Mozobail - instructions for use, dose, side effects, contraindications

Active substancePericrixforPericrixfor

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Mozobail

solution PC

Genzyme Europe BV Netherlands

Dosage form: & nbsphypodermic solution

Composition:

1 bottle contains:

active substance: plexixafor 24 mg;

Excipients: sodium chloride 5.9 mg, 0.1 M sodium hydroxide solution or 0.1 M solution of hydrochloric acid to pH 6.0-7.5, water for injection up to 1.2 ml.

Description:

Transparent colorless or light yellow liquid.

Pharmacotherapeutic group:Immunostimulating agent

ATX: & nbsp

L.03.A.X.16 Pericrixfor

Pharmacodynamics:

Mechanism of action

Pleriksafor is a biclamide derivative and is a selective reversible CXCR4 antagonist of the chemokine receptor, blocking it by binding to the cognate ligand, stromal cell factor-1α (SDF-1α), also known as CXCL12.

Plerixaphor-induced leukocytosis and an increase in circulating hematopoietic progenitor cells are thought to result from a disruption of the bond between CXCR4 and its cognate ligand, which results in the emergence of mature and pluripotent cells in the systemic circulation. CD34 + cells mobilized with plirixafor are functional and capable of engraftment, with a long-term potential for population recovery.

Pharmacodynamics

Two placebo-controlled clinical studies in patients with lymphoma and multiple myeloma (AMD3100-3101 and AMD3100-3102, respectively) was estimated increase of CD34 + cells (cells / ml) for 24 hours, during the day prior to the first apheresis (Table 1) . The estimated 24-hour period pleriksafora first dose (0.24 mg / kg) or placebo was administered 10-11 hr prior to apheresis.

Table 1. Increase in the number of CD34 + cells in peripheral blood after administration of the drug together with Mozobail granulocyte colony stimulating factor (G-CSF)

Study	The drug Mozobail + G-CSF		Placebo + G-CSF
Study	Median	The average (CO)	Median	The average (CO)
AMD3100-3101	5,0	6,1 (5,4)	1,4	1,9 (1,5)
AMD3100-3102	4,8	6,4 (6,8)	1,7	2,4 (7,3)

In pharmacodynamic studies in healthy volunteers using only peak pleriksafora mobilize CD34 + cells was observed within 6-9 hours after drug administration. In investigating the pharmacodynamics in healthy volunteers and in patients with mobilization circuit consisting of granulocyte colony stimulating factor (G-CSF) and pleriksafor at the same doses, there was a longer rise CD34 + cells in the peripheral blood within 4 h to 18 h after injection, the peak was observed between 10 h and 14 h.

Children

The efficacy 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 years with myelosuppression (due to chemotherapy used to treat malignant neoplasms) requiring autotransplantation of hematopoietic stem cells (see section "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 μg / kg once daily for 2 to 4 days, if necessary, prolong the course to 7 days).

Absorption

Periciksafor is rapidly absorbed after subcutaneous administration, the maximum concentration reaches approximately 30-60 min (t_max). After subcutaneous administration of plirixafor at a dose of 0.24 mg / kg, which was preceded by a preliminary treatment of G-CSF for 4 consecutive days, the maximum concentration (C_max) plirixafora in blood plasma and the average area under the pharmacokinetic curve "concentration-time" (AUC_0-₂₄) 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 volume of distribution of pleriksafor 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 pleriksafor was not metabolized by human hepatic microsomes and human embryonic hepatocytes. Also in vitro it was shown that the preparation does not inhibit the main metabolizing enzymes of cytochrome P450 (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 4A4 / 5). In experiments in vitro with human hepatocytes pleriksafor 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 plriixaphor.

Elimination

The main way of eliminating pleriksafora is excretion through the kidneys. After the administration of plirixafor in a dose of 0.24 mg / kg to healthy volunteers with normal renal function,about 70% of the drug was excreted in the urine unchanged during the first 24 hours after administration. The half-life of plasma (T_½) is 3-5 hours. According to research in vitro using cell models MDCKII and MDCKII-MDR1, pleriksafor is not a substrate or an inhibitor of P-glycoprotein.

