Composition, form of production and packaging
Concentrate for the preparation of solution for intraperitoneal administration is transparent, colorless.
co -maxomab 0.1 mg
[PRING] sodium citrate dihydrate 24.4 mg, citric acid monohydrate to pH 5.6, polysorbate 80 0.216 mg, water d / and up to 1 ml.
100 ОјL syringes (1) of borosilicate glass - blister packs (1) made of PVC / paper complete with cannula - packs of cardboard.
500 ОјL - syringes (1) made of borosilicate glass - blister packs (1) made of PVC / paper complete with cannula - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
Katumaxomab is a hybrid monoclonal trifunctional bispecific antibody against adhesion molecules of epithelial cells (EpCAM) and CD3 antigen.
Expression of the EpCAM antigen is expressed on the surface of the majority of malignant tumor cells. CD3 expression is mainly carried out on mature T lymphocytes, and is a component of T-lymphocyte receptors. The third binding site is the Fc fragment of katramaxomab, which interacts with ancillary immune cells carrying on their surface the Fcy receptor.
Due to the binding ability of co-tomaxomab, tumor cells, T-lymphocytes and accessory immune cells are in close proximity. Thus, a concerted immune response directed against tumor cells is induced, including mechanisms such as activation of T lymphocytes, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and phagocytosis. As a result of the combined action of these mechanisms, the death of tumor cells occurs.
The antitumor activity of kolomaksomab was studied in in vitro and in vivo studies. The efficacy of kolomaksomab has been confirmed in an in vitro study for tumor cells with low and high expression of the EpCAM antigen, regardless of the type of tumor. The activity of kolomaksomab was confirmed in vivo in models with immunologically induced ovarian cancer in mice, tumor development disappeared after treatment with intraperitoneal administration of co-menaxomab and human mononuclear cells.
The induction of human anti-mouse (rat and / or murine) antibodies (HAMAs / HARAs) is characteristic of mouse monoclonal antibodies. In the study, it was found that 5.6% of patients (in 7 out of 124) had NAMA antibodies before the 4-th administration of the drug. Anti-mouse NAMA antibodies are detected in 94% of patients 1 month after the last administration of kolomaksomab. No hypersensitivity reactions were observed.
In patients who had NAMA antibodies detected 8 days after the administration of katumaxomab, unlike patients who did not develop antibodies, the positive effect of antibody detection on the effectiveness of treatment was noted, as evidenced by the indicators of overall survival, time to the first carrying out of paracentesis and time until the next paracentesis.
The average geometric value of the maximum concentration ( Cmax ) of co-tomaxomab in blood plasma is 0.5 ng / ml (in the range from 0 to 2.3), the geometric mean value under the concentration-time curve (AUC) is 1.7 days? ng / ml (range from below the minimum value of the detection level to 13.5). The average geometric value of the half-life (T 1/2 ) is about 2.5 days (from 0.7 to 17 days). Interindividual variability of pharmacokinetic parameters in patients is significant.
Katumaksomab is defined in ascites fluid and blood plasma. The concentration of the drug increases in proportion to the increase in the dose of the drug and the number of administrations.
The concentration of the drug in the blood plasma tends to decrease after reaching the maximum concentration after the administration of each dose of the drug.Studies on the pharmacokinetics of co-tomaxomab in patients in special groups have not been conducted.
- treatment of carcinomatous ascites in patients with EpCAM-positive malignant tumors with ineffectiveness or inexpediency of standard therapy.
Treatment should be appointed and monitored by a surgeon who has experience in the diagnosis and treatment of patients with malignant neoplasms. It is necessary to adequately monitor the patient's condition after the administration of Removab. In baseline studies, patient monitoring continued for 24 hours after drug administration. Before the introduction of the drug, Removab is premedicated with non-narcotic analgesic and NSAIDs.
Dosage regimen Removab
The drug is administered as 4 intraperitoneal infusions:
1st dose of 10 mcg Day 0
2nd dose of 20 mcg Day 3
3rd dose of 50 mcg Day 7
4th dose of 150 mcg Day 10
Removab is administered as an intraperitoneal infusion at a constant rate for 3 hours or more. In clinical studies, the administration of the drug for 3 and 6 hours.Depending on the general condition of the patient, the first dose of four can be administered within 6 hours.
The period between drug administration is recommended not less than 2 full calendar days, when no infusions are performed. If there are pronounced adverse reactions, the interval may be increased. The total duration of treatment should not exceed 20 days. The dose of the drug is not recommended.
Patients with impaired hepatic function
The use of the drug in patients with severe impairment of liver function and / or metastatic liver damage by 70% or more, as well as in patients with obstruction or thrombosis portal portal of the liver has not been studied. The use of Removab in these diseases is possible only after the mandatory recording of the risk to the patient.
