Mozobil (Solution) Instructions for Use

Marketing Authorization Holder

Sanofi, B.V. (Netherlands)

Manufactured By

Genzyme Corporation (USA)

Packaging and Quality Control Release

EUROAPI UK, Limited (United Kingdom)

ATC Code

L03AX16 (Plerixafor)

Active Substance

Plerixafor (Rec.INN registered by WHO)

Dosage Form

Mozobil

Solution for subcutaneous administration 20 mg/1 ml: vial 1.2 ml 1 pc.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration in the form of a clear, colorless or pale yellow liquid.

Excipients: sodium chloride, 0.1M hydrochloric acid solution (to adjust pH to 6.0-7.5), 0.1M sodium hydroxide solution (to adjust pH to 6.0-7.5), water for injections.

1.2 ml – vials of colorless type I glass (1) – cardboard packs.

Clinical-Pharmacological Group

Immunostimulating drug

Pharmacotherapeutic Group

Immunostimulating agent

Pharmacological Action

Mechanism of action

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

The plerixafor-induced leukocytosis and increase in circulating hematopoietic progenitor cells are believed to result from the disruption of the interaction between CXCR4 and its cognate ligand, which leads to the release of both mature and pluripotent cells into the systemic circulation.

CD34+ cells mobilized by plerixafor are functional and capable of engraftment, with long-term repopulating potential.

Pharmacodynamics

Two placebo-controlled clinical studies in patients with lymphoma and multiple myeloma (AMD3100-3101 and AMD3100-3102, respectively) evaluated the increase in CD34+ cell count (cells/μL) over 24 hours, during the day before the first apheresis (Table 1).

During the evaluated 24-hour period, the first dose of plerixafor (0.24 mg/kg) or placebo was administered 10-11 hours before apheresis.

Table 1. Increase in CD34+ Cell Count in Peripheral Blood after Administration of Mozobil in Combination with Granulocyte Colony-Stimulating Factor (G-CSF)

In pharmacodynamic studies in healthy volunteers using plerixafor alone, the peak mobilization of CD34+ cells was observed within 6-9 hours after drug administration.

In pharmacodynamic studies in both healthy volunteers and patients using a mobilization regimen including G-CSF and Plerixafor at the same doses, a prolonged elevation of CD34+ cells in peripheral blood was observed from 4 hours to 18 hours after drug administration, with the peak noted between 10 hours and 14 hours.

Children

The efficacy and safety of Mozobil in children and adolescents under 18 years of age have not been studied in clinical trials.

The European Medicines Agency has waived the obligation for the company to provide results of studies on the use of Mozobil in children and adolescents under 18 years of age for myelosuppression (due to chemotherapy for the treatment of malignant neoplasms) requiring autologous hematopoietic stem cell transplantation.

Pharmacokinetics

The pharmacokinetics of plerixafor were studied in patients with lymphoma and multiple myeloma using the clinical dose (0.24 mg/kg) after prior treatment with G-CSF (10 μg/kg once daily for 2 to 4 days, extended to 7 days if necessary).

Absorption

Plerixafor is rapidly absorbed after subcutaneous administration, with C_max reached approximately 30-60 minutes (T_max) after administration.

After subcutaneous administration of plerixafor at a dose of 0.24 mg/kg, preceded by 4 consecutive days of G-CSF pretreatment, the C_max of plerixafor in plasma and the mean AUC_0-24 were 887±217 ng/ml and 4337±922 ng×h/ml, respectively.

Distribution

Plerixafor is moderately bound to human plasma proteins (up to 58%). The apparent V_d of plerixafor is 0.3 L/kg, indicating that the drug tends to distribute into the extravascular space but is not confined to it.

Metabolism

In in vitro experiments, Plerixafor was not metabolized by human liver microsomes and human embryonic hepatocytes.

In vitro studies also showed that the drug does not inhibit the major metabolizing cytochrome P450 isoenzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5).

In in vitro experiments with human hepatocytes, Plerixafor did not induce CYP1A2, CYP2B6, and CYP3A4 isoenzymes.

These data suggest that the potential for drug interactions mediated by the P450 system for plerixafor is low.

Elimination

The primary route of elimination for plerixafor is renal excretion. After administration of plerixafor 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. T_1/2 is 3-5 hours. According to in vitro studies using MDCKII and MDCKII-MDR1 cell models, Plerixafor is not a substrate or inhibitor of P-glycoprotein.