Special patient groups Patients with impaired renal function

In individuals with varying degrees of renal insufficiency pleriksafora clearance after a single dose (0.24 mg / kg) decreased; there was a positive correlation with creatinine clearance (CC). Average AUC_0-24 for pleriksafora administered to subjects with mild (QC 51-80 ml / min), moderate (QC 31-50 ml / min) and severe (QC ≤30 ml / min) degrees of renal insufficiency, amounted 5410, 6780 and 6990 ng * h / ml, respectively, that exceed the value of drug exposure observed in normal kidney (5070 ng * h / ml). Renal insufficiency did not exert influence on C_max.

Floor

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

Elderly patients

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

Children

Data on the pharmacokinetics in children are limited.

Indications:

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 a granulocyte colony-stimulating factor (G-CSF).

Contraindications:

Hypersensitivity to plerixafor or any excipients of the drug;
Pregnancy (see the section "Pregnancy and the period of breastfeeding");
Lactation (see section "Pregnancy and the period of breastfeeding");
Children and adolescence up to 18 years (due to lack of experience of use).

Pregnancy and lactation:

Pregnancy

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 Mozobail during pregnancy is possible only in those cases when the benefit from the application exceeds the potential risk.

Women of childbearing age

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

Breastfeeding period

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

Dosing and Administration:

Treatment with Mozobail should be prescribed and conducted by a qualified oncologist and / or hematologist. Mobilization and apheresis of cells should be carried out in cooperation with an 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 plirixafor is 0.24 mg / kg / day. The drug is administered subcutaneously 6-11 h prior to the onset of apheresis after a preliminary four-day therapy with G-CSF. In clinical studies, Mozobail was usually used for 2-4 consecutive days (up to 7 days of continuous use).

To calculate the dose of plerixaphor, the mean body weight, measured within 1 week prior to the administration of the first dose of the drug, is used.

In clinical studies, the dose of plerixaphor 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 Mozobail (in ml) is calculated by the formula: 0.012 x actual body weight (kg).

Given that the effect of the drug with increasing body weight increases, the dose of plriixafor should not exceed 40 mg / day.

Recommended concomitant medications

In the baseline clinical trials supporting Mozobail treatment, all patients received G-CSF at a dose of 10 μg / 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

Patients with impaired renal function

In case of creatinine clearance ≤ 50 ml / min, the dose of plirixafor should be reduced by one third, to 0.16 mg / kg / day (see the section "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 giving recommendations on dosing of the drug with creatinine clearance <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 creatinine clearance is ≤ 50 ml / min. The creatinine clearance (in ml / min) is calculated by the formula:

Men: CK (ml / min) = (body weight (kg) x (140 - age in years)) / (72 x serum creatinine (mg / dL))

Women: CK (ml / min) = 0.85 x value calculated from the formula for men

Children

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

Patients elderly (more than 65 years)

In elderly patients with normal renal function, dose adjustment is not required. When creatinine clearance ≤ 50 ml / min is recommended, change the dose of the drug (see above section "Patients with impaired renal function"). It should be remembered that with age, the likelihood of reducing renal function increases, so in elderly patients the dose of the drug should be selected with caution.

Mode of application

For subcutaneous administration. One bottle of Mozobail is intended for single use.

Before administration, the bottle should be inspected.If the product contains mechanical inclusions or there are discolourings of the solution, it can not 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 hypodermic injections, it is necessary to observe aseptic rules.

Studies on the compatibility of the drug Mozobail 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.

Side effects:

Data on the safety of the use of the drug Mozobail 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 subcutaneously. 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 Mozobail and G-CSF were studied and 292 patients who received placebo and G- CSF.The daily dose of G-CSF was 10 μg / kg in the morning for 4 consecutive days before the first injection of plexixapore or placebo, and also every morning before the apheresis.

Below are the undesirable reactions that were more frequently observed in the group receiving the drug Mozobail and G-CSF than in the placebo group and G-CSF. The incidence of adverse drug reactions associated with treatment was> 1% among patients receiving Mozobail, 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 (can not 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 Mozobail more often than in the placebo group associated with the use of the drug Mozobail during mobilization and apheresis in the phase III studies.

Immune system disorders

Infrequent: allergic reactions, anaphylactic reactions, including anaphylactic shock (See subsection "Post-marketing observations" and section "Special instructions").

Disorders of the psyche

Often: insomnia.

Disturbances from the nervous system

Often: headache, dizziness.

Disorders from the gastrointestinal 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.

Disturbances from musculoskeletal and connective tissue

Often: arthralgia, skeletal-muscular pain.

General disorders and disorders at the site of administration

Very often: reactions at the injection site. Often: fatigue, malaise.

