ÈRBITUKS ®
Active material: Cetuximab
When ATH: L01XC06
CCF: Anticancer drug. Monoklonalynыe antibodies
ICD-10 codes (testimony): C18, C19, C20, (C) 49.0
When CSF: 22.05
Manufacturer: MERCK KGaA (Germany)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Solution for infusion clear or slightly Opalescent from colorless to yellowish.
| 1 ml | |
| cetuksimab | 5 mg |
Excipients: glycine, polysorbate 80, sodium chloride, citric acid monohydrate, sodium hydroxide 1 m, water d / and.
10 ml – colorless glass vials (1) – packs cardboard.
20 ml – colorless glass vials (1) – packs cardboard.
50 ml – colorless glass vials (1) – packs cardboard.
100 ml – colorless glass vials (1) – packs cardboard.
Pharmacological action
Anticancer drug. Is a chimerical monoclonal antibody IgG1, directed against the epidermal growth factor receptor (EGFR).
EGFR signaling pathways involved in the control of cell survival, in cell cycle progression, Angiogenesis, cell migration and cellular invasion / metastasis process.
Èrbituks® binds to the EGFR protein with, is approximately 5-10 times greater than, characteristic of the endogenous ligands. Èrbituks® blocks the binding of endogenous ligands, EGFR, which leads to inhibition of receptor function. Further, it induces internalization of EGFR, that can lead to receptor downregulation. Èrbituks® also cytotoxic immune effector cells sensitized with regard to EGFR overexpressing tumor cells. The studies in vitro and in vivo Èrbituks® inhibits proliferation and induces apoptosis in human tumor cells, expressing EGFR. In vitro Èrbituks® inhibits the production of those angiogenic factors in tumor cells and blocks the migration of endothelial cells. In vivo Èrbituks® inhibits the production of those angiogenic factors in tumor cells and reduces the activity of angiogenesis and metastasis of tumors.
Èrbituks® is not associated with other receptors, belonging to the family of HER.
HRAS Proto-oncogene (viral oncogene homolog rat Sarcoma 2 Kirsten) is a descending Central EGFR signal converter. In the activation of EGFR KRAS tumors leads to increased cell proliferation, Pro-products of those angiogenic factors. KRAS is one of the most common oncogene activated in cancer. KRAS gene mutations occur in the active site (codon to confer resistance 12 and 13) as a result of the activation of the KRAS protein regardless of the EGFR signal.
In metastatic colorectal cancer KRAS mutation is found in 30-50% cases. The appearance of antibodies in humans antihimernye (AHAČ) It is a feedback class chimeric antibody. Current data for the elaboration of AHAČ limited. Generally, measurable titers have identified AHAČ 3.4% studied patients with frequencies from 0% to 9.6 % studies with similar readings. Appearance correlates with development not AHAČ gipercuvstvenosti reactions or any other undesirable effects Èrbituksa®.
Pharmacokinetics
The on/in infusion Èrbituksa® demonstrated dozozavisimuû farmakokinetiku weekly a drug in doses of 5 to 500 mg / m2 body surface area.
Absorption and distribution
In appointing Èrbituksa® the starting dose 400 mg / m2 the surface area of the body the average value (C)max amounted to 185 ± 55 µg/ml. Average Vd was approximately equivalent to the vascular field, krovosnabžaûŝej the affected area (2.9 l/m2 in the range of 1.5 to 6.2 l/m2). Average clearance match 0.022 l / h / m2 body surface area.
Serum concentrations reached stable values through 3 Week cetuximab monotherapy. The average value of Cmax 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. The study combined the appointment Èrbituksa® with average value reduction with irinotecan concentrations corresponded to the 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.
Cetuksimab has long T1/2 with the variation in values ranging from 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;
-monotherapy relapsing or metastatic squamous cell cancer of the head and neck with the ineffectiveness of previous chemotherapy.
Dosage regimen
Èrbituks® enter in/in infusion at a rate of not more than 10 mg / 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 body surface (pervaya infusion) as a 120-minute infusion and a further dose 250 mg / m2 the surface of the body in the form of 60-minute infusion.
Combined therapy Colorectal cancer should follow the recommendations for the modification of doses of chemotherapeutic drug, information contained in the present pharmaceutical preparation. Chemotherapy drug administered no earlier than 1 hours after the end of the infusion Èrbituksa®. Èrbituksom Therapy® It is recommended that you continue until signs of disease progression.
When applying Èrbituksa® treatment Squamous cell head and neck cancer in combination with radiation therapy, treatment Èrbituksom® We recommend starting 7 days prior to radiation therapy and to continue the weekly administration of radiation therapy to the closure.
Patients with recurrent or metastatic squamous cell head and neck cancer in combination with the chemotherapy drugs platinum-based (to 6 cycles) Èrbituks® used as a supporting therapy before signs of disease progression. Chemotherapy is appointed no earlier than 1 hours after the end of the infusion Èrbituksa®.
Recommendations for dose adjustment mode
With the development of skin reactions 3 toxicity according to the classification of the National Cancer Institute application Èrbituksa® to interrupt. 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.
