetuximab in the initial dose of 400 mg / m2 body surface area, the average volume of cetuximab distribution was approximately equivalent to the vascular region,

    blood supply to the affected area (2.9 l / m2, in the range of 1.5 l / m2 up to 6,2 l / m2).

    Mean maximum concentration of cetuximab in blood plasma (FROMmOh) was 185 μg / ml ± 55 μg / ml.

    The average clearance value was 0.022 l / h / m2 body surface area.

    When the drug is administered at the calculated dose cetuximab has a long period elimination half-life in the range of 70 to 100 hours.

    Concentrations of cetuximab in blood plasma reached stable values ​​at week 3 application of the drug in the monotherapy. FROMmOh cetuximab was 155.8 μg / ml at week 3 and 151.6 μg / ml at week 8, with the average values minimum concentration (Cmin) were

    41.3 μg / ml and 55.4 μg / ml, respectively. In a study on the combined use of Erbitux® with irinotecan Cmin cetuximab was 50.0 μg / ml at week 12 and 49.4 μg / ml at week 36.

    There are several ways in which the metabolism of antibodies is realized. All these routes include the stage of degradation of antibodies to smaller molecules.

    Pharmacokinetics in special populations.

    Pharmacokinetic characteristics cetuximab do not depend on race, sex, age.

    Pharmacokinetics in children. In the Phase I study, which included children (aged 1 to 18 years) with refractory solid tumors, cetuximab was administered in combination with irinotecan. The values ​​obtained for the parameters of the pharmacokinetics of cetuximab were comparable to those in adults.

    Indications:
    - metastatic colorectal cancer (mCRC) with the expression of EGFR and the wild type of RAS genes in combination with irinotecan-based chemotherapy or prolonged infusion of fluorouracil / calcium folinate with oxaliplatin;
    - metastatic colorectal cancer (mCRP) with EGFR expression and "wild" type of RAS genes as monotherapy in case of ineffectiveness of previous chemotherapy on the basis of irinotecan and oxapi- platinum and also with intolerance to irinotecan;
    - locally advanced squamous cell carcinoma of the head and neck (PRGSH) in combination with radiotherapy;
    - recurrent and / or metastatic squamous cell carcinoma of the head and neck (PWG) in combination with platinum-based chemotherapy;
    - recurrent and / or metastatic squamous cell carcinoma of the head and neck (PRGSH) as monotherapy for ineffectiveness previous chemotherapy on the basis of platinum preparations.
    Contraindications:
    - pronounced (grade 3 or 4 on the US National Cancer Institute's toxicity scale)
    - hypersensitivity to cetuximab;
    - Pregnancy;
    - the period of breastfeeding;
    - Children under 18 years of age (efficacy and safety of use not established);
    - use of Erbitux ® in combination with oxaliplatin-containing therapy in patients with mCRC with a mutant type of RAS gene or with unknown status of RAS genes.
    Before the start of combination therapy, it is necessary to evaluate contraindications to the use of concomitant chemotherapy and radiotherapy
    Carefully:With violations of the liver and / or kidney function, oppression of bone marrow hematopoiesis, cardiopulmonary diseases in history, old age.
    Pregnancy and lactation:EGFR is involved in the process of embryonic development. Limited observations in animals indicate the penetration of cetuximab and other IgG1 antibodies through the placental barrier. Teratogenic effect of the drug was not detected. However, a dose-dependent increase in the incidence of miscarriages was observed. Data on the use of the drug during pregnancy in humans are limited, so the use of the drug Erbitux® during pregnancy is contraindicated.
    Breastfeeding during the treatment with the drug Erbitux® and within 2 months after the administration of the last dose of the drug is contraindicated, since it is not known whether the drug Erbitux® penetrates into breast milk.
    Dosing and Administration:

    Therapy with Erbitux® should be performed under the supervision of a doctor who has experience in the use of antitumor drugs. During the infusion and for at least 1 hour after the end, careful monitoring of the patient's condition is necessary. Equipment should be prepared for resuscitation measures. Before the first infusion, at least 1 hour before the administration of cetuximab, a premedication antihistamines and glucocorticosteroids. 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 body surface area. The first dose should be administered slowly, at a rate not exceeding 5 mg / min. Recommended duration of infusion is 120 minutes. All subsequent weekly infusions are administered at a dose of 250 mg / m2 body surface area with a recommended infusion time of 60 minutes. The infusion rate should not exceed 10 mg / min.

    Colorectal cancer

    In patients with mCRC, Erbitux® mainly manifested in the form of lymphocytopenia. AT framework of randomized controlled a clinical trial in which 424 patients were included, the incidence of severe acute radiation dermatitis and mucositis, as well as delayed adverse effects of radiation therapy, was slightly higher in patients receiving radiation therapy in combination with cetuximab than in those receiving radiation therapy alone.

