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 2 mg.

    Excipients:

    sodium dihydrogen phosphate dihydrate, sodium phosphate dihydrate, sodium chloride, water for injection.

    Description:Transparent or slightly opalescent from a colorless to yellowish solution in which white and amorphous visible particles are allowed.
    Pharmacotherapeutic group:Antineoplastic agent - monoclonal antibodies.
    ATX: & nbsp

    L.01.X.C.06   Cetuximab

    Pharmacodynamics:
    Erbitux is a chimeric monoclonal antibody IgG1 directed against the epidermal growth factor receptor (EGFR). The EGFR signaling pathways are involved in the control of cell survival, in the development of the cell cycle, angiogenesis, cell migration and cellular invasion / metastasis process. Erbitux binds to EGFR with affinity, which is about 5-10 times higher than that characteristic of endogenous ligands. Erbitux blocks the binding of endogenous ligands of EGFR, which leads to inhibition of receptor functions. Further, it induces internalization of the EGFR, which can lead to a 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 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 tumor angiogenesis and metastasis.
    The appearance of anti-chimeric antibodies in humans (CHAPA) is the result of the action of a class of chimeric antibodies. Modern data on the development of the ChACH are limited. In general, measured CHAHA titers are detected in 3.7% of patients studied with frequencies from 0% to 8.5% in studies with similar indications. At the present time, there are no clear data on the neutralizing effect of CHAC on Erbitux. The appearance of CHAHA is not correlated with the development of hypersensitivity reactions or any other undesirable effects of cetuximab.
    Pharmacokinetics:

    Intravenous Erbitux infusions demonstrated dose-dependent pharmacokinetics with weekly administration of the drug in doses ranging from 5 to 500 mg / m2 body surface area.

    When Erbitux is prescribed in the initial dose of 400 mg / m2 body surface area the average volume of distribution was approximately equivalent to the vascular area (2.9 l / m2 in the range from 1.5 to 6.2 l / m2). The average value of Cmah was 185 ± 55 μg / ml. The average clearance was 0.022 l / h / m2 body surface area. Erbitux has a long half-life with varying values ​​in the range of 70 to 100 hours at the indicated dose.

    Serum Erbitux concentrations reached stable values ​​after three weeks of using cetuximab in monotherapy. The mean value of the peak of Erbitux concentration was 155.8 μg / ml at 3 weeks and 151.6 μg / ml at 8 weeks, at the same time, the corresponding mean values ​​of the reduced concentrations were 41.3 and 55.4 μg / ml, respectively. In a study on the combined use of Erbitux with irinotecan, the mean reduction in concentrations was 50.0 μg / ml at 12 weeks and 49.4 μg / ml at 36 weeks.

    Several routes have been described that can contribute to the metabolism of antibodies. All of these routes involve the biodegradation of antibodies to smaller molecules, i.e. small peptides or amino acids.

    Pharmacokinetics in special populations.

    The pharmacokinetic characteristics of Erbitux do not depend on race, sex, age, renal function and liver function.

    Indications:
    - metastatic colorectal cancer in combination with standard chemotherapy;
    - monotherapy for metastatic colorectal cancer in the case of failure of prior chemotherapy with oxaliplatin or irinotecan inclusion, and in case of intolerance of irinotecan;
    - locally advanced squamous cell carcinoma. head and neck in combination with radiotherapy;
    - recurrent or metastatic squamous cell carcinoma of the head and neck in case of failure of prior platinum-based chemotherapy drugs.
    Contraindications:
    Pronounced (grade 3 or 4) hypersensitivity to cetuximab.
    Pregnancy and lactation
    Children's age (efficacy and safety of use not established).
    Carefully:When the liver and / or kidney (Erbitux on application data at rates in excess bilirubin upper limit of normal (ULN) is more than 1.5 times, transaminases more than 5 times and serum creatinine of more than 1.5 is currently exceeding ULN time is not),oppression of bone marrow hematopoiesis, cardiopulmonary diseases in the anamnesis, elderly age, decrease in the functional status.
    Dosing and Administration:Erbitux is administered as an intravenous infusion at a rate of no more than 10 mg / min (5 mL / min). Before the infusion, it is necessary to perform a premedication with antihistamines.

    For all indications, the drug is administered once a week at an initial dose of 400 mg / m2 body surface (first infusion) in the form of a 120-minute infusion and then in a dose of 250 mg / m2 surface of the body in the form of a 60-minute infusion.

