Cetuximab

When ATH:
L01XC06

Pharmacological action

Anticancer drug. It is a chimeric monoclonal IgG1 antibody, directed against the epidermal growth factor receptor (EGFR).

Signal EGFR way involved in the control of cell survival, in cell cycle progression, Angiogenesis, cell migration and cellular invasion / metastasis process.

Cetuximab svyazыvaetsya with RЭFR with affinnostyyu, is approximately 5-10 times greater than, characteristic of the endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands, which leads to inhibition of receptor function. Further, it induces internalization of EGFR, that can lead to receptor downregulation. Cetuximab also sensitizes cytotoxic immune effector cells against tumor cells expressing EGFR. In studies in vitro and in vivo Cetuximab inhibits proliferation and induces apoptosis in human tumor cells, expressing EGFR. Cetuximab In vitro inhibits the production of angiogenic factors in tumor cells and blocks endothelial cell migration. In vivo Cetuximab inhibits the production of angiogenic factors in tumor cells and reduces the activity of angiogenesis and tumor metastasis.

The appearance of antibodies in humans antihimernye (CAXA) It is a feedback class chimeric antibody. Current data on the development of Chahal restricted. Generally, measured titers detected in Chahal 3.7% studied patients with frequencies from 0% to 8.5% studies with similar readings. At the moment there are no clear data on the neutralizing effect on Chahal Cetuximab. The emergence of Chahal did not correlate with the development of hypersensitivity reactions or any other undesirable effects of cetuximab.

Pharmacokinetics

In / infusion of cetuximab demonstrated dose-dependent pharmacokinetics at weekly administration of the drug in doses of 5 to 500 mg / m2 of body surface area.

Absorption and distribution

In the appointment of the initial dose of cetuximab 400 mg / body surface m2ploschadi mean Cmax value was 185 ± 55 pg / ml. Middle Vd was approximately equivalent to the vascular region (2.9 l / m2 in the range from 1.5 to 6.2 l / m2). Average clearance match 0.022 l / h / m2 of body surface area.

Serum concentrations reached stable values ​​through 3 Week cetuximab monotherapy. The average value of the peak concentration was 155.8 ug / mL in 3 week and 151.6 ug / mL in 8 weeks, in the same time, the average value of the corresponding reduction in the concentration was 41.3 and 55.4 ug / ml, respectively. In a study of cetuximab combined with irinotecan intended average value corresponded to reduce concentrations 50.0 ug / mL in 12 weeks 49.4 ug / mL in 36 weeks.

Metabolism and excretion

We describe several ways, which may contribute to the metabolism of antibodies. These pathways include biodegradation antibodies into smaller molecules, i.e. small peptides or amino acids.

Cetuximab has a long T1 / 2 values, varying in the range of 70 to 100 h at the indicated dose.

Pharmacokinetics in special clinical situations

The pharmacokinetic characteristics of cetuximab are independent of race, gender, age, kidney and liver function.

Testimony

- Metastatic colorectal cancer in combination with standard chemotherapy;

- Metastaticheskogo kolorektalynogo cancer monotherapy in case neэffektivnosti predshestvuyushtey chemotherapy with irinotecan or oxaliplatin vklyucheniem, as well as intolerance of 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 case of failure of prior chemotherapy drugs based on platinum.

Dosage regimen

Cetuximab is administered in the form of on / in infusion at a rate not more than 10 mg / min (5 ml / min). Before the infusion is necessary to conduct premedication with antihistamines.

For all indications a drug administered 1 once a week at an initial dose of 400 mg / m2 of body surface (pervaya infusion) as a 120-minute infusion and a further dose 250 mg / m2 body surface area as a 60-minute infusion.

In the combination therapy of colorectal cancer Irinotecan is usually administered in the same dose, which was used in the last year of the previous irinotecan-containing chemotherapy. However, it should adhere to the recommendations for dose modifications of irinotecan, information contained in the present pharmaceutical preparation. Irinotecan is administered no earlier than 1 h after infusion of cetuximab. Cetuximab therapy is recommended to continue until evidence of disease progression.

When using cetuximab for the treatment of squamous cell carcinoma of the head and neck in combination with radiation therapy, cetuximab treatment is recommended to start over 7 days prior to radiation therapy and to continue the weekly administration of radiation therapy to the closure.

