ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Mozobil 20 mg/ml solution for injection.
2.
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.
Solution for injection.
Clear, colourless to pale yellow solution, with a pH of 6.0-7.5 and an osmolality of
260 - 320 mOsm/kg.
4.
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
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-haematology centre with acceptable experience in this field and where the monitoring of
haematopoietic progenitor cells can be correctly performed.
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-CSF). In clinical trials, Mozobil has been commonly used
for 2 to 4 (and up to 7) consecutive days.
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:
female (kg):
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.
2
male (kg):
50 + 2.3 x ((Height (cm) x 0.394) – 60);
Recommended concomitant medicinal products
In pivotal clinical studies supporting the use of Mozobil, all patients received daily morning doses of
10 μg/kg G-CSF for 4 consecutive days prior to the first dose of plerixafor and on each morning prior
to apheresis.
Special populations
Renal impairment
Patients with creatinine clearance 20-50 ml/min should have their dose of plerixafor reduced by one-
third to 0.16 mg/kg/day (see section 5.2). Clinical data with this dose adjustment are limited. There is
insufficient clinical experience to make alternative posology recommendations for patients with a
creatinine clearance <20 ml/min, as well as to make posology recommendations for patients on
haemodialysis.
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 ≤ 50 ml/min is recommended (see Renal impairment
above). In general, care should be taken in dose selection for elderly patients due to the greater
frequency of decreased renal function with advanced age.
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).
Hypersensitivity to the active substance or to any of the excipients.
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-CSF for haematopoietic stem cell mobilisation in
patients with lymphoma or multiple myeloma‚ tumour cells may be released from the marrow and
subsequently collected in the leukapheresis product. The clinical relevance of the theoretical risk of
tumour cell mobilisation is not fully elucidated. In clinical studies of patients with non-Hodgkin’s
lymphoma and multiple myeloma, mobilisation of tumour cells has not been observed with plerixafor.
Tumour cell mobilisation in leukaemia patients
In a compassionate use programme, Mozobil and G-CSF have been administered to patients with
acute myelogenous leukaemia and plasma cell leukaemia. In some instances, these patients
experienced an increase in the number of circulating leukaemia cells. For the purpose of
haematopoietic stem cell mobilisation, plerixafor may cause mobilisation of leukaemic cells and
subsequent contamination of the apheresis product. Therefore, plerixafor is not recommended for
haematopoietic stem cell mobilisation and harvest in patients with leukaemia.
3
Haematological effects
Hyperleukocytosis
Administration of Mozobil in conjunction with G-CSF increases circulating leukocytes as well as
haematopoietic stem cell populations. White blood cell counts should be monitored during Mozobil
therapy. Clinical judgment should be exercised when administering Mozobil to patients with
peripheral blood neutrophil counts above 50,000 cells/μl.
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-CSF can cause splenic enlargement
cannot be excluded. Due to the very rare occurrence of splenic rupture following G-CSF
administration, individuals receiving Mozobil in conjunction with G-CSF who report left upper
abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity.
Sodium
Mozobil contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.
4.5
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-CSF did not impact patient safety or CD34+ cell yield.
Pregnancy
There are no adequate data on the use of plerixafor in pregnant women.
4
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.
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.
Safety data for Mozobil in conjunction with G-CSF in oncology patients with lymphoma and multiple
myeloma were obtained from 2 placebo-controlled Phase III studies and 10 uncontrolled Phase II
studies in 543 patients. Patients were primarily treated with daily doses of 0.24 mg/kg plerixafor by
subcutaneous injection. The exposure to plerixafor in these studies ranged from 1 to 7 consecutive
days (median = 2 days).
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-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily
morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on
each morning prior to apheresis. Adverse reactions that occurred more frequently with Mozobil and G-
CSF than placebo and G-CSF and were reported as related in ≥1% of the patients who received
Mozobil, during haematopoietic stem cell mobilisation and apheresis and prior to
chemotherapy/ablative treatment in preparation for transplantation are shown in Table 1. Adverse
reactions are listed by System Organ Class and frequency. Frequencies are defined according to the
following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to
< 1/100), rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from
the available data).
From chemotherapy/ablative treatment in preparation of transplantation through 12 months
post-transplantation, no significant differences in the incidence of adverse reactions were observed
across treatment groups.