Pharmacokinetics in special patient groups

In individuals with varying degrees of renal impairment, the clearance of plerixafor after a single dose (0.24 mg/kg) decreased; a positive correlation with CrCl was observed.

The mean AUC_0-24 values for plerixafor administered to subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31-50 ml/min), and severe (CrCl ≤30 ml/min) renal impairment were 5410, 6780, and 6990 ng×h/ml, respectively, which exceeds the drug exposure values observed with normal renal function (5070 ng×h/ml).

Renal impairment did not affect C_max.

A population analysis revealed no differences in the pharmacokinetics of plerixafor based on gender and age.

Pharmacokinetic data in children are limited.

Indications

• For enhancing the mobilization of hematopoietic stem cells into the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma in combination with G-CSF.

ICD codes

Dosage Regimen

Treatment with Mozobil should be prescribed and conducted by a qualified oncologist and/or hematologist.

Cell mobilization and apheresis should be performed in collaboration with an onco-hematology center with sufficient experience in this field, where proper monitoring of hematopoietic progenitor cell levels is possible.

The recommended dose of plerixafor is 0.24 mg/kg/day.

The drug is administered subcutaneously 6-11 hours before the start of apheresis after prior 4-day therapy with G-CSF.

In clinical studies, Mozobil was typically used for 2-4 consecutive days (up to 7 days of continuous use).

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

In clinical studies, the dose of plerixafor was calculated based on the body weight of patients whose deviation from ideal body weight did not exceed 175%.

The dosing regimen and treatment features for patients whose body weight deviation is more than 175% of ideal have not been studied.

The dose of Mozobil (in ml) is calculated by the formula: 0.012 × actual body weight (kg).

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

Recommended concomitant drugs

In the pivotal clinical studies supporting treatment with Mozobil, all patients received G-CSF at a dose of 10 μg/kg, in the morning, for 4 consecutive days prior to the first administration of plerixafor, and then every morning until apheresis was performed.

In patients with renal impairment with CrCl≤50 ml/min, the dose of plerixafor should be reduced by one-third to 0.16 mg/kg/day.

Clinical data on the use of the adjusted dose are limited.

The available clinical experience with plerixafor does not allow for dosing recommendations for CrCl<20 ml/min, nor for patients on hemodialysis.

Given that drug exposure increases with increasing body weight, the dose of plerixafor should not exceed 27 mg/day if CrCl≤50 ml/min. CrCl (ml/min) is calculated by the formula

Men

Women CrCl (ml/min) = 0.85 × value calculated by the formula for men.

Experience with 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.

In elderly patients (over 65 years) with normal renal function, dose adjustment is not required.

For CrCl≤50 ml/min, dose adjustment of the drug is recommended.

It should be remembered that the likelihood of decreased renal function increases with age, so the dose of the drug should be selected with caution in elderly patients.

Rules for drug administration

For subcutaneous administration. One vial of Mozobil is intended for single use.

Before administration, the vial should be inspected. If the drug contains mechanical inclusions or if there are changes in the color of the solution, it must not be administered.

Mozobil is a sterile preparation that does not contain preservatives, so aseptic technique must be observed during the process of drawing the vial contents into a syringe for subcutaneous injection.

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

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

Adverse Reactions

Safety data for Mozobil in combination with G-CSF in cancer patients with lymphoma and multiple myeloma were obtained from 2 placebo-controlled (phase III) and 10 uncontrolled (phase II) studies in 543 patients.

Patients received treatment with plerixafor at a dose of 0.24 mg/kg/day subcutaneously.

The duration of treatment in these studies ranged 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 receiving treatment with Mozobil and G-CSF, and 292 patients receiving placebo and G-CSF, were studied.

The daily dose of G-CSF was 10 μg/kg in the morning for 4 consecutive days prior to the first injection of plerixafor or placebo, and every morning until apheresis was performed.

Below are the adverse reactions that were observed more frequently in the group receiving Mozobil and G-CSF than in the placebo and G-CSF group.

The frequency of treatment-related adverse reactions was ≥1% among patients receiving Mozobil, during hematopoietic stem cell mobilization and apheresis, and prior to chemotherapy/myeloablative therapy in preparation for transplantation.

Adverse reactions are listed by system organ class and frequency of occurrence. Frequency was determined based on the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

When using chemotherapy/ablation as part of the preparation for transplantation, no significant difference in the frequency of adverse reactions between treatment groups was noted at 12 months after transplantation.