    Colorectal cancer

    With combined therapy irinotecan is usually given in the same dose that was used in the last course of the previous irinotecan-containing chemotherapy. However, follow the recommendations for modifying the doses of irinotecan, as described in the information on this medication. Irynotekan is introduced no earlier than 1 hour after the end of the infusion of Erbitux. Erbitux therapy is recommended to continue until signs of disease progression appear.

    Squamous cell carcinoma of the head and neck

    When Erbitux is used in combination with radiotherapy,Erbitux treatment is recommended to start 7 days before the start of radiation treatment and continue weekly injections until the end of radiotherapy

    . Recommendations for adjusting the dose regimen.

    With the development of skin reactions, the 3 degrees of toxicity according to the classification National Cancer Institute (NCI-CTC) Erbitux should be discontinued. The resumption of therapy is allowed only if the reaction is resolved to grade 2. If severe skin reactions occur for the first time, treatment can be resumed without changing the dose level.

    In the secondary or tertiary development of severe skin reactions, Erbitux should be discontinued again. 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 is resolved to 2 degrees.

    If severe skin reactions develop for the fourth time or are not resolved to 2 degrees of severity during the discontinuation of the drug, Erbitux therapy should be discontinued.

    Recommendations for the use of Erbitux.

    Erbitux is administered intravenously via an internal linear filter using an infusion pump, a gravity drop system, or a syringe pump. For infusion it is necessary to use a separate infusion system.At the end of the infusion, the system should be washed with a sterile 0.9% solution of sodium chloride. Erbitux is a colorless solution that can contain whitish amorphous particles of the preparation that do not affect its quality. Nevertheless, the solution must be filtered through an internal linear filter with a pore size of 0.2-0.22 micrometers during the administration of the preparation. Erbitux is compatible with:

    => polyethylene, ethyl vinyl acetate or polyvinyl chloride bags for

    infusion solutions,

    => polyethylene, ethyl vinyl acetate, polyvinyl chloride, polybutadiene or polyurethane infusion systems,

    => polyether sulphonic, polyamide or polysulfone linear filters.

    Erbitux can not be mixed with other medicines.

    Filtration in a system with an infusion pump or gravitational dropper. Before administration, the required amount of the drug with a sterile syringe (minimum volume 50 ml) is transferred from the vials to a sterile container or bag for infusion solutions. Next, you should install an appropriate linear filter in the infusion system, which must be moistened before starting the infusion with Erbitux or 0.9% sterile sodium chloride solution.Using a gravitational dropper or infusion pump, set the rate of administration in accordance with the recommendations.

    Filtration in a system with a syringe pump. Before administration, the required amount of the drug from the vial is collected in a sterile syringe with a minimum volume of 50 ml. The syringe with the solution of the drug is placed in the syringe pump. The corresponding linear filter is connected to the infusion set, then the infusion system is connected to the syringe. Set the rate of administration according to the directions and start the infusion after pre-wetting the linear filter with Erbitux or with a sterile 0.9% solution of sodium chloride. Repeat the procedure until the total volume of the preparation is fully infused.

    When signs of blockage of the filter appear during the infusion, it must be replaced. Erbitux solution does not contain antibacterial preservatives or bacteriostatic components, therefore, when handling it, you must strictly follow the rules of aseptic. The drug is recommended to use as soon as possible after opening the bottle.

    If the drug was not used immediately,the time and storage conditions of the ready-to-use preparation 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 20 hours at + 25 ° C.

    Side effects:

    The following undesirable phenomena noted with the use of Erbitux are distributed according to the frequency of occurrence in accordance with the following gradation: 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) is extremely rare (<1/10000).

    Infusion reactions: very often - mild to moderate fever, chills, nausea, vomiting, headache, dizziness, dyspnea; often expressed infusion reactions (usually develop during the first hour of the first infusion and in rare cases can lead to death), including airway obstruction (bronchospasm, stridor, hoarseness, difficulty speaking), urticaria, lowering blood pressure, loss of consciousness , angina pectoris. The main mechanism for the development of these reactions is not established. Perhaps some of them may be anaphylactoid / anaphylactic in nature.

