Instruction for use: Mozobil

Dosage form: Solution for subcutaneous administration

Active substance: Plerixaforum

ATX

L03AX16 Pleriksafor

Pharmacological group:

Immunostimulating agent [Stimulators of hemopoiesis]

The nosological classification (ICD-10)

C85 Other and unspecified types of non-Hodgkin's lymphoma: Lymphoma of mixed type; Lymphomas from cells of the mantle zone; Malignant lymphoma; Lymphoma non-Hodgkin's disease; Lymphocytic lymphoma

C90.0 Multiple myeloma: Multiple myeloma; Myeloma

Composition

Solution for subcutaneous administration 1 vial.

active substance: Pryrixaffor 24 mg

Auxiliary substances: sodium chloride - 5.9 mg; 0.1 M solution of sodium hydroxide or 0.1 M solution of hydrochloric acid - to pH 6.0-7.5; Water for injection - up to 1.2 ml

Description of dosage form

Transparent colorless or light yellow liquid.

Pharmachologic effect

Mode of action - Immunomodulating, hematopoietic, mobilizing hematopoietic stem cells.

Pharmacodynamics

Mechanism of action

Periciksorp is a biclamide derivative and is a selective reversible CXCR4 antagonist of the chemokine receptor, blocking it by binding to the cognate ligand, the stromal cell factor-lα (SDF-lα), also known as CXCL12. It is believed that the plercixaphor-induced leukocytosis and the increase in the number of circulating hematopoietic progenitor cells result from a disruption of the bond between CXCR4 and its cognate ligand, which results in the emergence of mature as well as pluripotent cells in the systemic circulation. CD34 + cells mobilized with plirixafor are functional and capable of engraftment, with a long-term recovery potential of the population.

Pharmacodynamics

In two placebo-controlled clinical trials involving patients with lymphoma and multiple myeloma (AMD3100-3101 and AMD3100-3102, respectively), an increase in the CD34 + cell count (cells / μl) over 24 hours was assessed over the course of the day before the first apheresis (see Table 1). 1). In the estimated 24-hour period, the first dose of plirixafor (0.24 mg / kg) or placebo was administered 10 to 11 hours before apheresis.

Table 1

An increase in the number of CD34 + cells in the peripheral blood after the administration of the drug Mozobail together with G-CSF

In studies of pharmacodynamics in healthy volunteers using only pleriksaphor, the peak of mobilization of CD34 + cells was observed within 6-9 h after administration of the drug. In the study of pharmacodynamics in both healthy volunteers and patients using a mobilization regimen including granulocyte colony-stimulating factor (G-CSF) and pryrixaphor in the same doses, a longer rise of CD34 + cells in the peripheral blood was observed for 4 to 18 hours after Administration of the drug, the peak was noted between 10 and 14 hours.

Children. The effectiveness and safety of the use of the drug Mozobail in children and adolescents under the age of 18 years in clinical studies have not been studied.

The European Medical Agency refused to provide the company with the results of studies on the use of the drug Mozobail in children and adolescents under the age of 18 with myelosuppression (due to chemotherapy used to treat malignant neoplasms) requiring autotransplantation of hematopoietic stem cells (see "Method of administration and dose").

Pharmacokinetics

The pharmacokinetics of plerixaphor have been studied in patients with lymphoma and multiple myeloma using a clinical dose (0.24 mg / kg) after preliminary treatment with G-CSF (10 mkg / kg once daily for 2 to 4 days, if necessary, prolong the course to 7 days).

Absorption

Periciksafor is rapidly absorbed after SC administration, Cmax is reached after approximately 30-60 minutes (Tmax). After sc administration of plirixafor at a dose of 0.24 mg / kg, which was preceded by preliminary treatment of G-CSF for 4 consecutive days, Cmax plirixaphor in plasma and mean AUC0-24 were (887 ± 217) ng / ml and ( 4337 ± 922) ng · h / ml, respectively.

Distribution

Pleriksafor moderately binds to human plasma proteins (up to 58%). The apparent Vd of plirixafore in humans is 0.3 l / kg, which indicates that the drug is prone to distribution in the extravascular space, but is not limited to them.