Below are the adverse reactions observed in the Mozobil group more frequently than in the placebo group, associated with the use of Mozobil during mobilization and apheresis in Phase III studies.

Immune system disorders: uncommon – allergic reactions, anaphylactic reactions, including anaphylactic shock.

Psychiatric disorders: common – insomnia.

Nervous system disorders common – headache, dizziness.

Gastrointestinal disorders: very common – diarrhea, nausea; common – flatulence, abdominal pain, vomiting, abdominal distension, dry mouth, epigastric discomfort, constipation, dyspeptic symptoms, oral mucosal hypesthesia.

Skin and subcutaneous tissue disorders: common – hyperhidrosis, erythema.

Musculoskeletal and connective tissue disorders: common – arthralgia, musculoskeletal pain.

General disorders and administration site conditions: very common – injection site reactions; common – fatigue, malaise.

Adverse reactions in patients with lymphoma and multiple myeloma receiving Mozobil in controlled Phase III studies and uncontrolled studies, including a Phase II study in which Mozobil was used as monotherapy for hematopoietic stem cell mobilization, were similar.

In cancer patients, the frequency of adverse reactions did not differ by disease, age, or gender.

Allergic reactions: allergic reactions included one or more of the following adverse reactions: urticaria (n=2), periorbital edema (n=2), dyspnea (n=1) or hypoxia (n=1).

These reactions were mild or moderate in severity and occurred within approximately 30 minutes after administration of Mozobil.

Myocardial infarction: according to clinical studies, 7 out of 679 cancer patients experienced myocardial infarction after stem cell mobilization with plerixafor and G-CSF.

All cases of myocardial infarction were observed at least 14 days after the last administration of Mozobil.

Additionally, two female patients participating in the individual investigational drug use program experienced myocardial infarction after stem cell mobilization with plerixafor and G-CSF.

One of the myocardial infarction cases occurred 4 days after the last administration of Mozobil.

The lack of a temporal association in 8 out of 9 patients and the risk profile of the participants who experienced myocardial infarction do not allow Mozobil to be considered 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 studies using Mozobil (cancer patients and healthy volunteers) who received Plerixafor at a dose of ≤0.24 mg/kg.

In most cases, these events were observed within 1 hour after administration of Mozobil.

Gastrointestinal disorders: in clinical studies of Mozobil in cancer patients, reports of severe gastrointestinal disorders (including diarrhea, nausea, vomiting, abdominal pain) were rare.

Paresthesia: paresthesia is often observed in cancer patients after autologous transplantation due to the numerous medical procedures performed.

In placebo-controlled Phase III clinical studies, the frequency of paresthesia was 20.6% and 21.2% in the plerixafor and placebo groups, respectively.

Hyperleukocytosis: in Phase III studies, an increase in leukocyte count on the day before apheresis or on any apheresis day to 100×10⁹/L and above was observed in 7% of patients receiving Mozobil and in 1% of patients receiving placebo.

In this case, there were no complications or clinical manifestations of leukocytosis.

Elderly patients: 24% of participants in the two placebo-controlled clinical studies of plerixafor were over 65 years old.

No significant differences in the frequency of adverse reactions were observed in the subgroup of elderly patients (compared to younger patients).

Post-marketing surveillance

Below are the adverse reactions reported during the post-marketing period of Mozobil use, in addition to those recorded during clinical trials.

The frequency of adverse reactions could not be determined, as reports were received from a population with an uncertain number of patients, as well as the possible relationship with the use of the drug.

Immune system disorders: anaphylactic reactions, including anaphylactic shock.

Psychiatric disorders unusual dreams, nightmares.

Contraindications

• Pregnancy;
• Lactation (breastfeeding);
• Childhood and adolescence under 18 years (due to lack of experience of use);
• Hypersensitivity to plerixafor or any excipients of the drug.

Use in Pregnancy and Lactation

Data on the use of plerixafor in pregnant women are insufficient.

Animal studies have shown the teratogenic effect of the drug.

The patient should be informed that the use of plerixafor during pregnancy may lead to congenital malformations.

The use of Mozobil during pregnancy is possible only in cases where the benefit of use outweighs the potential risk.

Women of childbearing potential must use effective contraception during treatment.

