1. Name Of The Medicinal Product
Mozobil
2. Qualitative And Quantitative Composition
1 ml solution contains 20 mg plerixafor.
Each vial contains 24 mg plerixafor in 1.2 ml solution.
Excipients
Each ml contains approximately 5 mg (0.2 mmol) of sodium.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection.
Clear, colourless to pale yellow solution, with a pH of 6.0
4. Clinical Particulars
4.1 Therapeutic Indications
Mozobil is indicated in combination with G-CSF to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma whose cells mobilise poorly (see section 4.2).
4.2 Posology And Method Of Administration
Mozobil therapy should be initiated and supervised by a physician experienced in oncology and/or haematology. The mobilisation and apheresis procedures should be performed in collaboration with an oncology
Posology
The recommended dose of plerixafor is 0.24 mg/kg body weight/day. It should be administered by subcutaneous injection 6 to 11 hours prior to initiation of apheresis following 4 day pre-treatment with granulocyte-colony stimulating factor (G
The weight used to calculate the dose of plerixafor should be obtained within 1 week before the first dose of plerixafor. In clinical studies, the dose of plerixafor has been calculated based on body weight in patients up to 175% of ideal body weight. Plerixafor dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated. Ideal body weight can be determined using the following equations:
| 50 + 2.3 x ((Height (cm) x 0.394) – 60); |
| 45.5 + 2.3 x ((Height (cm) x 0.394) – 60). |
Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day.
Recommended concomitant medicinal products
In pivotal clinical studies supporting the use of Mozobil, all patients received daily morning doses of 10 μg/kg G
Special populations
Renal impairment
Patients with creatinine clearance 20
Based on increasing exposure with increasing body weight the dose should not exceed 27 mg/day if the creatinine clearance is lower than 50 ml/min.
Paediatric population
The experience in paediatric patients is limited. The safety and efficacy of Mozobil in paediatric patients have not been established in controlled clinical studies.
Elderly patients (> 65 years old)
No dose modifications are necessary in elderly patients with normal renal function. Dose adjustment in elderly patients with creatinine clearance
Method of administration
For subcutaneous injection. Each vial of Mozobil is intended for single use only.
Vials should be inspected visually prior to administration and not used if there is particulate matter or discolouration. Since Mozobil is supplied as a sterile, preservative-free formulation, aseptic technique should be followed when transferring the contents of the vial to a suitable syringe for subcutaneous administration (see section 6.3).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Potential for tumour cell mobilisation in patients with lymphoma and multiple myeloma
The effect of potential re-infusion of tumour cells has not been adequately studied.
When Mozobil is used in conjunction with G
Tumour cell mobilisation in leukaemia patients
In a compassionate use programme, Mozobil and G
Haematological effects
Hyperleukocytosis
Administration of Mozobil in conjunction with G
Thrombocytopenia
Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving Mozobil. Platelet counts should be monitored in all patients receiving Mozobil and undergoing apheresis.
Laboratory monitoring
White blood cell and platelet counts should be monitored during Mozobil use and apheresis.
Allergic reactions
Mozobil has been uncommonly associated with potential systemic reactions related to subcutaneous injection such as urticaria, periorbital swelling, dyspnoea, or hypoxia (see section 4.8). Symptoms responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously. Appropriate precautions should be taken because of the potential for these reactions.
Vasovagal reactions
Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections (see section 4.8). Appropriate precautions should be taken because of the potential for these reactions.
Splenomegaly
In preclinical studies, higher absolute and relative spleen weights associated with extramedullary haematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor subcutaneous administration in rats at doses approximately 4 fold higher than the recommended human dose.
The effect of plerixafor on spleen size in patients has not been specifically evaluated in clinical studies. The possibility that plerixafor in conjunction with G
Sodium
Mozobil contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed. In vitro tests showed that plerixafor was not metabolised by P450 CYP enzymes, did not inhibit or induce P450 CYP enzymes. Plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study.
In clinical studies of patients with Non-Hodgkin's lymphoma, the addition of rituximab to a mobilisation regimen of plerixafor and G
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data on the use of plerixafor in pregnant women.
