Erbitux infusion solution 5mg/ml vial 20ml

Composition

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1 ml (1 bottle) contains:

Active ingredients:

cetuximab 2 mg (100 mg).

Auxiliary substances:

sodium dihydrogen phosphate dihydrate,

sodium phosphate dihydrate,

sodium chloride,

d/i water.

Pharmacological action

Pharmacodynamics

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

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

Cetuximab binds to EGFR with an affinity that is approximately 5-10 times higher than that characteristic of endogenous ligands. Blocks the binding of endogenous EGFR ligands, which leads to inhibition of receptor functions. Further, it induces internalization of EGFR, which can lead to negative regulation of the receptor. Cetuximab also sensitizes cytotoxic immune effector cells against EGFR-expressing tumor cells. In vitro and in vivo studies, cetuximab inhibits 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.

It does not bind to other receptors belonging to the HER family.

The KRAS proto-oncogene (homologue of the rat sarcoma 2 Kirsten viral oncogene) is a top-down central signal converter for EGFR. In tumors, activation of KRAS EGFR leads to increased proliferation and production of pro-angiogenic factors. The KRAS oncogenic mutation, which leads to its constitutive activity, is one of the most common oncogenic mutations in cancer. As a result of a mutation in the active region (codons 12 and 13), the KRAS protein is in the activated state and transmits a proliferation signal to the nucleus, regardless of the EGFR signal.

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

Pharmacokinetics

When cetuximab was administered at an initial dose of 400 mg / m2_{, the mean cmax} was 185±55 µg / ml. The mean vd was approximately equivalent to the vascular area supplying the affected area (2.9 l / m2 in the range of 1.5 to 6.2 l/m2). The mean clearance was 0.022 l / h / m2.

C_ss was achieved after 3 weeks of cetuximab monotherapy. _{The mean cmax} was 155.8 mcg / ml at 3 weeks and 151.6 mcg / ml at 8 weeks, while the corresponding mean reduced concentrations were 41.3 and 55.4 mcg / ml, respectively. When cetuximab was co-administered with irinotecan, the mean reduction in concentrations was 50.0 mcg / ml at 12 weeks and 49.4 mcg / ml at 36 weeks.

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

Cetuximab has a long-term T_1/2 with varying values in the range from 70 to 100 hours at the specified dose.

Indications

• Metastatic colorectal cancer with expression of EGFR and wild-type KRAS in combination with standard chemotherapy;
• monotherapy for metastatic colorectal cancer in case of failure of prior chemotherapy with the inclusion of irinotecan or oxaliplatin, and irinotecan intolerance;
• locally common 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 based on platinum drugs;
• monotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck after failure of prior chemotherapy based on platinum drugs.

Use during pregnancy and lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Breast-feeding is contraindicated during cetuximab therapy and for 2 months after the last dose.

Contraindications

• Pregnancy;
• lactation (breast-feeding);
• childhood (efficacy and safety of use have not been established);
• severe (grade 3 or 4) hypersensitivity to cetuximab.

Side effects

From the nervous system: often-headache.

From the side of the organ of vision: often-conjunctivitis; sometimes-blepharitis, keratitis.

From the respiratory system: sometimes-pulmonary embolism.

From the digestive system: often – diarrhea, nausea, vomiting; very often-increased activity of liver enzymes (AST, ALT, ALP).

Dermatological reactions: very often – acne-like rash and / or itching of the skin, dry skin, peeling, hypertrichosis, nail changes (for example, paronychia). In 15% of cases, dermatological reactions are pronounced, and in some cases skin necrosis develops. Most skin reactions develop in the first 3 weeks of treatment and usually go away without consequences after discontinuation of the drug (subject to recommendations for adjusting the dosage regimen).

Violation of the integrity of the skin in some cases can lead to the development of superinfections, which can cause inflammation of subcutaneous fat, erysipelas, or staphylococcal epidermal necrolysis (Lyell’s syndrome) or sepsis.

From the side of metabolism: very often – hypomagnesemia; very often-hypocalcemia, anorexia with a decrease in body weight.

From the side of the blood coagulation system: sometimes-deep vein thrombosis.

Infusion reactions: very often-mild or moderate infusion reactions (fever, chills, nausea, vomiting, headache, dizziness, shortness of breath); often – severe infusion reactions (usually develop within the first hour of the first infusion or several hours after the first or subsequent infusions), including airway obstruction (bronchospasm), decreased or increased blood pressure, loss of consciousness or shock. In rare cases, there is angina, myocardial infarction or cardiac arrest. The main mechanism of these reactions has not been established. Perhaps some of them may be anaphylactoid/anaphylactic in nature.

Other: mucositis that can lead to nosebleeds.

Interaction

The use of cetuximab in combination with fluorouracil infusion, compared with the use of fluorouracil alone, may cause an increase in the incidence of myocardial ischemia and coronary artery thrombosis (up to myocardial infarction), as well as palmar-plantar syndrome.

How to take, course of use and dosage

Administered intravenously as an infusion. Before the infusion, premedication with antihistamines and prednisone is necessary.

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

With the development of toxic reactions, the dosage regimen is adjusted according to special schemes.

Special instructions

Use with caution in patients with impaired liver and/or kidney function (there are currently no data on the use of cetcusimab with bilirubin values more than 1.5 times, transaminases more than 5 times and serum creatinine more than 1.5 times the ULN), with bone marrow hematopoiesis depression, a history of cardiopulmonary diseases, as well as in elderly patients.

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, a white blood cell count < 3000 / µl, an absolute neutrophil count < 1500/µl, and a platelet count < 100,000/µl.

Serum electrolyte concentrations and correction of electrolyte disturbances should be monitored before starting cetuximab therapy and periodically during treatment due to the possible development of reversible hypokalemia (due to diarrhea), hypomagnesemia, and hypocalcemia.

When cetuximab is administered, infusion reactions usually develop during the first infusion or within 1 hour after the end of the drug use, but they can occur after several hours, as well as with repeated injections.

If a patient has a mild or moderate infusion-related reaction, the infusion rate should be reduced. With subsequent infusions, cetuximab should also be administered at a reduced rate.

The development of severe symptoms of an infusion reaction requires immediate and final discontinuation of cetuximab treatment and may require urgent medical attention.

Individual cases of interstitial pulmonary disorders are described, for which there was no causal relationship with the use of cetuximab. If interstitial lung disorders develop during therapy, treatment should be discontinued and appropriate therapy should be prescribed.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

If symptoms appear that affect the ability to concentrate and react quickly, during the treatment period, it is recommended to stop driving and perform potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Solution for infusions

Storage conditions

At a temperature of 2-8 °C (do not freeze)

Shelf life

3 years

Active ingredient

Cetuximab

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Cancer