Empliciti lyophilizate concentrate 300mg vial 340mg, 1pc

Composition

1 vial contains*:

Active ingredient: elotuzumab 340 mg and 440 mg,

excipients: sodium citrate dihydrate 16,6 21,5 mg or mg; citric acid monohydrate of 2.44 mg or of 3.17 mg; sucrose 510 mg or 660 mg; Polysorbate 80 3,40 4,40 mg or mg.

* Packing is subject to perezagruzki 40 mg patients (13.3%) for 300 mg and 40 mg (10%) of 400 mg, which is necessary to ensure complete extraction of the stated dosage. The recoverable amount of elotuzumab in a single vial is 300 mg and 400 mg, respectively.

Pharmacological action

PHARMACOTHERAPY GROUP:

antitumor agent, monoclonal antibodies

ATX Code: L01XC23

PHARMACOLOGICAL ACTION

Pharmacodynamics

Elotuzumab is a human immunostimulating monoclonal IgGl antibody that specifically binds to the SLAMF7 protein (7 representative in the family of lymphocyte activation signaling molecules). SLAMF7 is expressed in large numbers on myeloma cells, regardless of the type of cytogenetic abnormalities. SLAMF7 is also expressed on natural killer cells, normal plasma cells, and other immune cells, including some T cells, monocytes, B cells, and dendritic cells. SLAMF7 is not detected on healthy tissue cells and hematopoietic stem cells.

Elotuzumab directly activates natural killers via SLAMF7 and Fc receptors and thereby enhances their anti-myeloma activity in vitro. Elotuzumab also binds to SLAMF7 on myeloma cells, which contributes to their interaction with natural killers and the destruction of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In preclinical studies, elotuzumab showed synergistic activity when co-administered with lenalidomide.

There are no data on carcinogenicity or mutagenicity of the drug in animals and humans.

Pharmacokinetics

The pharmacokinetics of elotuzumab were studied in patients with multiple myeloma treated with the drug in doses from 0.5 to 20 mg / kg. Elotuzumab has a non-linear pharmacokinetics, the clearance of the drug decreases from 17.5 to 5.8 ml / day / kg with an increase in the dose from 0.5 to 20 mg/kg. This suggests that clearance depends on the interaction with the target, which leads to a more than proportional increase in the area under the concentration-time curve (AUC). The volume of distribution of elotuzumab is close to the volume of intravascular space and does not depend on the dose of the drug. According to the results of population pharmacokinetic analysis, the typical volume of central distribution is 4.04 liters. When elotuzumab is administered at a dose of 10 mg / kg, the concentration of the drug in the blood decreases to approximately 3% of the previously reached maximum equilibrium concentration. In mouse models of xenograft, it was found that the maximum therapeutic efficacy of the drug is observed at a plasma concentration of elotuzumab of 70 mcg / ml. In humans, the use of elotuzumab at a dose of 10 mg/kg achieves an equilibrium concentration of more than 70 mcg / ml in blood plasma.

The metabolism of elotuzumab has not been characterized. Monoclonal antibodies are expected to degrade into small peptides and amino acids during catabolism.

Special patient groups

The clearance of elotuzumab increases with increasing body weight, which is the basis for calculating the dose of the drug per patient’s body weight. Population pharmacokinetic analysis showed no dependence of elotuzumab clearance on age (37 to 88 years), gender, race, baseline lactate dehydrogenase (LDH) activity, albumin concentration, renal impairment, or the presence of mild to severe renal impairment (with or without hemodialysis) or mild hepatic impairment.

The impairment of renal function

, the Pharmacokinetic properties elotuzumab were studied in the appointment of combination therapy with lenalidomide and dexamethasone in patients with multiple myeloma and normal renal function (creatinine clearance of more than 90 ml/min), severe impaired renal function, requiring dialysis (creatinine clearance less than 30 ml/min) or end-stage of renal dysfunction requiring dialysis (creatinine clearance less than 30 ml/min). There were no clinically significant differences in drug clearance between patients with severe renal impairment (with and without dialysis) and patients with normal renal function.