Based on the pharmacodynamic mechanism of action, plerixafor is suggested to cause congenital malformations when administered during pregnancy. Studies in animals have shown teratogenicity (see section 5.3). Mozobil should not be used during pregnancy unless the clinical condition of the woman requires treatment with plerixafor.
Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment.
Breastfeeding
It is not known whether plerixafor is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Mozobil.
4.7 Effects On Ability To Drive And Use Machines
Mozobil may influence the ability to drive and use machines. Some patients have experienced dizziness, fatigue or vasovagal reactions; therefore caution is advised when driving or operating machinery.
4.8 Undesirable Effects
Safety data for Mozobil in conjunction with G
In the two Phase III studies in non-Hodgkin's lymphoma and multiple myeloma patients (AMD3100-3101 and AMD3100-3102, respectively), a total of 301 patients were treated in the Mozobil and G
From chemotherapy/ablative treatment in preparation of transplantation through 12 months post
Table 1. Adverse reactions occurring more frequently with Mozobil than placebo and considered related to Mozobil during mobilisation and apheresis in phase III studies
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* Events included one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnoea (n = 1) or hypoxia (n = 1). These events were generally mild or moderate and occurred within approximately 30 min after Mozobil administration.
The adverse reactions reported in patients with lymphoma and multiple myeloma who received Mozobil in the controlled Phase III studies and uncontrolled studies, including a Phase II study of Mozobil as monotherapy for haematopoietic stem cell mobilisation, are similar. No significant differences in the incidence of adverse reactions were observed for oncology patients by disease, age, or gender.
Myocardial infarction
In clinical studies, 7 of 679 oncology patients experienced myocardial infarctions after haematopoietic stem cell mobilisation with plerixafor and G
Hyperleukocytosis
White blood cell counts of 100 x 109/l or greater were observed, on the day prior to or any day of apheresis, in 7% patients receiving Mozobil and in 1% patients receiving placebo in the Phase III studies. No complications or clinical symptoms of leukostasis were observed.
Vasovagal reactions
In Mozobil oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions (orthostatic hypotension and/or syncope) following subcutaneous administration of plerixafor doses
Gastrointestinal disorders
In Mozobil clinical studies of oncology patients, there have been rare reports of severe gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.
Paresthesiae
Paresthesiae are commonly observed in oncology patients undergoing autologous transplantation following multiple disease interventions. In the placebo-controlled Phase III studies, the incidence of paresthesiae was 20.6% and 21.2% in the plerixafor and placebo groups, respectively.
Elderly patients
In the two placebo-controlled clinical studies of plerixafor, 24% of patients were
4.9 Overdose
No case of overdose has been reported. Based on limited data at doses above the recommended dose and up to 0.48 mg/kg the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other immunostimulants; ATC code: L03AX16
Mechanism of action
Plerixafor is a bicyclam derivative, a selective reversible antagonist of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α(SDF-1α), also known as CXCL12. Plerixafor-induced leukocytosis and elevations in circulating haematopoietic progenitor cell levels are thought to result from a disruption of CXCR4 binding to its cognate ligand, resulting in the appearance of both mature and pluripotent cells in the systemic circulation. CD34+ cells mobilised by plerixafor are functional and capable of engraftment with long-term repopulating capacity.
Clinical efficacy and safety
In two Phase III randomised-controlled studies patients with non-Hodgkin's lymphoma or multiple myeloma received Mozobil 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G6 cells/kg) and minimal (2 x 106 cells/kg) numbers of CD34+ cells/kg within a given number of days, as well as the primary composite endpoints which incorporated successful engraftment are presented in Tables 2 and 4; the proportion of patients reaching optimal numbers of CD34+ cells/kg by apheresis day are presented in Tables 3 and 5.