Undesirable reactions in patients with lymphoma and multiple myeloma,who received Mozobail in controlled Phase III studies and uncontrolled studies, including a Phase II trial in which the Mozobail drug was used in monotherapy for the mobilization of hematopoietic stem cells, are similar. In patients with cancer, the frequency 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 reactions: urticaria (n= 2), periorbital edema (n= 2), shortness of breath (n= 1) or hypoxia (n= 1). These reactions were mild or moderate in severity and occurred within about 30 minutes after the administration of the Mozobail drug.

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

Vasovagal reactions

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

Disorders from the gastrointestinal tract

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

Paresthesia

Paresthesias are often observed in cancer patients after autotransplantation due to numerous medical procedures.In placebo-controlled Phase III clinical trials, paresthesia rates were 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 x 10⁹/ l and higher was observed in 7% of patients who received the drug Mozobail, and in 1% of patients who received placebo. There were no complications or clinical manifestations of leukocytosis.

Elderly patients

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.

Postmarketing observations

Below are the undesirable reactions reported in the post-marketing period of Mozobail supplementation in addition to those that were recorded during clinical trials. It was not possible to determine the frequency of undesired reactions, since reports about them were obtained from a population with an undetermined number of patients, as well as the possible relationship with the use of the drug.

Immune system disorders

Anaphylactic reactions, including anaphylactic shock.

Disorders of the psyche: unusual dreaming, nightmares.

Overdose:

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

Interaction:

Studies to study the interactions of this drug have not been conducted. Tests conducted in vitro, showed that pleriksafor It is not metabolized by cytochrome P450 isoenzymes, nor does it inhibit or enhance their activity. According to research in vitro, pleriksafor is not a substrate or an inhibitor of P-glycoprotein.

The addition of rituximab to the "mobilization regime" (pleriksafor 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.

Special instructions:

Mobilization of tumor cells in patients with leukemia

The drug Mozobail 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, there was an increase in the number of circulating leukemia cells. Pericrixfor, designated for the mobilization of hematopoietic stem cells, can cause the mobilization of tumor cells and their subsequent entry into the apheresis product. therefore pleriksafor It is not recommended to be used in leukemia for the mobilization of hematopoietic stem cells and their subsequent collection.

Hematological effects

Hyperleukocytosis

The drug Mozobail, 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 Mozobail should monitor the number of white blood cells. Every case of prescribing Mozobail should be carefully evaluated for patients with a neutrophil count in peripheral blood exceeding 50,000 cells / μl.

Thrombocytopenia

Thrombocytopenia is a known complication of apheresis and is observed in patients receiving the drug Mozobail.The number of platelets must be monitored in all patients who receive the drug Mozobail 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. With the use of the drug Mozobail 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, there was no mobilization of tumor cells with the use of plerixafor.

Allergic reactions

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

Vasovagal reactions

After subcutaneous injections of the drug, vasovagal reactions, orthostatic hypotension and / or syncope (see the "Side effect" section) may be noted. In connection with the possibility of developing such reactions, appropriate precautions must be observed. In general, these reactions developed within 1 h after application of the drug Mozobail.

Splenomegaly

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

In clinical studies, the effect of pleriksafore on the size of the spleen was not specifically evaluated. Thus, the possibility of enlarging the spleen against the background of taking plriixafor and G-CSF can not 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 Mozobail 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 Mozobail and passing apheresis, it is necessary to control the number of leukocytes and blood platelets.

Sodium

Each dose of the drug Mozobail contains less than 1 mmol sodium (23 mg), that is, it practically does not contain it.

Effect on the ability to drive transp. cf. and fur:

Since some patients have dizziness, fatigue, or vasovagal reactions, care must be taken when driving vehicles and engaging in other potentially hazardous activities.

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

Form release / dosage:

A solution for subcutaneous administration of 20 mg / ml.

Packaging:

1.2 ml of solution in a bottle of colorless glass type I, sealed with a rubber stopper and crimped with an aluminum cap with a plastic lid of the "flip-off" type. 1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store at temperatures between 15 ° C and 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002352

Date of registration:27.01.2014 / 14.09.2016

Expiration Date:27.01.2019

The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands

Manufacturer: & nbsp

GENZYME, Ltd. United Kingdom

PATHEON UK, Ltd. United Kingdom

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp11.06.2018

Illustrated instructions

Instructions

Mozobail (Mozobil)