Patients with impaired renal function
The use of the drug in patients with severe impairment of renal function has not been studied.
The use of Removab is possible only after taking into account the risk to the patient.
In elderly patients the dose adjustment of Removab was not studied. In baseline studies, more than 30% of patients were over 65 years of age.
Instruction on the technique of drug administration
The drug is administered only intraperitoneally in the form of infusion.
Any other ways of administering the drug, including bolus, are unacceptable!
Preparation for the infusion
Before administration, the drug is diluted with a sterile 0.9% solution of sodium chloride. A ready-to-use solution of Removab is administered intraperitoneally for 3 or more hours at a constant rate through the pump system.
Equipment for the administration of Removab
For the administration of Removab, the use of only the following equipment is recommended:
- 50 ml polypropylene syringes
- polyethylene perfusion tubes having an internal diameter of 1 mm and a length of 150 cm
- Polycarbonate valves for infusion / Y-connectors
- catheters made of uncoated polyurethane or with silicone coating
- sterile 0.9% sodium chloride solution for injection
- perfusion pump system
Dilution of the drug
The preparation for the introduction is prepared by an experienced medical worker in compliance with the necessary requirements for sterility. It should be noted that the outer surface of the syringe is not sterile.
Depending on the dose of Removab in a 50 ml syringe, an appropriate amount of 0.9% sodium chloride solution is collected (see Table 1)
Moving the piston, additionally create about 3 ml of the air buffer layer in a syringe having a volume of 50 ml.
Remove the protective cap from the pre-filled syringe containing Removab.
In the package, a cannula is attached to the syringe, for each syringe with the drug, use a new cannula.
The tube is inserted into a 50 ml syringe with 0.9% sodium chloride solution so that its end is placed directly into the solution.
All contents of the syringe (concentrate of Removab preparation and air buffer), directly in 0.9% solution of sodium chloride.
The plunger of the syringe should not be moved in the opposite direction to completely enter the entire volume of the preparation and to eliminate contamination.
A 50 ml syringe is closed with a lid and gently mixed. Air bubbles remove.
To a 50 ml syringe, which is used for intraperitoneal administration of the drug, attach a sticker that is fixed on the inner surface of the cardboard pack and contains the inscription "Ready-made solution of Removab preparation., Only for intraperitoneal administration." The sticker is used as a precautionary measure, which is necessary in order to additionally draw attention to the fact that the drug Removab is injected intraperitoneally.
The syringe is attached to the infusion pump system.
Table 1. Preparation of Removab preparation for vitriline injection
Infusion number / dose Number of pre-filled syringes with Removab preparation Total volume of concentrate for preparation of a solution for Remuvab infusion Solution for sodium chloride injection 0.9% Final volume for administration
10 Ојg pre-filled syringe 50 Ојg pre-filled syringe
1st injection 10 Ојg 1 0.1 ml 10 ml 10.1 ml
2nd injection 20 Ојg 2 0.2 ml 20 ml 20.2 ml
3rd injection 50 Ојg 1 0.5 ml 49.5 ml 50 ml
4 th introduction 150 mcg 3 1.5 ml 48.5 ml 50 ml
The process of infusion administration of the drug
The procedure is carried out by an experienced doctor. The catheter for intraperitoneal administration is administered under the supervision of ultrasound. The catheter is used for draining the abdominal cavity, excising the ascites fluid, as well as for introducing diluted concentrate of the Removab preparation and for 0.9% sodium chloride solution. The catheter is placed in the abdominal cavity for the entire treatment period. Remove the catheter the day after the last infusion of the drug. Before each administration of the drug, ascites fluid is removed through the catheter until its spontaneous discharge or symptoms disappear (eg, dyspnea, nausea, abdominal pain or bloating). Also, 500 ml of a 0.9% solution of sodium chloride are injected through the catheter beforehand to ensure a uniform distribution of antibodies in the abdominal cavity. Removab is administered intraperitoneally for 3 or more hours at a constant rate using an infusion pump system:
A 50 ml syringe containing an infusion solution with Removab is placed in the pump.
The perfusion tube connected to the pump is pre-filled with a solution with Removab. We recommend the use of a perfusion tube with an internal diameter of 1 mm and a length of 150 cm.
The perfusion tube is connected to the Y-connector.
In parallel with the administration of Removab, 250 ml of 0.9% sodium chloride solution is injected through the I-fusion valve / Y-connector and the perfusion catheter conductor.
The speed of the pump is regulated depending on the volume of the drug required for administration during the prescribed time of infusion.
When the content of the 50 ml syringe containing the Removab preparation ends, it is replaced by a 50 ml syringe containing 20 ml of 0.9% sodium chloride solution, its contents are administered for the remaining prescribed infusion time in order to rinse the unused volume of the drug solution in perfusion conductor (about 2 ml) under unchanged conditions. The remaining amount of sodium chloride solution can be poured.