Table 2. Study AMD3100-3101 efficacy results - CD34+ cell mobilisation in non-Hodgkin's lymphoma patients
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ap-value calculated using Pearson's Chi-Squared test
bStatistically significantly more patients achieved 6 cells/kg in 6 cells/kg in
Table 3. Study AMD3100-3101 – Proportion of patients who achieved 6 CD34+ cells/kg by apheresis day in non-Hodgkin's lymphoma patients
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Table 4. Study AMD3100-3102 efficacy results – CD34+ cell mobilisation in multiple myeloma patients
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ap-value calculated using Cochran-Mantel-Haenszel statistic blocked by baseline platelet count
bStatistically significantly more patients achieved 6 cells/kg in 6 cells/kg in 6 cells/kg in
Table 5. Study AMD3100-3102 – Proportion of patients who achieved 6 CD34+ cells/kg by apheresis day in multiple myeloma patients
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Rescue patients
In study AMD3100-3101, 62 patients (10 in the Mozobil + G-CSF group and 52 in the placebo + G-CSF group), who could not mobilise sufficient numbers of CD34+ cells and thus not could not proceed to transplantation, entered into an open-label Rescue procedure with Mozobil and G-CSF. Of these patients, 55 % (34 out of 62) mobilised 6/kg CD34+ cells and had successful engraftment. In study AMD3100-3102, 7 patients (all from the placebo + G-CSF group) entered the Rescue procedure. Of these patients, 100% (7 out of 7) mobilised 6/kg CD34+ cells and had successful engraftment.
The dose of haematopoietic stem cells used for each transplant was determined by the investigator and all haematopoietic stem cells that were collected were not necessarily transplanted. For transplanted patients in the Phase III studies, median time to neutrophil engraftment (10-11 days), median time to platelet engraftment (18-20 days) and graft durability up to 12 months post-transplantation were similar across the Mozobil and placebo groups.
Mobilisation and engraftment data from supportive Phase II studies (plerixafor 0.24 mg/kg dosed on the evening or morning prior to apheresis) in patients with non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma were similar to those data for the Phase III studies.
In the placebo-controlled studies, fold increase in peripheral blood CD34+ cell count (cells/μl) over the 24-hour period from the day prior to the first apheresis to just before the first apheresis was evaluated (Table 6). During that 24-hour period, the first dose of plerixafor 0.24 mg/kg or placebo was administered 10-11 hours prior to apheresis.
Table 6. Fold increase in peripheral blood CD34+ cell count following Mozobil administration
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Pharmacodynamic effects
In pharmacodynamic studies in healthy volunteers of plerixafor alone, peak mobilisation of CD34+ cells was observed from 6 to 9 hours after administration. In pharmacodynamic studies in healthy volunteers of plerixafor in conjunction with G
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Mozobil in children aged 0 to 1 year in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous hematopoietic stem cell transplant (see section 4.2 for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with Mozobil in children aged 1 to 18 years in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous hematopoietic stem cell transplant (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic Properties
The pharmacokinetics of plerixafor have been evaluated in lymphoma and multiple myeloma patients at the clinical dose level of 0.24 mg/kg following pre-treatment with G
Absorption
Plerixafor is rapidly absorbed following subcutaneous injection, reaching peak concentrations in approximately 30-60 minutes (tmax). Following subcutaneous administration of a 0.24 mg/kg dose to patients after receiving 4-days of G-CSF pre-treatment, the maximal plasma concentration (Cmax) and systemic exposure (AUC0-24) of plerixafor were 887 ± 217 ng/ml and 4337 ± 922 ng.hr/ml, respectively.
Distribution
Plerixafor is moderately bound to human plasma proteins up to 58%. The apparent volume of distribution of plerixafor in humans is 0.3 l/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space.
Metabolism
Plerixafor is not metabolized in vitro using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug-metabolising CYP450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, and CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in P450-dependent drug-drug interactions.
Elimination
The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthy volunteers with normal renal function, approximately 70% of the dose was excreted unchanged in urine during the first 24 hours following administration. The elimination half-life (t1/2) in plasma is 3in vitro study with MDCKII and MDCKII-MDR1 cell models.