Recommendations for dose adjustment mode

With the development of skin reactions 3 toxicity classification according to National Cancer Institute cetuximab should be interrupted. Resumption of treatment is permitted only in the case of reducing the toxicity of the reaction to 2 degrees.

If severe skin reactions occur for the first time, Treatment can be resumed without any change in dose.

In secondary and tertiary development of severe skin reactions, cetuximab should be interrupted again. Therapy may be resumed with the drug at lower doses (200 mg / m2 of body surface after the second occurrence of the reaction and 150 mg / m2 - after third), If the toxicity of the reaction was reduced to 2 degrees.

If severe skin reactions occur a fourth time or are not allowed to 2 severity during drug withdrawal, cetuximab therapy should be discontinued.

Terms of use of the drug

Cetuximab is administered in / through the internal line filter using an infusion pump, gravity drip system or a syringe pump.

For infusion, use a separate infusion system. At the end of the infusion system should be rinsed with sterile 0.9% sodium chloride solution.

Cetuximab is a colorless solution, which may comprise a whitish amorphous drug particles, which do not impact on the quality. Nonetheless, the solution should be filtered through the internal line filter having a pore size 0.2-0.22 micrometers during injection.

Cetuximab sovmestim with poliэtilenovыmi, etilvinilatsetatnymi or PVC bags for infusion solutions, with polyethylene, etilvinilatsetatnymi, polyvinylchloride, polybutadiene or polyurethane infusion sets and polietersulfonovymi, polyamide or polysulfone linear filters.

Cetuximab should not be mixed with other drugs.

Filtration system with an infusion pump or gravity drip.

Before the introduction of the required amount of the drug using a sterile syringe (the minimum volume of 50 ml) is transferred from the vial into a sterile container or bag for infusion solutions. This is followed by an infusion system set the appropriate line filter, which should be wetted before the start of infusion of cetuximab or 0.9% sterile sodium chloride solution. Using a gravity drip or infusion pump rate of administration should be set in accordance with the recommendations.

Filtration system with a syringe pump

Before the introduction of the required amount of the drug from the vial into a sterile syringe recruited minimum volume in 50 ml. A syringe with a solution of the drug in the syringe pump set. The corresponding linear filter is connected to a set for infusion, then the infusion system is connected to a syringe. It should set the rate of introduction, in accordance with the instructions and start the infusion after the pre-wetting line filter cetuximab or sterile 0.9% sodium chloride solution. Repeat the procedure until the calculated volume of the infusion of the drug.

If signs of filter plugging during the infusion needs to be replaced.

The solution contains cetuximab antimicrobial preservative or bacteriostatic components in connection, Handling them should strictly abide by the rules of aseptic. The drug is recommended as soon as possible after opening the bottle.

If the drug was not used immediately, time and conditions of storage of ready-to-use formulation before use shall not exceed 24 hours at a temperature of from 2 ° to 8 ° C..

In use the drug retains its chemical and biochemical properties for 20 hours at 25 ° C.

Side effect

The following adverse events, marked by the application of cetuximab, distributed incidence according to the following gradation: Often (? 1/10), often (from ? 1/100 to <1/10), infrequently (from ? 1/1000 to <1/100), rarely (from ? 1/10000 to <1/1000), rarely (<1/10000).

Infusion Reactions: very often - mild to moderate fever, chills, nausea, vomiting, headache, dizziness, breathlessness; often – expressed infusion reactions (usually develop within the first hour of the first infusion and in rare cases can be fatal), including airway obstruction (bronchospasm, stridor, hoarseness, difficulty in speech), krapivnicu, decrease in blood pressure, loss of consciousness, stenokardiю. The basic mechanism of these reactions is not installed. Maybe some of them may be of anaphylactoid / anaphylactic nature.

Dermatological reactions: very often - acne-like rash and / or itching, xerosis, peeling, hypertryhoz, nail changes (eg, paronixija). IN 15% dermatological reactions are pronounced, in rare cases develop skin necrosis. The majority of skin reactions develop within the first 3 week of treatment and usually pass without consequences after drug withdrawal (in compliance with recommendations for correct dosing regimen). Violation of the integrity of the skin in some cases can lead to superinfections, that can cause inflammation of the subcutaneous fat, erysipelas and even staphylococcal epidermal necrolysis (Lyell's syndrome) or sepsis.