The liver

Pharmacokinetic properties elotuzumab were studied in patients with mild liver failure (total bilirubin less than or equal to the upper limit of normal (ULN) and ACT ULN; or total bilirubin of 1.0 to 1.5 times ULN or any value ACT) in comparison with patients with normal hepatic function (total bilirubin and ACT within the rules). There were no differences in the clearance of elotuzumab between the above groups of patients. The pharmacokinetics of the drug have not been studied in patients with moderate hepatic insufficiency (increased total bilirubin from 1.5 to 3.0 ULN, any ACT value) and severe hepatic insufficiency (total bilirubin more than 3.0 ULN, any ACT value).

ECG disorders

The possible effect of elotuzumab on prolongation of the QTc interval was studied in patients using dosages of 10 and 20 mg / kg both as monotherapy and in combination with lenalidomide and dexamethasone. No changes in the mean values of the QT interval were detected. Analysis of clinical ECG parameters and elotuzumab serum concentrations did not reveal a significant effect of the drug on repolarization. No clinically significant changes in heart rate, PR interval duration, QRS complex duration, atrioventricular conduction or depolarization, or cases of pirouette-type ventricular tachycardia were observed in clinical trials.

Indications

Elotuzumab in combination with lenalidomide and dexamethasone is indicated for the treatment of patients with multiple myeloma who have received one or more previous courses of therapy.

Contraindications

• Hypersensitivity to any component of the drug.
• Children under 18 years of age due to the lack of efficacy and safety data.
• Pregnancy and lactation due to the lack of efficacy and safety data.
• Moderate to severe hepatic impairment.
• If there are contraindications to the use of combination therapy drugs, see the instructions for use of the corresponding drugs.

Side effects

The following adverse reactions were reported in patients with multiple myeloma receiving combination therapy with Empliciti 8. Most of the adverse reactions were mild or moderate (grade 1 or 2). These reactions are presented by system-organ classes and frequency. The frequency of occurrence is defined as: very common (>1/10); common (>>1/100,1/1000,1/10000, >>

a Herpes zoster combines a group of terms: herpes Zoster, oral herpes, herpetic viral infections

b pneumonia combines a group of terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, influenza pneumonia and pneumococcal pneumonia

Infusion reactions

In a clinical study involving patients with multiple myeloma, infusion reactions were observed in approximately 10% of patients who were premedicated and treated with Empliciti® in combination with lenalidomide and dexamethasone (N=318). The incidence of mild to moderate infusion reactions was > 50% among patients who did not undergo premedication. All reports of infusion reactions were classified as grade 3 or lower. Grade 3 infusion reactions were observed in 1% of patients. The most frequently reported symptoms of an infusion reaction were fever, chills, and hypertension. 5% of patients required discontinuation of Empliciti ® use for an average of 25 minutes due to an infusion reaction, and 1% of patients discontinued treatment due to the appearance of infusion reactions. Among patients who experienced an infusion-related reaction,70% (23/33)developed a reaction during the first dose.

Infections

The incidence of infections, including pneumonia, was higher in the Amplicity group than in the control group. In a clinical study involving patients with multiple myeloma, infections were reported in 81.4% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone (N=318), and in 74.4% of patients treated with lenalidomide and dexamethasone (N=317). Grade 3-4 infections were reported in 28% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone, and in 24.3% of patients treated with lenalidomide and dexamethasone. Fatal infections were rare and occurred in 2.5% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone, and in 2.2% of patients treated with lenalidomide and dexamethasone. The incidence of pneumonia was higher in the group treated with Empliciti® in combination with lenalidomide and dexamethasone compared to the group treated with lenalidomide and dexamethasone: 15.1% and 11.7% of patients, with a fatal outcome of 0.6% and 0%, respectively.

Secondary malignancies

The incidence of secondary malignancies was higher in patients treated with Empliciti® than in the control group. In a clinical trial involving patients with multiple myeloma, invasive secondary malignancies were reported in 6.9% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone (N=318), and in 4.1% of patients treated with lenalidomide and dexamethasone (N=317). It is known that secondary malignancies are associated with lenalidomide exposure, which was observed for a longer period of time in patients receiving combination therapy with Empliciti, lenalidomide and dexamethasone than in patients receiving lenalidomide and dexamethasone therapy. The incidence of hematological tumors was similar in the two treatment groups (1.6%). Solid tumors were observed in 2.5% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone and in 1.9% of patients treated with lenalidomide and dexamethasone. Skin cancer (not melanoma) was reported in 3.1% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone, and in 1.6% of patients treated with lenalidomide and dexamethasone.