At the secondary and tertiary development of severe skin reactions use Èrbituksa® again, you must abort. Therapy may be resumed with the drug at lower doses (200 mg / m2 the surface of the body after the second occurrence of reactions and 150 mg / m2 -After the 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, Èrbituksom therapy® discontinue.
Terms of use of the drug
Èrbituks® introducing/using 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.
Èrbituks® compatible with polyethylene, etilvinilatsetatnymi or PVC bags for infusion solutions, with polyethylene, etilvinilatsetatnymi, polyvinylchloride, Polybutadiene or polyurethane infusion systems and polypropylene syringes for syringe pump.
Èrbituks® do not mix 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. 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 quantity of the drug vial is typed in a sterile syringe. A syringe with a solution of the drug in the syringe pump set, then the infusion system is connected to a syringe. You should set the speed in accordance with the instructions and begin infusion. Repeat the procedure until the calculated volume of the infusion of the drug.
Solution Èrbituksa® contains no antibacterial preservatives or bacteriostatic components, Therefore when dealing with them should comply strictly with the rules upgrades. 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 48 hours at 25 ° C.
Side effect
The main side effects Èrbituksa® – skin reactions (80%), gipomagniemiya (10%), infusion reactions with moderate manifestation of symptoms (>10%), infusion reactions with marked symptoms (1%).
The following adverse events, marked in the application Èrbituksa®, distributed incidence according to the following gradation: Often (≥ 1/10), often (of ≥ 1/100 to <1/10), infrequently (of ≥ 1/1000 to <1/100), rarely (of ≥ 1/10 000 to <1/1000), rarely (<1/10 000).
From the nervous system: often – headache.
On the part of the organ of vision: often - conjunctivitis; infrequently – .Aloe, keratit.
The respiratory system: infrequently-pulmonary embolism.
From the digestive system: often – diarrhea, nausea, vomiting; very often, increase in liver enzymes (IS, GOLD, Alkaline phosphatase).
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.
Metabolism: Often – gipomagniemiya; Often – hypocalcemia, Anorexia with losing weight.
From the blood coagulation system: infrequently – deep vein thrombosis.
Infusion Reactions: very often-weakly or moderately expressed infusion reactions (fever, chills, nausea, vomiting, headache, dizziness, breathlessness); often – expressed infusion reactions (usually develop within the first hour of the first infusion or a few hours after the first or subsequent infusions), including airway obstruction (bronchospasm), decrease in blood pressure, loss of consciousness or shock. In rare cases, notes angina, myocardial infarction or cardiac arrest. The basic mechanism of these reactions is not installed. Maybe some of them may be of anaphylactoid / anaphylactic nature.
Other: mucositis, that can lead to bleeding nosovomu.
Contraindications
- Pregnancy;
- Lactation (breast-feeding);
- Children's age (efficacy and safety have not been established);
- Expressed (3 or 4 degrees) hypersensitivity to cetuximab.
FROM caution You should use the drug in human liver and/or kidney (data on the application of Èrbituks®and when indicators of 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, cardio-pulmonary diseases in history, and elderly patients.
Pregnancy and lactation
Use of the drug is contraindicated in pregnancy and lactation.
During treatment Èrbituksom®, and for at least 3 months after treatment, you must use reliable methods of contraception.
Cautions
Èrbituksom Therapy® should be under the supervision of a physician, with experience of anticancer drugs.
Recommended monitoring and serum electrolytes and electrolyte correction of infringements prior to the therapy Èrbituksom® and periodically during treatment because of the possible development of reversible gipocalziemii (as a result of diarrhoea;), gipomagniemii, hypokalemia.
With the introduction of Èrbituksa® 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 final cessation of treatment Èrbituksom® and may result in the need for emergency medical care.
Special attention should be given to immunocompromised patients with heart and lung diseases in history.
Described isolated cases of interstitial lung disorders, for which there were no causal relationship with the use of Èrbituksa®. In the case of interstitial lung violations while therapy Èrbituksom®, drug treatment should be discontinued and appropriate therapy appoint.
If you experience skin reactions 3-4 degree of dose and mode of introduction Èrbituksa® must be adjusted in accordance with the above recommendations.
When using Èrbituksa® in combination with chemotherapy should carefully read the instruction on the medical application of chemotherapy drug.
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).
Nora Berra visit application has not been well studied in patients with oppression kostnomozgovy blood, 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 efficacy of Èrbituksa® the children have 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 400 mg / m2 body surface area.
Drug Interactions
Use Èrbituksa® infusion in combination with fluorouracil compared to using only fluorouracil may cause increased incidence of coronary ischemia and thrombosis (until myocardial infarction), as well as the Palmar-Plantar syndrome.
Evidence that, irinotecan that has an impact on the safety profile of Èrbituksa® Conversely there is no. The joint appointment Èrbituksa® and irinotekana changes farmakokineticeskih parameters of both drugs were observed.
Other studies on interaction of Èrbituksa® the person has not been.
Due to the lack of research on the compatibility of Èrbituks blending® with other drugs is prohibited.
Conditions of supply of pharmacies
The drug prescription.
Conditions and terms
The drug should be stored out of reach of children at a temperature of 2 ° to 8 ° C, Do not freeze. Shelf life – 3 year.