Data on the possible penetration of plerixafor into breast milk are not available, so the risk to the breastfed infant cannot be excluded.

Breastfeeding should be discontinued during therapy with Mozobil.

Use in Renal Impairment

In patients with renal impairment with CrCl≤50 ml/min, the dose of plerixafor should be reduced by one-third to 0.16 mg/kg/day.

The available clinical experience with plerixafor does not allow for dosing recommendations for CrCl<20 ml/min, nor for patients on hemodialysis.

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age (due to lack of experience with its use).

Geriatric Use

In elderly patients with normal renal function, dose adjustment is not required. For CrCl ≤50 ml/min, dose adjustment of the drug is recommended.

Special Precautions

Tumor Cell Mobilization in Patients with Leukemias

Mozobil and G-CSF were administered in acute myeloid and plasmacytic leukemias as part of an investigational drug program on an individual basis. In some cases, an increase in the number of circulating leukemic cells was observed.

Plerixafor, administered for the mobilization of hematopoietic stem cells, may cause mobilization of tumor cells with their subsequent entry into the apheresis product. Therefore, Plerixafor is not recommended for use in leukemias for the mobilization of hematopoietic stem cells and their subsequent collection.

Hematological Effects

Hyperleukocytosis. Mozobil, administered in combination with G-CSF, increases not only the population of hematopoietic stem cells but also the number of circulating leukocytes.

White blood cell counts should be monitored during Mozobil administration. Each case of Mozobil administration in patients with a peripheral blood neutrophil count exceeding 50,000 cells/µL should be carefully evaluated.

Thrombocytopenia. Thrombocytopenia is a known complication of apheresis and is observed in patients receiving Mozobil.

Platelet counts should be monitored in all patients receiving Mozobil and planned for apheresis.

Potential for Tumor Cell Mobilization in Patients with Lymphoma and Multiple Myeloma

The consequences of potential tumor cell reinfusion have not been adequately studied.

When using Mozobil in combination with G-CSF (for hematopoietic stem cell mobilization in lymphoma or multiple myeloma), tumor cells may be released from the bone marrow and subsequently collected during leukapheresis.

The clinical significance of the potential risk of tumor cell mobilization has not been fully determined. In clinical studies involving patients with non-Hodgkin’s lymphoma and multiple myeloma, tumor cell mobilization was not observed with the use of plerixafor.

Allergic Reactions

Mild to moderate allergic reactions resolved spontaneously or were managed with appropriate therapy (e.g., antihistamines, corticosteroids, hydration, oxygen therapy).

Serious hypersensitivity reactions, including anaphylactic reactions (some of which were life-threatening with clinically significant decreases in blood pressure and shock), have been reported in patients receiving Mozobil.

It is recommended to observe patients 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

Vasovagal reactions, orthostatic hypotension, and/or syncope may occur after subcutaneous injections of the drug. Due to the possibility of such reactions, appropriate precautions must be taken.

These reactions mainly occurred within 1 hour after Mozobil administration.

Splenomegaly

In preclinical studies, an increase in the absolute and relative spleen weight, associated with extramedullary hematopoiesis, was observed with long-term (2-4 weeks) daily administration of plerixafor to rats (subcutaneous injections; the drug dose exceeded the dose recommended for humans by 4 times).

In clinical studies, the effect of plerixafor on spleen size was not specifically assessed.

Thus, the possibility of spleen enlargement during treatment with plerixafor and G-CSF cannot be completely ruled out. In very rare cases, G-CSF administration leads to splenic rupture.

This should be kept in mind when patients receiving Mozobil in combination with G-CSF complain of pain in the left upper quadrant and/or in the scapular or shoulder area.

Laboratory Parameter Monitoring

White blood cell and platelet counts should be monitored in patients receiving Mozobil and undergoing apheresis.

Sodium

Each dose of Mozobil contains less than 1 mmol sodium (23 mg), i.e., it is essentially sodium-free.

Effect on Ability to Drive and Use Machines

Since some patients experienced dizziness, fatigue, or vasovagal reactions, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities.

If the described adverse events occur, one should refrain from performing these activities.

Overdose

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

Drug Interactions

No drug interaction studies have been conducted. Tests conducted in vitro have shown that Plerixafor is not metabolized by cytochrome P450 isoenzymes and does not inhibit or enhance their activity. According to in vitro studies, Plerixafor is not a substrate or inhibitor of P-glycoprotein.

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

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.