    Side effects:

    The main undesirable effects of cetuximab are skin reactions, which are noted in> 80% of patients; hypomagnesemia y> 10% patients; and infusion reactions of mild or moderate severity in> 10% of patients of severe degree,> 1% of patients.

    Below is a list of adverse events that occur with the use of Erbitux®. To indicate the frequency of adverse events, the following

    classification: very often (>1/10), often (from >1/100 to <1/10), infrequently (from > 1/1000 to <1/100), rarely (from > 1/10000 to <1/1000), very rarely (<1/10000), the frequency is unknown (can not be estimated based on available data).

    Impaired nervous system:

    Often: headache.

    The frequency is unknown: aseptic meningitis.

    Disorders from the side of the organ of vision:

    Often: conjunctivitis.

    Infrequent: blepharitis, keratitis (including ulcerative).

    Disturbances from the respiratory system, chest and mediastinal organs:

    Infrequent: pulmonary embolism.

    Rarely: interstitial lung disease.

    Disorders from the gastro-intestinal tract:

    Often: diarrhea, nausea, vomiting.

    Disturbances from the skin and subcutaneous fabrics:

    Very often: skin reactions. Skin reactions can develop in more than 80% of patients (mainly an acne-like rash and / or less often itching, dry skin, peeling, hypertrichosis or nail damage, for example, paronychia). About 15% Skin reactions are pronounced in nature, in some cases necrosis develops. Most skin reactions develop during the first three weeks of therapy and are usually resolved without consequences after discontinuation of the drug, subject to recommendations for adjusting the dosage regimen. Very rarely: Stevens-Johnson syndrome / toxic epidermal necrolysis.

    The frequency is unknown: superinfection of skin lesions (skin lesions, induced by the use of the drug may lead to the development of superinfections that can cause inflammation of the subcutaneous fat, face or lead to potentially fatal complications such as staphylococcal toxic epidermal syndrome, necrotizing fasciitis or sepsis).

    Disorders from the metabolism and nutrition:

    Very often: hypomagnesemia.

    Often: dehydration, including as a result of diarrhea or mucositis, hypocalcemia, anorexia, which can lead to weight loss.

    Disorders from the vascular system:

    Infrequent: deep vein thrombosis.

    Disorders and disorders associated with the administration of the drug:

    Very often: infusion-dependent reactions are light and of moderate severity (see section "Special instructions"), mucositis, in some cases, severe. Mucositis can cause nasal bleeding.

    Often: severe infusion-dependent reactions, which in some cases may lead to death (see section "Special instructions"), fatigue.

    Disorders from the liver and bile ducts:

    Very often: aspartate aminotransferase (ACT), alanine aminotransferase (ALT), alkaline phosphatase (APF).

    Combination therapy:

    When using cetuximab in combination

    with chemotherapy should also study the instructions for the use of these drugs.

    When the use of cetuximab in combination with chemotherapy on the basis of platinum drugs may increase the frequency of severe leukopenia or severe neutropenia and, in this connection, an increase in the incidence of infectious complications such as febrile neutropenia, pneumonia and sepsis, compared with platinum-based monotherapy. When cetuximab was used in combination with fluoropyrimidines, there was an increase in the incidence of myocardial ischemia, including myocardial infarction and congestive heart failure, as well as palmar-plantar syndrome (palmar-plantar erythrodysesthesia) compared with monotherapy fluoropyrimidines.

    When cetuximab was used in combination with local radiation therapy, the development of additional undesirable effects typical for radiation therapy, such as mucositis, radiation dermatitis, dysphagia or leukopenia, was observed in the head and neck regions, mainly manifested in the form of lymphocytopenia. The randomized controlled clinical The study, which included 424 patients, the incidence of severe acute radiation dermatitis and mucositis, as well as delayed adverse effects of radiation therapy, was slightly higher in patients receiving radiotherapy in combination with cetuximab than those receiving radiation therapy alone.

    Overdose:

    At present, there is limited experience with single doses higher than 400 mg / m body surface area or weekly doses higher than 250 mg / m2 body surface area.