Deep vein thrombosis

In a clinical study involving patients with multiple myeloma, deep vein thrombosis was reported in 7.2% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone (N=318), and in 3.8% of patients treated with lenalidomide and dexamethasone (N=317). Among aspirin-treated patients, deep vein thrombosis was reported in 4.1% of patients treated with Empliciti® in combination with lenalidomide and dexamethasone, and in 1.4% of patients treated with lenalidomide and dexamethasone. The incidence of deep vein thrombosis observed among the treatment groups was similar for patients receiving prophylactic therapy with low molecular weight heparin (2.2% in both treatment groups) and for patients receiving vitamin K antagonists, and the rates were 0% for patients receiving Empliciti® in combination with lenalidomide and dexamethasone, and 6.7% for patients receiving lenalidomide and dexamethasone.

Immunogenicity

Empliciti®, like other protein preparations, has immunogenicity.

Antibody formation was observed in 18.5% of patients (treated with Empliciti® and the corresponding antibody level was measured). Neutralizing antibodies were detected in 6.4% of patients. In most patients, the immunogenicity of the drug was transient and was observed only at the beginning of therapy, and disappeared after 2-4 months. There was no correlation between the presence of antibodies to the drug in blood plasma and changes in pharmacokinetic parameters, efficacy and safety of the drug.

Interaction

No pharmacokinetic studies have been conducted to investigate drug interactions with Empliciti®. The drug is a human monoclonal antibody. Due to the fact that antibodies are not metabolized by cytochrome P 450 isoenzymes and other isoenzymes, inhibition or induction of these isoenzymes does not affect the pharmacokinetics of elotuzumab when co-administered with other drugs. However, due to the fact that Empliciti® is used in combination with lenolidamide and dexamethasone, it is necessary to read the interaction information in the instructions of these drugs.

How to take, course of use and dosage

The drug should be administered under the supervision of a doctor who has experience in the treatment of multiple myeloma.

Patients should receive premedication prior to each dose of Empliciti®.

Dosage regimen

The recommended dose of Empliciti® in combination with dexamethasone is 10 mg / kg as an intravenous infusion on days 1,8,15,22 for the first two 28-day cycles and every two weeks in subsequent cycles on days 1 and 15. Treatment should continue until the disease progresses or until signs of intolerable toxicity appear. Dexamethasone should be used as follows:

• On the days of Empliciti® use, dexamethasone should be taken 28 mg orally 3 to 24 hours before Empliciti® use, and 8 mg intravenously 45 to 90 minutes before Empliciti®use.
• On days when Empliciti® is not administered, but a dose of dexamethasone is prescribed, it should be taken at a dose of 40 mg orally.
• The recommended dose of lenalidomide is 25 mg orally once daily on days 1-21 of each 28-day cycle, at least 2 hours after use of elotuzumab.

The scheme of use of doses is presented in Table 1.

Table 1: Recommended schedule of use of Empliciti® in combination with lenalidomide and dexamethasone

1 following Premedication drugs takes 45-90 minutes before the imposition of Empliciti®: 8 mg dexamethasone intravenously, a blocker of H 1-histamine receptors: diphenhydramine (25-50 mg orally or intravenously) or a similar product; blocker H-2 histamine receptors: ranitidine (50 mg IV or 150 mg orally) or similar drugs; acetaminophen (650-1000 mg orally).

2 Cycle 28 days

3 Not earlier than 2 hours after use of Amplicity®.

4 Oral dexamethasone (28 mg) 3-24 hours prior to Empliciti use.

Instructions for use of the drug

Amplicity® should be started at a rate of 0.5 ml per minute. If well tolerated, the rate of use can be incrementally increased, as described in Table 2. The maximum rate of use should not exceed 5 ml per minute.

Table 2: Rate of use of Amplicity ®

* Maintain this rate until the use is complete, about 1 hour, depending on the patient’s body weight.