The respiratory system: very often - shortness of breath.

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

From the digestive system: very often - a slight to moderate increase in liver enzymes (IS, GOLD, Alkaline phosphatase).

Other: gipomagniemiya; in combination with irinotecan develop typical side effects of irinotecan (the safety profile of irinotecan and cetuximab in their joint application is not changed); in combination with radiotherapy additionally marked undesired effects, associated with radiotherapy, while radiation dermatitis and mucositis develops a bit more often, than during a radiation therapy.

Contraindications

- Pregnancy;

- Lactation (breast-feeding);

- Children's age (efficacy and safety have not been established);

- Expressed (3 or 4 degrees) hypersensitivity to cetuximab.

With care use in patients with impaired liver and / or kidney (data on the use of cetuximab in bilirubin more than 1.5 times, transaminase more than 5 times and serum creatinine of more than 1.5 exceeding ULN no), suppression of bone marrow hematopoiesis, heart and lung diseases in history, and in the elderly, with a decrease in functional status.

Pregnancy and lactation

Use of the drug is contraindicated in pregnancy and lactation.

During treatment with cetuximab, and for at least 3 months after treatment, you must use reliable methods of contraception.

Application for violations of liver function

With care use in patients with hepatic dysfunction.

Application for violations of renal function

With care use in patients with impaired renal function.

Cautions

Cetuximab therapy should be under the supervision of a physician, with experience of anticancer drugs.

With the introduction of cetuximab infusion reactions usually develop on the background of the first infusion or within 1 hours after drug administration, however, they can also occur in a few hours, and also after repeated administration. Patients should be warned about the possibility of delayed reactions and instructed to seek medical attention as soon as they occur.

If a patient a detectable response, infusion-related mild or moderate form, It should reduce the rate of infusion. Subsequent injections should be administered as a drug with reduced speed.

Development expressed symptoms of infusion reactions require immediate and definitive cessation lecheniyatsetuksimabom and may result in the need for emergency medical care.

Particular attention should be given to immunocompromised patients with reduced functional status and patients with diseases of the heart and lungs in the anamnesis.

Dyspnea can develop in a short time after administration of cetuximab, as one of the symptoms of infusion reactions, but she also observed a few weeks after the end of therapy, what, perhaps, It was due to the underlying disease. Risk factors for the occurrence of dyspnea, which may be severe and have long, are old age, reduced functional status and cardiac abnormalities and / or a history of respiratory function. When shortness of breath during the course of therapy with cetuximab, the patient should be examined for signs of progressive pulmonary disorders. Described isolated cases of interstitial lung disorders, for which there was no evidence of a causal relationship with cetuximab. In the case of interstitial lung disorders during therapy with cetuximab, drug treatment should be discontinued and appropriate therapy appoint.

If you experience skin reactions 3-4 degree of dose and regimen of administration of cetuximab must be 'corrected in accordance with the above recommendations.

When using cetuximab in combination with irinotecan should carefully read the instructions for medical use of irinotecan.

To date, accumulated experience with the drug only in patients with normal renal function and liver (Levels of serum creatinine and bilirubin exceeding ULN not more than 1.5 times, and transaminase levels over 5 time).

The use of cetuximab has not been studied in those with depression of bone marrow hematopoiesis, ie. at the level of hemoglobin < 9 g / dl, white blood cell count < 3000/l, absolute neutrophil <1500/l and platelet counts < 100 000/l.

Use in Pediatrics

Safety and effectiveness of cetuximab in children has not been studied.

Effects on ability to drive vehicles and management mechanisms

Studies on the effect of the drug on the ability to drive and control technology was conducted. If the patient observes treatment-related symptoms, affecting its concentration and reaction time, it is recommended to give up driving and the performance of potentially hazardous activities, require high concentration and speed of psychomotor reactions.

Overdose

Cases of overdose have not been described. There is currently no experience with single doses, which would exceed 500 mg / m2 of body surface area.

Drug Interactions

Evidence that, irinotecan that affects the safety profile of cetuximab and conversely absent. The joint appointment of cetuximab and irinotecan change the pharmacokinetic parameters of both drugs was observed.

Other studies on vzaimodeystviyutsetuksimaba a person has not been.

Due to lack of research data on the compatibility of cetuximab mixed with other drugs are prohibited.