Special populations
Renal impairment
Following a single dose of 0.24 mg/kg plerixafor, clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with creatinine clearance (CrCl). Mean values of AUC0-24 of plerixafor in subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31max.
Gender
A population pharmacokinetic analysis showed no effect of gender on pharmacokinetics of plerixafor.
Elderly
A population pharmacokinetic analysis showed no effect of age on pharmacokinetics of plerixafor.
Paediatric population
There are limited pharmacokinetic data in paediatric patients.
5.3 Preclinical Safety Data
The results from single dose subcutaneous studies in rats and mice showed plerixafor can induce transient but severe neuromuscular effects (uncoordinated movement), sedative-like effects (hypoactivity), dyspnea, ventral or lateral recumbency, and/or muscle spasms. Additional effects of plerixafor consistently noted in repeated dose animal studies included increased levels of circulating white blood cells and increased urinary excretion of calcium and magnesium in rats and dogs, slightly higher spleen weights in rats, and diarrhea and tachycardia in dogs. Histopathology findings of extramedullary hematopoiesis were observed in the liver and spleen of rats and/or dogs. One or more of these findings were usually observed at systemic exposures in the same order of magnitude or slightly higher than the human clinical exposure.
An in vitro general receptor activity screen showed that plerixafor, at a concentration (5 µg/ml) several fold higher than the maximum human systemic level, has moderate or strong binding affinity for a number of different receptors predominantly located on pre-synaptic nerve endings in the CNS and/or the PNS (N-type calcium channel, potassium channel SKCA, histamine H3, acetylcholine muscarinic M1 and M2, adrenergic α1B and α2C, neuropeptide Y/Y1 and glutamate NMDA polyamine receptors). The clinical relevance of these findings is not known.
Safety pharmacology studies with IV administered plerixafor in rats showed respiratory and cardiac depressant effects at systemic exposure slightly above the human clinical exposure, whilst SC administration elicited respiratory and cardiovascular effects only at higher systemic levels.
SDF-1α and CXCR4 play major roles in embryo-foetal development. Plerixafor has been shown to cause increased resorptions, decreased foetal weights, retarded skeletal development and increased foetal abnormalities in rats and rabbits. Data from animal models also suggest modulation of foetal haematopoiesis, vascularization, and cerebellar development by SDF-1α and CXCR4. Systemic exposure at No Observed Adverse Effect Level for teratogenic effects in rats and rabbits was of the same magnitude or lower as found at therapeutic doses in patients. This teratogenic potential is likely due to its pharmacodynamic mechanism of action.
In rat distribution studies concentrations of radiolabelled plerixafor was detected in reproductive organs (testes, ovaria, uterus) two weeks after single or 7 daily repeated doses in males and after 7 daily repeated doses in females. The elimination rate from tissues was slow.
The potential effects of plerixafor on male and female fertility and post-natal development have not been evaluated in non-clinical studies.
Carcinogenicity studies with plerixafor have not been conducted.Plerixafor was not genotoxic in an adequate battery of genotoxicity tests.
Plerixafor inhibited tumour growth in in vivo models of non-Hodgkin's lymphoma, glioblastoma, medulloblastoma, and acute lymphoblastic leukaemia when dosed intermittently. An increase of non-Hodgkin's lymphoma growth was noted after a continuous administration of plerixafor for 28 days. The potential risk associated with this effect is expected to be low for the intended short term duration of dosing plerixafor in humans.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Hydrochloric acid, concentrated (pH adjustment)
Sodium hydroxide, if needed (pH adjustment)
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, Mozobil must not be mixed with other medicinal products.
6.3 Shelf Life
Unopened vial
3 years.
After opening
From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
Clear type I glass 2 ml vial with a chlorobutyl/butyl rubber stopper and aluminium seal with a plastic flip-off cap. Each vial contains 1.2 ml solution.
Pack size of 1 vial.
6.6 Special Precautions For Disposal And Other Handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.
8. Marketing Authorisation Number(S)
EU/1/09/537/001
9. Date Of First Authorisation/Renewal Of The Authorisation
07/2009
10. Date Of Revision Of The Text
03/2010
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.
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