Changing the use mode

If the use of one of the drugs is suspended, interrupted, or discontinued, therapy with the remaining drugs can be continued according to the schedule. However, if the use of dexamethasone is suspended or discontinued, the use of Empliciti® should be based on a clinical assessment of the risk of hypersensitivity reactions.

If infusion reactions of grade 2 or higher develop, the use of Empliciti® should be suspended and appropriate treatment should be prescribed. After reducing the severity of the infusion reaction to grade 1 or lower, Empliciti® should be resumed at a rate of 0.5 ml per minute and, if well tolerated, gradually increased by 0.5 ml per minute every 30 minutes to the rate at which the infusion reaction developed. If there is no re-development of infusion reactions, you can continue to increase the rate of use according to the scheme (see Table 2 Rate of use of Empliciti®).

In patients who have previously developed infusion reactions, vital signs should be monitored every 30 minutes for 2 hours after the end of Empliciti®use. If the infusion reaction develops again, the drug use should be stopped and not resumed on this day. Very severe infusion reactions may require discontinuation of Empliciti therapy and emergency treatment.

Suspension of therapy and modification of the treatment regimen with dexamethasone and lenalidomide should be carried out according to clinical indications.

Patients with mild infusion reactions may receive Empliciti® at a reduced rate of use and under close medical supervision.

Rules for preparing the solution

The concentrate and infusion solution are prepared under aseptic conditions.

Empliciti® is compatible with the following types of infusion equipment:

• Glass vials, polyvinyl chloride (PVC) and polyolefin bags for infusions;
• Polyvinyl chloride (PVC) systems for intravenous use with an automatic infusion pump;
• Polyethersulfone (pore size: 0.2-1.2 microns) and nylon (pore size: 0.2 microns) flow filters for infusion systems.

Partially used vials of the drug should be disposed of in accordance with local guidelines.

Rules for preparing the solution

• The dosage of the drug is determined taking into account the patient’s weight-10 mg / kg. Based on the dose prescribed to the patient, the number of vials of the drug required for use is determined. To prepare a single dose for use per patient, more than 1 vial may be required.
• Remove the protective plastic cap from the bottle. The stopper of the bottle is wiped with sterile cotton soaked in alcohol.
• The contents of each vial are dissolved in water for injection as indicated in Table 3, using a syringe of the appropriate volume (needle size 18 or less).

Table 3: Dilution and Dissolution Instructions for Amplicity®

• To reduce foaming, water is added slowly, holding the plunger of the syringe with your fingers. The solvent jet is directed strictly to the wall of the vial (and not to the lyophilizate).
• Gently stir in a circular motion, holding the bottle vertically. Then turn the bottle over to dissolve all the powder that may be in the top of the bottle or on the stopper. DO NOT SHAKE.
• The lyophilizate should be dissolved within 10 minutes. After complete dissolution, leave the resulting solution for another 5-10 minutes before further dilution.
• The resulting concentrate is a clear or strongly opalescent liquid from colorless to light yellow in color. Do not use a solution of a different color or containing foreign particles. Discard vials with altered color or particles.
• After dissolution, the required volume of concentrate is taken from each bottle for the calculated dose, but not more than the maximum -16 ml from a 400 mg bottle and 12 ml from a 300 mg bottle. Further dilution is carried out in a vial of a sterile infusion system using 230 ml of 0.9% sodium chloride solution for infusions or a sterile 5% dextrose solution for infusions. The volume of 0.9% sodium chloride solution for infusions or sterile 5% dextrose solution for infusions is selected so that the concentration of elotuzumab in the solution is not more than 5 ml/kg of the patient’s body weight at any administered dose of the drug.
• The prepared solution is stirred by carefully turning the infusion container over. Do not shake the bottle before use! The prepared solution should not be frozen.
• Before use, it is necessary to conduct a visual inspection of the prepared solution of the drug for the presence of mechanical inclusions and discoloration. Empliciti ® solution is a clear or strongly opalescent solution, from colorless to light yellow.
• – The drug should be administered through a sterile infusion system with low protein binding capacity with a sterile, non-pyrogenic flow filter (pore size 0.2-1.2 microns) and an automatic infusion pump.
• Amplicity® should be started at a rate of 0.5 ml per minute. If the use is well tolerated, the infusion rate can be gradually increased, as indicated in Table 2. The maximum infusion rate should not exceed 5 ml per minute.
• The drug should not be administered as a rapid intravenous injection or as a bolus injection.
• Do not mix Empliciti® with other medicinal products in the same bottle or infusion system and do not administer it simultaneously with other infusions.
• After each dose of Empliciti®, the infusion system should be flushed with a sterile 0.9% isotonic sodium chloride solution for infusions or a sterile 5% dextrose solution for infusions. From the point of view of microbiological purity, the prepared solution should be used immediately. Otherwise, the prepared solution can be stored in a dark place for up to 24 hours at a temperature of 2-8 °C (Of the specified 24 hours, the drug solution can be at room temperature (20-25 °C) and daylight for no more than 8 hours, including the time required for drug use). The prepared solution must not be frozen!
• The unused remainder of Amplicity® in the vial and the empty vial must be destroyed.

