Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP, Amsterdam, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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. Results showed that, in case tumour cells are mobilised, the number of tumour cells mobilised is not increased upon Mozobil plus G-CSF compared to G-CSF alone.
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.
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 × 109/L.
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.
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. Cases of anaphylactic reactions, including anaphylactic shock, have been reported from world-wide post-marketing experience. Appropriate precautions should be taken because of the potential for these 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.
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. Cases of splenic enlargement and/or rupture have been reported following the administration of Mozobil in conjunction with growth factor G-CSF. 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.
Mozobil contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.
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.
Women of childbearing potential have to use effective contraception during treatment.
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.
It is unknown 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.
The effects of plerixafor on male and female fertility are not known (see section 5.3).
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 machines.
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 (301 patients) and 10 uncontrolled Phase II studies (242 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 g/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.
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.
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).
Table 1. Adverse reactions occurring more frequently with Mozobil than placebo and considered related to Mozobil during mobilisation and apheresis in phase III studies:
Not known: Splenomegaly, splenic rupture (see section 4.4)**
Uncommon: Allergic reaction* Anaphylactic reactions, including anaphylactic shock (see section 4.4)**
Common: Insomnia
Uncommon: Abnormal dreams, nightmares
Common: Dizziness, headache
Very common: Diarrhoea, nausea
Common: Vomiting, abdominal pain, stomach discomfort, dyspepsia, abdominal distention, constipation, flatulence, hypoaesthesia oral, dry mouth
Common: Hyperhidrosis, erythema
Common: Arthralgia, musculoskeletal pain
Very common: Injection and infusion site reactions
Common: Fatigue, malaise
* The frequency of allergic reactions presented is based on adverse reactions that occurred in the oncology studies (679 patients). 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.
** From post-marketing experience
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.
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.
White blood cell counts of 100 × 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.
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 ≤0.24 mg/kg. The majority of these events occurred within 1 hour of Mozobil administration.
In Mozobil clinical studies of oncology patients, there have been rare reports of severe gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.
Paraesthesia is commonly observed in oncology patients undergoing autologous transplantation following multiple disease interventions. In the placebo-controlled Phase III studies, the incidence of paraesthesia was 20.6% and 21.2% in the plerixafor and placebo groups, respectively.
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.
Thirty patients were treated with 0.24 mg/kg of Mozobil in an open label, multicenter, controlled study (DFI 12860) (see section 5.1). The safety profile in this paediatric study was consistent with what has been observed in adults.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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