5
Table 1. Adverse reactions occurring more frequently with Mozobil than placebo and
considered related to Mozobil during mobilisation and apheresis in phase III studies
Immune system disorders
Uncommon Allergic reaction*
Psychiatric disorders
Common Insomnia
Nervous system disorders
Common Dizziness, headache
Gastrointestinal disorders
Very common Diarrhoea, nausea
Common Vomiting, abdominal pain, stomach
discomfort, dyspepsia, abdominal distention,
constipation, flatulence, hypoaesthesia oral,
dry mouth
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 and infusion site reactions
Common Fatigue, malaise
*
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-CSF. All events occurred at least 14 days after last
Mozobil administration. Additionally, two female oncology patients in the compassionate use
programme experienced myocardial infarction following haematopoietic stem cell mobilisation with
plerixafor and G-CSF. One of these events occurred 4 days after last Mozobil administration. Lack of
temporal relationship in 8 of 9 patients coupled with the risk profile of patients with myocardial
infarction does not suggest Mozobil confers an independent risk for myocardial infarction in patients
who also receive G-CSF.
Hyperleukocytosis
White blood cell counts of 100 x 10
9
/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
6
of plerixafor doses ≤ 0.24 mg/kg. The majority of these events occurred within 1 hour of Mozobil
administration.
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 ≥ 65 years old. No
notable differences in the incidence of adverse reactions were observed in these elderly patients when
compared with younger ones.
4.9
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.
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 G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or
placebo and on each morning prior to apheresis. Optimal (5 or 6 x 10
6
cells/kg) and minimal
(2 x 10
6
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.
7
Table 2. Study AMD3100-3101 efficacy results - CD34+ cell mobilisation in non-Hodgkin’s
lymphoma patients
Efficacy endpoint
b
Mozobil and
G-CSF
(n = 150)
Placebo and
G-CSF
(n = 148)
p-value
a
Patients achieving ≥ 5 x 10
6
cells/kg in ≤ 4
apheresis days and successful engraftment
86 (57.3%)
28 (18.9%)
<0.001
Patients achieving ≥ 2 x 10
6
cells/kg in ≤ 4
apheresis days and successful engraftment
126 (84.0%)
64 (43.2%)
< 0.001
a
p-value calculated using Pearson’s Chi-Squared test
b
Statistically significantly more patients achieved ≥ 5 x 10
6
cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=89;
59.3%) than with placebo and G-CSF (n=29; 19.6%), p<0.001; statistically significantly more patients achieved
≥ 2 x 10
6
cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=130; 86.7%) than with placebo and G-CSF (n=70;
47.3%), p<0.001.
Table 3. Study AMD3100-3101 – Proportion of patients who achieved ≥ 5 x 10
6
CD34+
cells/kg by apheresis day in non-Hodgkin’s lymphoma patients
Days
Proportion
a
in Mozobil and G-CSF
(n=147
b
)
Proportion
a
in Placebo and G-CSF
(n=142
b
)
1
27.9%
4.2%
2
49.1%
14.2%
3
57.7%
21.6%
4
65.6%
24.2%
a
Percents determined by Kaplan Meier method
b
n includes all patients who received at least one day of apheresis
Table 4. Study AMD3100-3102 efficacy results – CD34+ cell mobilisation in multiple
myeloma patients
Efficacy endpoint
b
Mozobil and
G-CSF
(n = 1
48
)
Placebo and
G-CSF
(n = 1
54
)
p-value
a
Patients achieving ≥ 6 x 10
6
cells/kg in ≤ 2
apheresis days and successful engraftment
104 (70.3%)
53 (34.4%)
<0.001
a
p-value calculated using Cochran-Mantel-Haenszel statistic blocked by baseline platelet count
b
Statistically significantly more patients achieved ≥ 6 x 10
6
cells/kg in ≤ 2 apheresis days with Mozobil and G-CSF
(n=106; 71.6%) than with placebo and G-CSF (n=53; 34.4%), p<0.001; statistically significantly more patients achieved
≥ 6 x 10
6
cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=112; 75.7%) than with placebo and G-CSF (n=79;
51.3%), p<0.001; statistically significantly more patients achieved ≥ 2 x 10
6
cells/kg in ≤ 4 apheresis days with Mozobil
and G-CSF (n=141; 95.3%) than with placebo and G-CSF (n=136; 88.3%), p=0.031.
Table 5. Study AMD3100-3102 – Proportion of patients who achieved ≥ 6 x 10
6
CD34+
cells/kg by apheresis day in multiple myeloma patients
Days
Proportion
a
in Mozobil and G-CSF
(n=144
b
)
Proportion
a
in Placebo and G-CSF
(n=150
b
)
1
54.2%
17.3%
2
77.9%
35.3%
3
86.8%
48.9%
4
86.8%
55.9%
a
Percents determined by Kaplan Meier method
b
n includes all patients who received at least one day of apheresis
8
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 ≥ 2 x10
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 ≥ 2 x10
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
Mozobil and G-CSF
Placebo and G-CSF
Study
Mean
(SD)
Mean
(SD)
Median
Median
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)
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-CSF administered at identical dose regimen to that in
studies in patients, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to
18 hours after plerixafor administration with peak response between 10 and 14 hours.