    From the skin and skin appendages: very often - an acne-like rash and / or skin itching, dry skin, peeling, hypertrichosis, nail damage (eg paronychia). In 15% skin reactions are of a pronounced nature, in single cases skin necrosis develops. Most skin reactions develop during the first 3 weeks of treatment and usually go through without consequences after the interruption of treatment, subject to recommendations for adjusting the dose regimen. Disturbance of the integrity of the skin in some cases can lead to the development of superinfections that can lead to inflammation of subcutaneous fat, erysipelatous inflammation or potentially deadly complications such as staphylococcal epidermal necrolysis (Lyell's syndrome) or sepsis.

    From the respiratory system: very often - shortness of breath.

    On the part of the organs of vision: often - conjunctivitis.

    From the hepatic-biliary system: very often - a slight or moderate increase in the activity of liver enzymes (ACT, ALT, alkaline phosphatase).

    Other: hypomagnesemia; when combined with irinotecan, characteristic side effects of irinotecan develop (the safety profile of irinotecan andErbitux in their joint application does not change); In combination with radiotherapy, undesirable effects associated with radiation therapy are additionally noted, with mucositis and radiation dermatitis developing somewhat more often than with one radiation therapy.

    Overdose:

    Cases of overdose are not described. At present, there is no experience with single doses that would exceed 500 mg / m2 body surface area.

    Interaction:
    The data that irinotecan has an impact on the safety profile of Erbitux and vice versa. With the joint administration of Erbitux and irinotecan, no changes in the pharmacokinetic parameters of both drugs were observed.
    There were no other studies on the interaction of Erbitux in humans.
    Due to the lack of compatibility studies, Erbitux should not be mixed with other drugs.
    Special instructions:
    Erbitux therapy should be performed under the supervision of a doctor who has experience using antitumor drugs.
    When Erbitux is administered, infusion reactions usually develop on the background of the first infusion or within 1 hour after the endadministration of the drug, however, they can occur after a few hours, as well as with repeated administration. The patient should be warned about the possibility of such delayed reactions and instructed about the need to consult a doctor immediately after they occur.
    If the patient has a reaction associated with infusion in mild or moderate form, the rate of infusion should be reduced. For subsequent infusions, the drug should also be administered at a reduced rate.
    The development of severe symptoms of an infusion reaction requires immediate and definitive cessation of Erbitux treatment and may entail the need for emergency medical care.
    Particular attention should be given to patients with reduced functional status and with heart disease and lungs, in the history.
    Dyspnea may develop shortly after the administration of Erbitux as one of the symptoms of an infusion reaction, but it was also observed a few weeks after the end of therapy, which may have been associated with a major disease. Risk factors for the occurrence of dyspnea, which can be severe and long-term,are elderly age, reduced functional status and cardiac and / or respiratory function disorders in the anamnesis. When dyspnea occurs during the course of Erbitux therapy, the patient should be examined for signs of progression of pulmonary diseases. Individual cases of interstitial pulmonary disorders have been described, for which no causal relationship was found with the use of Erbitux. In the case of the development of interstitial lung disorders with Erbizuks, treatment with the drug should be discontinued and appropriate therapy should be prescribed.
    When skin reactions of 3-4 degrees occur, the dose and mode of administration of Erbitux should be corrected in accordance with the recommendations given above. When using Erbitux in combination with irinotecan should carefully read the instructions for the medical use of irinotecan. To date, the experience of using the drug only in patients with an adequate level of kidney and liver functioning has been accumulated (serum creatinine and bilirubin levels did not exceed the upper limit of the norm by more than 1.5 times, and the level of transaminases more than 5 times).
    The use of cetuximab has not been studied in patients with oppression of bone marrow hematopoiesis, i.e. with a hemoglobin level <9 g / dl, a white blood cell count <3 000 / μL, an absolute number of neutrophils <1500 / μl and a platelet count <100,000 / μl. The safety and efficacy of Erbitux in children have not been studied.
    During treatment with Erbitux and also for at least 3 months after, it is necessary to use reliable contraceptive methods.
    Studies on the effect of the drug on the ability to drive and control technology was not conducted. If the patient notes the treatment-related symptoms that affect his ability to concentrate and the speed of the reaction, it is recommended to give up driving and performing potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.
    Form release / dosage:Solution for infusion.
    Packaging:Solution for infusions of 100 mg / 50 ml in bottles of clear glass, clogged with bromobutyl stopper with aluminum rolling. For 1 bottle with instructions for use in a cardboard bundle.
    Storage conditions:Store at 2-8 ° C. Do not freeze. Keep out of the reach of children.
    Shelf life:2 years.Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LСP-000016
    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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