The catheter is closed until the next administration of the drug.
One day after the last dose of the preparation, the final ablation of the abdominal cavity is carried out until the spontaneous excretion of ascitic fluid is terminated, after which the catheter is removed.
Characteristics of the security profile
For the safety profile of Removab, the symptoms associated with the release of cytokines and those associated with gastrointestinal disorders are generally characteristic.
Cytokine-releasing reactions, such as fever, chills, nausea and vomiting, occur very often with an intensity of 1-2 degrees (according to version 3 of the General Terminology of Criteria for Adverse Effects of the National Cancer Institute, USA). The resulting symptoms are associated with the mechanism of action of co-mammaxomab and generally are completely reversible.
The syndrome of a systemic inflammatory response that includes tachycardia, fever and / or dyspnea, and has an intensity that threatens the life of the patient is less frequent, occurs within 24 hours after the administration of Removab, and ceases with symptomatic therapy. Gastrointestinal reactions, such as abdominal pain, nausea, vomiting and diarrhea occur frequently, in most cases have intensity 1 or 2, but may be more severe, and stop in response to adequate symptomatic therapy.
The safety profile of kolumaksomab, when administered for 3 and 6 hours, was generally comparable in the nature, frequency and severity of adverse reactions. With a three-hour administration of the drug, chills and a decrease in blood pressure (1/2 degree), diarrhea (of varying intensity), and increased fatigue (1/2 degree) were most often observed.
Adverse reactions are grouped according to the frequency of occurrence: very often (? 1/10); often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000), including individual messages. Separately (*) marked adverse reactions related to serious.
Infectious and parasitic diseases: often - infections, urinary tract infections; infrequently - inflammatory skin lesions (erythema inducible) *, infections associated with the use of a catheter *.
From the hemopoietic system and lymphatic system: often - anemia, lymphopenia, leukocytosis, neutrophilic leukocytosis, thrombocytosis; infrequently, thrombocytopenia *.
From the immune system: often - reactions caused by the release of cytokines *, hypersensitivity reactions.
From the side of metabolism and nutrition: often - decreased appetite * / anorexia, dehydration *, hypokalemia, hyponatremia, hypocalcemia, hypoproteinemia, hyperglycemia, hypoalbuminemia.
Disorders of the psyche: often - insomnia, anxiety.
From the nervous system: often - headache, dizziness; infrequently, convulsions *.
From the side of the hearing organ and labyrinthine disturbances: often - vertigo.
On the part of the cardiovascular system: often - tachycardia *, including sinus tachycardia, lowering blood pressure *, increasing blood pressure, hot flashes, redness of the face.
On the part of the respiratory system: often - shortness of breath *, pleural effusion *, hypoxia *, cough; infrequently - pulmonary embolism *.
From the digestive system: very often - abdominal pain *, nausea *, vomiting *, diarrhea *; often - constipation *, bloating, dyspepsia, flatulence, skin and ileum obstruction *, ulcerative lesions of the gastric mucosa, reflux esophagitis; infrequently - gastrointestinal bleeding *, intestinal obstruction *.
From the hepatobiliary system: often - cholangitis, hyperbilirubinemia.
From the skin and subcutaneous tissues: often - skin rash, erythema, skin itching, hyperhidrosis, allergic dermatitis *; infrequently - skin reactions *.
From the osteomuscular system and connective tissue: often - back pain, myalgia, arthralgia.
From the urinary system: often - proteinuria, hematuria, leukocyturia; infrequently acute renal failure.
General disorders and disorders at the injection site: very often - fever *, fatigue *, chills *, pain; often - a syndrome of systemic inflammatory response *, asthenia, edema, including peripheral, chest pain, flu-like syndrome, a feeling of malaise, redness at the site of insertion of the catheter; infrequently - extravasation *, inflammation at the injection site *, worsening of the general condition *.
* serious adverse reactions
Description of individual adverse reactions
Criteria for assessing the severity of adverse reactions according to the classification of STAAE of the National Institute of Malignant neoplasms, USA (version 3): 1 degree - mild, 2 degrees - moderate; 3 degrees - heavy, 4 degrees - life-threatening.
Symptoms of severe degree due to ejection of cytokines
In 4.4% of patients, the body temperature increased to 3 degrees, the same severity was noted in cytokine release syndrome (1.2%), and such symptoms as chills (1.0%), nausea (3.7%), vomiting (5 , 6%), dyspnea (1.4%) and a decrease and increase in blood pressure (1.9% / 1.2%). One patient (0.2%) had shortness of breath, and 3 patients (0.6%) had a decrease in blood pressure of 4 degrees of severity. The use of symptomatic therapy reduces the severity of pain and febrile syndrome.