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).
9
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-CSF (10 μg/kg once daily for
4 consecutive days).
Absorption
Plerixafor is rapidly absorbed following subcutaneous injection, reaching peak concentrations in
approximately 30-60 minutes (t
max
). 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 (C
max
) and
systemic exposure (AUC
0-24
) 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 (t
1/2
)
in plasma is
3-5 hours. Plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an
in 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 AUC
0-24
of plerixafor in 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.hr/ml, respectively, which were higher than the exposure observed in healthy subjects with
normal renal function (5070 ng.hr/ml). Renal impairment had no effect on C
max.
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
10
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 SK
CA
, histamine H
3
, acetylcholine muscarinic
M
1
and M
2
, adrenergic α1
B
and α2
B
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.
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.
11
C
, neuropeptide Y/Y
1
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.
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
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.
8.
EU/1/09/537/001
9.
07/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
12
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Genzyme Ltd.
37 Hollands Road
Haverhill, Suffolk
CB9 8PU
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Mozobil 20 mg/ml solution for injection
Plerixafor
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 20 mg plerixafor.
Each vial contains 24 mg plerixafor in 1.2 ml solution.
3.
LIST OF EXCIPIENTS
Excipients: sodium chloride, hydrochloric acid (concentrated) and sodium hydroxide for pH
adjustment and water for injections. See leaflet for further information.
4.
Solution for injection
1 vial
24 mg/1.2 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use.
For single use only.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
17
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
11.
Genzyme Europe B.V.
Gooimeer 10
NL-1411 DD Naarden
The Netherlands
12.
EU/1/09/537/001
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted.
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Mozobil 20 mg/ml solution for injection
Plerixafor
Subcutaneous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
24 mg/1.2 ml
6.
OTHER
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
Mozobil 20 mg/ml solution for injection
plerixafor
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or nurse.
In this leaflet
:
1. What Mozobil is and what it is used for
2. Before you use Mozobil
3. How to use Mozobil
4. Possible side effects
5.
How to store Mozobil
6.
Further information
1.
WHAT MOZOBIL IS AND WHAT IT IS USED FOR
Mozobil contains the active substance plerixafor which blocks a protein on the surface of blood stem
cells. This protein “ties” blood stem cells to the bone marrow. Plerixafor improves the release of stem
cells into the blood stream (mobilisation). The stem cells can then be collected by an apheresis
machine, and subsequently frozen and stored until your transplant.
If mobilisation is poor, Mozobil is used to help collect blood stem cells for transplantation in patients
with lymphoma (a cancer of the white blood cells) and multiple myeloma (a cancer that affects plasma
cells in the bone marrow).
2.
BEFORE YOU USE MOZOBIL
DO NOT use Mozobil
•
if you are allergic (hypersensitive) to plerixafor or any of the other ingredients of Mozobil
(listed in section 6, ‘What Mozobil contains’)
Take special care with Mozobil
Tell your doctor:
•
if you have or have had any heart problems.
•
if you have kidney problems. Your doctor may adjust the dose.
•
if you have high white blood cell counts.
•
if you have low platelet counts.
•
if you have a history of feeling faint or lightheaded on standing or sitting or have fainted before
upon injections.
•
if you are under 18 years of age. The effects of Mozobil on children and adolescents have not
been studied.
Your doctor may perform
regular blood tests
to monitor your blood cell count.
It is not recommended to use Mozobil for stem cell mobilisation if you have leukaemia (a cancer of
the blood or bone marrow).
21
-
If you have any further questions, ask your doctor.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
You should not use Mozobil if you are pregnant, since there is no experience with Mozobil in pregnant
women. It is important to tell your doctor if you are, think you may be or are planning to become
pregnant. It is recommended to use contraception if you are of child-bearing age.
You should not breast-feed if you are using Mozobil, since it is not known if Mozobil is excreted in
human milk.
Driving and using machines
Mozobil may cause dizziness and fatigue. Therefore, you should avoid driving if you feel dizzy, tired
or unwell.
Important information about some of the ingredients of Mozobil
Mozobil is essentially sodium-free. It contains less than 1 mmol sodium (23 mg) per dose.
3.
HOW TO USE MOZOBIL
Your medicine will be injected by a doctor or a nurse.
You will first receive G-CSF, then you will be given Mozobil
Mobilisation will be started by first giving you another medicine called G-CSF (granulocyte-colony
stimulating factor). G-CSF will help Mozobil to work properly in your body. If you want to know
more about G-CSF ask your doctor and read the corresponding package leaflet.
How much Mozobil is given?
The usual dose is 0.24 mg/kg body weight/day. Your Mozobil dose will depend on your body weight,
which should be measured the week before you receive your first dose. If you have moderate or severe
kidney problems, your doctor will reduce the dose.