Overdose

There was one case of drug overdose when using 23.3 mg / kg of elotuzumab in combination with lenalidomide and dexamethasone. At the same time, the patient did not experience infusion reactions and other symptoms, and did not require any additional treatment associated with an overdose. The patient continued therapy with Amplicity®.

The maximum tolerated dose has not been established. In clinical trials, approximately 78 patients received elotuzumab at a dose of 20 mg / kg without developing toxic effects. In case of overdose, treatment should consist of symptomatic drug therapy in accordance with the side effects that occur, with careful monitoring of the patient.

Special instructions

Infusion reactions

Empliciti® may cause the development of infusion reactions. Infusion reactions have been reported in clinical trials in approximately 10% of patients treated with Empliciti®, lenalidomide and dexamethasone.

All marked infusion reactions were not higher than the 3rd degree of severity. In clinical trials, grade 3 infusion reactions occurred in 1% of patients treated with lenalidomide and dexamethasone in combination therapy. The most common adverse reactions were fever, chills, and hypertension. In a combination therapy study with lenalidomide and dexamethasone,5% of patients required discontinuation of Empliciti ® due to the development of infusion reactions at an average of 25 minutes, and 1% of patients had to cancel the drug due to infusion reactions. Among patients who experienced infusion reactions,70% (in the case of combination with lenalidomide and dexamethasone) experienced them during the first dose.

Combination therapy with the use of the drug

Empliciti® is used in combination with other medications; therefore, the warnings and precautions applied to these medications will also be relevant for combination therapy that includes elotuzumab. These include the potential risk to the fetus, the presence and transfer of the drug/antibody with semen and blood, and the prohibition of blood and/or sperm donation. Before starting treatment, it is necessary to take into account the instructions for the use of all drugs used in combination with Empliciti®.

Infections

In clinical trials involving patients with multiple myeloma, the incidence of infections, including pneumonia, was higher among patients treated with Empliciti®. It is necessary to monitor the condition of patients and apply standard therapy for the treatment of infectious diseases.

Secondary malignancies

In a clinical trial involving patients with multiple myeloma, which compared Empliciti® therapy in combination with lenalidomide and dexamethasone and lenalidomide and dexamethasone therapy, the incidence of secondary malignancies, in particular solid tumors and skin cancer (not melanoma), was higher among patients treated with Empliciti®. It is known that secondary malignancies are associated with lenalidomide exposure, which was for a longer period of time in patients treated with Empliciti® in combination with lenalidomide and dexamethasone than in patients treated with lenalidomide and dexamethasone. The incidence of hematological tumors was similar in the two treatment groups. Patients should be monitored for the development of secondary malignancies.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

Studies of the effect of the drug on the ability to drive vehicles and work with mechanisms have not been conducted.

Form of production

Lyophilizate for preparation of concentrate for preparation of infusion solution

Storage conditions

Store at a temperature of 2 to 8 °C in a place protected from light. Do not freeze it. Keep out of reach of children!

Shelf

life is 3 years.

Active ingredient

Elotuzumab

Conditions of release from pharmacies

Prescription