Systemic inflammatory response syndrome
In 4,6% of patients, the syndrome of the systemic inflammatory response is observed within 24 hours after the administration of Removab. In 3 patients (0.6%) there were 4 degrees of severity. Symptomatic therapy reduces the severity of clinical manifestations of the syndrome.
In 48.4% of patients there is pain in the abdomen, in 9.9% of its intensity reaches 3 degrees of severity, symptomatic therapy can reduce the severity of the pain syndrome.
- severe general condition of the patient (body mass index <17, Karnovsky index <60);
- acute infectious processes;
- age up to 18 years;
- increased sensitivity to katumaksomabu, proteins murine (rat and / or mouse) origin, as well as other components of the preparation, severe general condition of the patient (body mass index <17, Karnofsky index <60).
Due to insufficient clinical experience Removab drug application in patients with severe liver and liver metastases over 70% of patients with thrombosis of the central and portal vein of the liver, obstruction in severe hepatic veins; with severely impaired renal function, a decision on the application of Removab the drug can be taken after the mandatory monitoring of the possible risk to the patient.
PREGNANCY AND LACTATION
Contraindicated during pregnancy and lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
Due to insufficient clinical experience with severe impairment of renal function, the decision to use the drug Removab can be made after the mandatory monitoring of the possible risk to the patient.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Due to insufficient clinical experience of the drug Removab in patients with severe liver and liver metastases over 70% of patients with thrombosis of the central and portal vein of the liver, the decision to use the drug Removab can be taken after mandatory account possible risk for the patient.
APPLICATION FOR CHILDREN
Contraindicated in children under 18 years.
Removab drug can not be mixed with other drugs and forbidden administered bolus or by any other method than the method described above intraperitoneal (i.p.) infusion.
Women of childbearing potential must use effective and reliable methods of contraception during treatment with Removab.
Symptoms caused by the release of cytokines
Due to the fact that when binding katumaksomaba with cells of the immune system and the tumor cells begin release of inflammatory mediators and cytokines possessing cytotoxic activity in patients having clinical symptoms such as fever, nausea, vomiting, chills. Often there is shortness of breath, decreased or increased blood pressure. In order to prevent severe pain syndrome and a significant increase in body temperature in patients prior to drug infusion administration Removab recommended to introduce 1000 mg of paracetamol administered intravenously. Despite the holding of pre-medication, there may be 3 degrees of severity of the symptoms listed above. In such cases, to enhance the sedation should be used, and other drugs.
Systemic inflammatory response in cytotoxic activity observed katumaksomaba often it develops within 24 hours after drug administration Removab manifested by fever, palpitations, increased respiratory rate, blood in the formula noted leukocytosis. The use of non-narcotic analgesics and non-steroidal anti-inflammatory drugs can reduce the risk and severity of the syndrome.
emergence of abdominal pain occurs frequently, is short-lived and is probably due, primarily, a way of using the drug - administration as intraperitoneal infusion.
The general condition of patients, and body mass index
Prior to treatment with Removab should assess the overall condition of the patient, the abdominal cavity after draining and removing ascites determine body mass index (> 17) and the Karnofsky index (> 60).
Acute infectious diseases
In the presence of factors influencing the immushguyu system, e.g., acute infectious diseases, the use Removaba not recommended.
Draining the abdominal cavity for removing ascites
For administration Removab only drug recommended to use the following equipment:
- polypropylene syringes 50 ml
- Polyethylene perfusion tube having an inner diameter of 1 mm and a length of 150 cm
- polycarbonate valves for infusion / Y-Connectors
- catheters made of polyurethane or uncoated silicone coated
syringe stored in a consumer package for protection from exposure to light.
Storage ready to use solution of the drug Removab
Ready-to-use solution is physically and chemically stable for 48 hours at 2 to 8 В° C and for 24 hours at a temperature of not higher than 25 В° C.
According to the requirements of the microbial sterility, the preparation should be used immediately after dilution. If the introduction of the drug is delayed, the timing of its use and storage conditions are the responsibility of the consumer, but should not exceed 24 hours at 2 to 8 В° C, considering that the drug dilution was conducted in compliance with the necessary conditions of sterility.
Impact on vehicles and other machinery control ability
In the period of treatment with Removab may cause a number of symptoms associated with the infusion administration of the drug, which can have an adverse effect on the ability to drive a car and complex mechanisms, so prior to the termination of symptoms, patients should refrain from carrying out activities requiring high concentration and psychomotor speed.
No cases of overdose have been reported. Accidental excess of recommended doses noted increased severity of adverse reactions (up to 3 degrees of severity).
Studies have been conducted to study the interaction of the drug.
TERMS OF RELEASE FROM PHARMACY
TERMS AND CONDITIONS OF STORAGE
In the dark place at a temperature of 2 to 8 В° C. Keep out of the reach of children. Shelf life - 2 years.