Metabolism

In experiments in vitro, plerixafor was not metabolized by human hepatic microsomes and human embryonic hepatocytes. It was also shown in vitro that the preparation does not inhibit the main metabolizing isoenzymes of cytochrome P450 (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 / 5). In experiments in vitro with human hepatocytes, plirixafor did not induce isoenzymes CYP1A2, CYP2B6 and CYP3A4. The data obtained suggest that the potential for drug interactions mediated by the P450 system is low for plriixafor.

Elimination

The main way of eliminating pleriksafora is excretion through the kidneys. After the administration of preexaphor at a dose of 0.24 mg / kg to healthy volunteers with normal renal function, approximately 70% of the drug was excreted unchanged in the urine within the first 24 hours after administration. T1 / 2 from the plasma is 3-5 hours. According to in vitro studies using the cellular models MDCKII and MDCKII-MDR1, plriixafor is not a substrate or inhibitor of P-glycoprotein.

Special patient groups

Patients with impaired renal function. In persons with varying degrees of renal failure, the clearance of pleriksafor after a single dose (0.24 mg / kg) decreased; There was a positive correlation with Cl creatinine. The mean AUC0-24 pli riksafora in patients with mild (Cl creatinine 51-80 ml / min), moderate (Cl creatinine 31-50 ml / min) and severe (Cl creatinine ≤30 ml / min) degree of renal failure were 5410, 6780 And 6,990 ng · h / ml, respectively, which exceeds the drug exposure values observed with normal kidney function (5,070 ng · h / ml). Renal failure did not affect Cmax.

Floor. Population analysis did not reveal differences in the pharmacokinetics of plerixafore by sex.

The elderly. Population analysis did not reveal differences in the pharmacokinetics of plerixafore by age.

Children. Data on the pharmacokinetics in children are limited.

Indication of the drug Mozobil

To increase the mobilization of hematopoietic stem cells in the peripheral bloodstream for the purpose of their collection and subsequent autotransplantation to patients with lymphoma and multiple myeloma combined with granulocyte colony-stimulating factor (G-CSF).

Contraindications

Increased sensitivity to plerixafor or any excipients of the drug;

Pregnancy (see "Application during pregnancy and lactation");

Lactation (see "Application in pregnancy and lactation");

Children and adolescents under 18 years (due to lack of experience of use).

Application in pregnancy and breastfeeding

Data on the use of plerixafora in pregnant women is not enough. Studies in animals showed the presence of a teratogenic effect of the drug. The patient should be informed that the use of plerixafor during pregnancy can lead to congenital malformations. The use of the drug Mozobil during pregnancy is possible only in those cases when the benefit from the application exceeds the potential risk to the fetus.

Women of childbearing age need to use effective contraception during treatment.

Data on the possible penetration of plriixafor into breast milk are not available, so the risk for an infant cannot be ruled out. During treatment with the drug Mozobil should stop breastfeeding.

Side effects

Data on the safety of the use of the drug Mozobil in combination with G-CSF in cancer patients with lymphoma and multiple myeloma were obtained in 2 placebo-controlled (phase III) and 10 uncontrolled studies (phase II) in 543 patients. Patients received treatment with plexixapore at a dose of 0.24 mg / kg / day p / c. The duration of treatment in these studies was from 1 to 7 days continuously (median - 2 days).

In two studies (Phase III) involving patients with non-Hodgkin's lymphoma and multiple myeloma (AMD3100-3101 and AMD3100-3102, respectively), 301 patients treated with Mozobil and G-CSF and 292 patients receiving placebo and G-CSF . The daily dose of G-CSF was 10 mkg / kg in the morning for 4 consecutive days before the first injection of plirixafor or placebo, and every morning before the apheresis.

Below are the undesirable reactions that were more often observed in the group receiving the drug Mozobil and G-CSF than in the placebo group and G-CSF. The incidence of adverse reactions associated with treatment was> 1% among patients receiving Mozobil, with mobilization of hematopoietic stem cells and apheresis, and before chemotherapy / myeloablation therapy in preparation for transplantation. Undesirable reactions are indicated in accordance with the system-organ class and frequency of occurrence. The frequency was determined based on the following criteria: very often (≥1 / 10); Often (≥1 / 100 to <1/10); Infrequently (≥1 / 1000 to <1/100); Rarely (≥1 / 10000 to <1/1000); Very rarely <1/10000), the frequency is unknown (cannot be estimated from available data).