    Interaction:
    When using Erbitux® in combination with chemotherapeutic agents, instructions for the use of appropriate drugs should be studied. Cetuximab in combination with chemotherapy on the basis of platinum preparations in comparison with the use of only platinum drugs increases the frequency of severe leukopenia or severe neutropenia, which may be accompanied by concomitant infectious complications, in particular fibrillar neutropenia, pneumonia and sepsis.See also "Special instructions").
    The use of cetuximab in combination with fluoropyrimidines in comparison with the use of fluoropyrimidines alone caused an increase in the incidence of myocardial ischemia, including myocardial infarction and congestive heart failure, as well as the incidence of palmar-plantar syndrome.
    With the combined use of cetuximab and irinotecan, no changes in the pharmacokinetic parameters of both drugs have been observed.
    When combined with cetuximab plus capecitabine and oxaplatin (XELOX), the incidence of severe diarrhea may increase.
    Special instructions:

    Infusion-dependent. including anaphylactic reactions. Often there may be severe infusion, including anaphylactic reactions. In some cases, these reactions may lethal. With the development of a severe infusion-dependent reaction, immediate and final discontinuation of the Erbitux® preparation and emergency treatment if necessary. Some of these reactions may be anaphylactic or anaphylactoid in nature or a cytokine release syndrome (CRS).Symtomas can occur during the first infusion and within a few hours after it, or when performing subsequent infusion. It is recommended to warn patients about the possibility of infusion reactions with delayed onset and instruct them about the need to contact the doctor in case of developing symptoms or signs of infusion reactions. Symptoms may include bronchospasm, hives, increased or decreased blood pressure, loss of consciousness or shock. In rare cases, there are attacks of angina pectoris, myocardial infarction and cardiac arrest.

    Anaphylactic reactions can develop already within a few minutes after the start of infusion. for example, in connection with the patient's already available antibodies IgE, cross reacting with cetuximab. These reactions are usually accompanied by bronchospasm and urticaria. They can occur despite premedication. The risk of anaphylactic reactions is significantly increased in patients with an allergy to red meat or a history of tick bites, or with positive antibody test results IgE to cetuximab (α-1-S-galactose).In such patients, zstuximab should be used only after a thorough assessment of the relationship between the expected benefit and the potential risk, including the possibility of using alternative therapies, and under the close supervision of well-trained personnel and with ready-to-use resuscitation equipment.

    The first dose should be administered slowly; the infusion rate should not exceed 5 mg / min. Careful monitoring of indicators of vital functions should be carried out for at least two hours. If the introduction of the first dose of infusion reactions occur within the first 15 minutes, the infusion should be discontinued. Before the subsequent infusion, it is necessary to carefully evaluate the ratio of the expected benefits to possible risks, including whether the patient has IgE antibodies.

    With the development of an infusion reaction at later stages of drug administration or during subsequent infusions, further management of the patient will depend on the severity of the reactions:

    a) 1 degree: continued slow infusion under close supervision.

    b) 2nd degree: continued slow infusion and immediate relief of symptoms.

    c) 3 and 4 degrees: immediate cessation of infusion, intense relief of symptoms; further use of cetuximab is contraindicated.

    Cytokine release (CRS) syndrome usually develops within one hour after completion of the infusion; The bronchospasm and urticaria develop less frequently in this condition. The degree of severity of CRS associated with the first infusion is usually more pronounced.

    Infusion reactions of mild or moderate severity often include symptoms such as fever, chills, dizziness, or dyspnea, which usually occur with the first infusion of cetuximab.

    With an infusion-dependent reaction of mild or moderate severity, it is recommended to reduce the rate of administration of the drug.

    For subsequent infusions, the drug should be administered at a reduced rate.

    It is necessary to carry out careful monitoring of patients, especially with the first administration of the drug. Particular attention should be paid to patients with severe general conditions and concomitant diseases of the heart or lungs.

    Infusion-dependent reactions

    With an infusion-dependent reaction of mild or moderate severity, it is recommended to reduce the rate of administration of the drug.For subsequent infusions, the drug should be administered at a reduced rate. With the development of a severe infusion-dependent reaction, the Erbitux® drug should be immediately discontinued and emergency therapy should be carried out if necessary. Repeated use of the drug Erbitux ® in this case is contraindicated.

    With the introduction of the drug Erbitux®, infusion reactions usually develop during the first infusion or within 1 hour of admission.

    Application in the elderly

    Correction of the dose of the drug in the elderly is not required, but the experience of its use in patients aged > 75 years is limited.

    Effect on the ability to drive transp. cf. and fur:
    Studies on the effect of the drug on the ability to drive and other mechanisms have not been carried out. If the patient has treatment-related symptoms that affect the ability to concentrate and respond quickly, it is not recommended to drive the car or work with the mechanisms until the symptomatology is resolved.
    Form release / dosage:Solution for infusions 5 mg / ml.
    Packaging:For 20 or 100 ml in a vial of colorless glass with a stopper of brombutyl rubber, crimped with an aluminum ring with a snap-off plastic lid.For 1 bottle with instructions for use in a cardboard pack, sealed with a transparent sticker.
    Storage conditions:
    Store at 2-8 ° C. Keep out of the reach of children.
    Shelf life:4 years. Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LCP-002745/09
    The owner of the registration certificate:Merck KGaAMerck KGaA Germany
    Manufacturer: & nbsp
    Representation: & nbspPHARMONYX PHARMONYX Russia
    Information update date: & nbsp16.10.2015
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