How is Mozobil given?
Mozobil is given by subcutaneous injection (under your skin).
When is Mozobil given for the first time?
You will receive your first dose of Mozobil 6 to 11 hours before apheresis (collection of your blood
stem cells).
How long will Mozobil be given?
Treatment with Mozobil lasts 2 to 4 consecutive days (in some cases up to 7 days), until enough stem
cells have been collected for your transplant. In a few cases, enough stem cells may not be collected,
and the collection attempt will be stopped.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Mozobil can cause side effects, although not everybody gets them.
Please tell your doctor immediately if
•
shortly after receiving Mozobil, you experience rash, swelling around the eyes, shortness of
breath or lack of oxygen, feeling lightheaded on standing or sitting, feeling faint or fainting
•
you have pain in the upper left abdomen (belly) or at the tip of your shoulder.
22
Side effects may occur with certain frequencies, which are defined as follows:
•
very common: affects more than 1 user in 10
•
common: affects 1 to 10 users in 100
•
uncommon: affects 1 to 10 users in 1,000
•
rare: affects 1 to 10 users in 10,000
•
very rare: affects less than 1 user in 10,000
•
not known: frequency cannot be estimated from the available data.
Very common side effects
•
diarrhoea, nausea (feeling sick), injection site redness or irritation
Common side effects
•
headache
•
dizziness, feeling tired or unwell
•
difficulty in sleeping
•
flatulence, constipation, indigestion, vomiting
•
stomach symptoms such as pain, swelling or discomfort
•
dry mouth, numbness around the mouth
•
sweating, generalised redness of the skin, joint pains, pains in muscles and bones.
Uncommon side effects
•
allergic reactions such as skin rash, swelling around the eyes, shortness of breath
Rarely, gastrointestinal side effects may be severe (diarrhoea, vomiting, stomach pain and nausea).
Heart attacks
In clinical trials, patients with risk factors for a heart attack uncommonly suffered heart attacks after
being given Mozobil and G-CSF. Please inform your doctor immediately if you experience chest
discomfort.
Pins and needles and numbness
Pins and needles and numbness are common in patients being treated for cancers. About one in five
patients suffered from these feelings. However, these effects do not seem to occur more frequently
when you use Mozobil.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or nurse.
5.
HOW TO STORE MOZOBIL
Keep out of the reach and sight of children.
Do not use Mozobil after the expiry date which is stated on the carton and vial.
This medicinal product does not require any special storage conditions.
After opening the vial, Mozobil should be used immediately.
Medicines should not be disposed of via wastewater or household waste. The pharmacist will dispose
of medicines no longer required. These measures will help to protect the environment.
23
6.
FURTHER INFORMATION
What Mozobil contains
-
The active substance is plerixafor. Each ml solution for injection contains 20 mg plerixafor. Each
vial contains 24 mg plerixafor in 1.2 ml solution.
-
The other ingredients are sodium chloride, hydrochloric acid (concentrated) and sodium hydroxide
for pH adjustment and water for injections.
What Mozobil looks like and contents of the pack
Mozobil is supplied as a clear colourless or pale yellow solution for injection in a glass vial with a
non-latex rubber stopper. Each vial contains 1.2 ml solution.
Each pack contains 1 vial.
Marketing Authorisation Holder
Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.
Manufacturer
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom.
24
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien/
Luxemburg/Luxembourg
Genzyme Belgium N.V.
Tel/Tél: + 32 2 714 17 11
Italia/Malta
Genzyme Srl (Italia/Italja)
Tel: +39 059 349 811
България
Търговско представителство на
Genzyme CEE GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet
Tel: +36 1 310 7440
Česká Republika/Slovenská Republika/Slovenija
Genzyme Czech, s.r.o.
Tel: +420 227 133 665
Nederland
Genzyme Europe B.V.
Tel: +31 35 699 1200
Danmark/Norge/Sverige/Suomi/Finland/
Ísland
Genzyme A/S, (Danmark/Tanska/Danmörk)
Tlf/Puh./Sími: + 45 32 71 2600
Österreich
Genzyme Austria GmbH
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska Sp. z o.o. (Poola/Polija/Lenkija)
Tel: + 48 22 24 60 900
Ελλάδα/Κύπρος
Genzyme Hellas Ltd (Ελλάδα)
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal S.A.
Tel: +351 21 422 0100
España
Genzyme, S.A.
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanţa pentru
România
Tel: +40 21 24 34 228
France
Genzyme S.A.S.
Tél: +33 (0) 825 825 863
United Kingdom/Ireland
Genzyme Therapeutics Ltd. (United Kingdom)
Tel: +44 1865 405200
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
25
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/mozobil.html
Copyright © 1995-2021 ITA all rights reserved.