With the use of chemotherapy / ablation in preparation for transplantation, there was no significant difference in the incidence of adverse reactions between treatment groups at 12 months after transplantation.

Below are the undesirable reactions observed in the group of the drug Mozobil more often than in the placebo group associated with the use of the drug Mozobil during mobilization and apheresis in phase III studies.

Disorders from the immune system: infrequently - allergic reactions, anaphylactic reactions, including anaphylactic shock (see Post-marketing observations and "Special instructions").

Mental disorders: often - insomnia.

Disturbances from the nervous system: often - headache, dizziness.

Disorders from the digestive tract: very often - diarrhea, nausea; Often - flatulence, abdominal pain, vomiting, bloating, dry mouth, discomfort in the epigastric region, constipation, dyspeptic phenomena, hypoesthesia of the oral mucosa.

Disturbances from the skin and subcutaneous tissues: often - hyperhidrosis, erythema.

Disorders from the musculoskeletal and connective tissue: often - arthralgia, musculoskeletal pain.

General disorders and disorders at the injection site: very often - reactions at the injection site; Often - fatigue, malaise.

Undesirable reactions in patients with lymphoma and multiple myeloma who received Mozobil in controlled Phase III studies and uncontrolled studies, including a phase II study in which Mozobil was used in monotherapy for the mobilization of hematopoietic stem cells, are similar. In patients with cancer, the incidence of adverse reactions did not differ depending on the disease, age or sex.

Allergic reactions

Allergic reactions included one or more of the following adverse events: urticaria (n = 2), periorbital edema (n = 2), dyspnea (n = 1), or hypoxia (n = 1). These phenomena were of mild or moderate severity and occurred within about 30 minutes after the administration of the drug Mozobil.

Myocardial infarction

According to clinical studies, 7 of the 679 cancer patients underwent myocardial infarction after stem cell mobilization with the help of plirixafor and G-CSF. All cases of myocardial infarction were observed at least 14 days after the last injection of Mozobil. In addition, two patients participating in a program for the use of the study drug individually, underwent myocardial infarction after stem cell mobilization with the help of plirixafor and G-CSF. One of the cases of myocardial infarction occurred 4 days after the last injection of the drug Mozobil.

The absence of a temporary connection in 8 of 9 patients and the risk profile of participants who underwent myocardial infarction do not allow considering Mozobil drug to be an independent risk factor for myocardial infarction in patients receiving G-CSF.

Vasovagal reactions

Vasovagal reactions (orthostatic hypotension and / or syncope) were observed in less than 1% of participants in clinical trials using Mozobil (cancer patients and healthy volunteers) who received plriixafor at a dose of <0.24 mg / kg. In most cases, these phenomena were observed within 1 hour after the administration of the drug Mozobil.

Disorders from the digestive tract

In clinical studies on the use of the drug Mozobil in oncological patients reports of severe violations of the gastrointestinal tract (including diarrhea, nausea, vomiting, abdominal pain) were rarely recorded.

Paresthesia

Often observed in cancer patients after autotransplantation due to numerous medical procedures. In placebo-controlled Phase III clinical trials, the incidence of paresthesias was 20.6% and 21.2% in the plirixafore and placebo groups, respectively.

Hyperleukocytosis

In Phase III studies, an increase in the number of white blood cells a day before apheresis or on any day of apheresis to 100 · 109 / L and above was observed in 7% of patients receiving Mozobil and 1% of patients receiving placebo. There were no complications or clinical manifestations of leukocytosis.

Patients of advanced age

24% of participants in two placebo-controlled clinical trials for the use of plerixafor were older than 65 years. Significant differences in the incidence of adverse reactions in the subgroup of elderly patients (compared with younger patients) were not observed.

Post-marketing observations

Below are the undesirable reactions that were reported in the post-marketing period of the Mozobil drug supplement in addition to those that were documented during clinical trials. The frequency of undesirable reactions could not be determined; Reports about them were obtained from a population with an undetermined number of patients, as well as a possible relationship with the use of the drug.

From the immune system: anaphylactic reactions, including anaphylactic shock.

Disorders of the psyche: unusual dreams, nightmares.

Interaction

Studies to study the interactions of this drug have not been conducted. Tests carried out in vitro have shown that plerixafor is not metabolized by cytochrome P450 isoenzymes, nor does it suppress or enhance their activity. According to in vitro studies, plriixafor is not a substrate or an inhibitor of P-glycoprotein.

The addition of rituximab to the mobilization regimen (plriixafor and G-CSF) in clinical trials involving patients with non-Hodgkin's lymphoma did not affect the safety of the patient or the concentration of CD34 + cells.

Dosing and Administration

SC.

Treatment with Mozobil should be prescribed and conducted by a qualified oncologist and / or hematologist. Mobilization and apheresis of cells should be carried out in cooperation with the oncohematological center, which has sufficient experience in this field, where it is possible to properly control the level of hematopoietic progenitor cells.

Doses. The recommended dose of plerixafor is 0.24 mg / kg / day. The drug is injected w / c for 6-11 h before the onset of apheresis after a preliminary four-day therapy with G-CSF. In clinical trials, Mozobail was usually administered for 2-4 consecutive days (up to 7 days of continuous use).

To calculate the dose of plyriksafora, the average body weight, measured for 1 week before the first dose of the drug, is used.

In clinical studies, the dose of plirixafor was calculated based on the body weight of patients whose body weight deviations from ideal were not more than 175%. The dosage regimen and treatment features of patients whose body weight deviations are more than 175% of the ideal were not studied.

The dose of Mozobil (in ml) is calculated by the formula: 0.012 × actual body weight (kg). Given that the effect of the drug with increasing body weight increases, the dose of plerixafor should not exceed 40 mg / day.

Recommended concomitant medications

In the baseline clinical trials supporting Mozobil treatment, all patients received G-CSF at a dose of 10 mkg / kg, in the morning, for 4 consecutive days before the first injection of plirixafor, and then every morning before the apheresis.

Use of the drug in specific patient groups

Impaired renal function. At Cl creatinine <50 ml / min, the dose of plercixaphor should be reduced by a third, to 0.16 mg / kg / day (see "Pharmacokinetics"). Clinical data on the use of the adjusted dose of the drug are limited. The existing experience of clinical use of plerixafora does not allow us to give recommendations on the dosing of the drug with Cl creatinine <20 ml / min, as well as in patients on hemodialysis. Given that the effect of the drug with increasing body weight increases, the dose of plriixafor should not exceed 27 mg / day if Cl creatinine <50 ml / min.

Female: Cl creatinine (mL / min) = 0.85 × value, calculated by the formula for men.

Children. The experience of using the drug in children is limited. The safety and efficacy of Mozobil for the treatment of children have not been evaluated in controlled clinical trials.

Patients of advanced age (more than 65 years). In elderly patients with normal renal function, dose adjustment is not required. With Cl creatinine <50 ml / min, it is recommended to change the dose of the drug (see above "Violation of kidney function"). It should be remembered that with age, the probability of reducing renal function is increasing, so elderly patients should be selected with caution.

Mode of application

PC. 1 fl. The drug Mozobil is intended for single use.

Before administration, the bottle should be inspected. If the preparation contains mechanical inclusions or there are discolourings of the solution, it cannot be introduced. The drug Mozobail is a sterile drug that does not contain preservatives, therefore, in the process of recruitment of the contents of the vial into the syringe for injections, it is necessary to observe aseptic rules.

Studies on the compatibility of the drug Mozobil with other drugs have not been conducted, so it should not be mixed with other drugs in one syringe.

The drug remaining after the administration of the required dose should be destroyed.

Overdose

There were no cases of overdose. Given the limited data on the use of the drug at a dose exceeding the recommended dose (up to 0.48 mg / kg / day), it can be assumed that the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension and / or syncope may increase.

Special instructions

Mobilization of tumor cells in patients with leukemia

The drug Mozobil and G-CSF was prescribed for acute myeloid and plasmacytic leukemia as part of a program for the use of the study drug individually. In some cases, an increase in the number of circulating leukemic cells was observed. Periciksor, appointed for the mobilization of hematopoietic stem cells, can cause the mobilization of tumor cells and their subsequent entry into the product of apheresis. Therefore, plriixafor is not recommended for use in leukemia for the mobilization of hematopoietic stem cells and their subsequent collection.

Hematological effects

Hyperleukocytosis. The drug Mozobil, administered in combination with G-CSF, increases not only the population of hematopoietic stem cells, but also the number of circulating leukocytes. During the application of the drug Mozobil should monitor the number of leukocytes. Every case of prescribing Mozobil should be carefully evaluated for patients in whom the number of neutrophils in the peripheral blood exceeds 50,000 cells / μl.

Thrombocytopenia. It is a known complication of apheresis and is observed in patients receiving the drug Mozobil. The number of platelets should be monitored in all patients who receive the drug Mozobil and who plan to conduct apheresis.

The possibility of mobilizing tumor cells in patients with lymphoma and multiple myeloma. The consequences of potential reinfusion of tumor cells have not been properly studied. When using the drug Mozobil in combination with G-CSF (for mobilization of hematopoietic stem cells with lymphoma or multiple myeloma), tumor cells can be released from the bone marrow and subsequently picked up in leukophoresis.

The clinical significance of the possible risk of mobilizing tumor cells has not been fully determined. In clinical studies involving patients with non-Hodgkin's lymphoma and multiple myeloma, no mobilization of tumor cells was observed with the use of plerixafor.

Allergic reactions

Mild and moderate allergic reactions (see "Side effects") were resolved spontaneously or supervised by appropriate therapy (eg antihistamines, GCS, hydration, oxygen therapy). Serious hypersensitivity reactions, incl. Anaphylactic reactions, some of which were life-threatening with a clinically significant decrease in blood pressure and shock, were reported in patients receiving Mozobil. It is recommended that patients be observed during and after the administration of Mozobil for at least 30 minutes after each use of the drug. The potential risk of allergic reactions requires appropriate precautions.

Vasovagal reactions

After sc injection of the drug, vasovagal reactions, orthostatic hypotension and / or syncope (see "Side effects") may be noted. In connection with the possibility of developing such reactions, appropriate precautions should be observed. In general, these reactions developed within 1 h after application of the drug Mozobil.

Splenomegaly

In pre-clinical studies, an increase in the absolute and relative mass of the spleen associated with extramedullary hematopoiesis was observed with prolonged (2-4 weeks) daily administration of pleriksafor to rats (injections, the dose of the drug exceeded the dose recommended for humans 4-fold).

In clinical studies, the effect of plerixafore on the size of the spleen was not specifically evaluated. Thus, the possibility of enlarging the spleen against the background of taking plirixafor and G-CSF cannot be completely ruled out. In very rare cases, the appointment of G-CSF leads to rupture of the spleen. This should be remembered when patients receiving the drug Mozobil in combination with G-CSF, complain of pain in the left hypochondrium and / or in the area of the shoulder blade or shoulder.

Control of laboratory indicators

In patients receiving the preparation Mozobil and passing apheresis, it is necessary to control the number of leukocytes and blood platelets.

Sodium

Each dose of Mozobil contains less than 1 mmol of sodium (23 mg), i.e. Practically does not contain it.

Impact on the ability to drive vehicles and engage in other potentially hazardous activities. Since some patients have dizziness, fatigue, or vasovagal reactions, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities.

When these undesirable phenomena appear, one should refrain from performing these activities.

Release form

Solution for subcutaneous administration, 20 mg / ml. For 1.2 ml of solution in a vial of colorless glass type I, sealed with a rubber stopper, crimped with an aluminum cap with a plastic cap of the flip-off type. On 1 fl. In a cardboard box.

Manufacturer

Pateion UK Limited, Great Britain.

Issued quality control: Genzyme Co., Ltd., United Kingdom.

The owner of the registration certificate: Genzyme Europe BV, the Netherlands.

The claims of consumers should be sent to the address of the company's representative office in Russia: 125009, Moscow

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Mozobil

At room temperature 15-30 ° C.

Keep out of the reach of children.

Shelf life of the drug Mozobil

3 years.

Do not use after the expiry date printed on the package.