Composition

Each ml of the sterile solution contains:

Plerixafor………………20mg

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.

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 to 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.

Biotransformation

Plerixafor is not metabolised 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 3 to 5 hours. In patients with renal impairment, the rate of elimination has been found to be reduced. 

Plerixafor is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in adult patients with lymphoma or multiple myeloma whose cells mobilise poorly.

Plerixafor 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.

Age over 60 and/ or prior myelosuppressive chemotherapy and/or extensive prior chemotherapy and/or a peak circulating stem cell count of less than 20 stem cells/microliter, have been identified as predictors of poor mobilisation.

Adult

Administer daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first evening dose of Plerixafor and on each day prior to apheresis.

The recommended daily dose of plerixafor by subcutaneous injection (SC), given 6 to 11 hours before starting apheresis, usually for up to 4 consecutive days, is:

• 20 mg fixed dose or 0.24 mg/kg of body weight for patients weighing ≤ 83 kg.
• 0.24 mg/kg of body weight for patients weighing > 83 kg.

Use the patient’s actual body weight to calculate the volume of Plerixafor to be administered. 

Each vial delivers 1.2 mL of 20 mg/mL solution, and the volume to be administered to patients should be calculated from the following equation: 

0.012 × patient’s actual body weight (in kg) = volume to be administered (in mL).

In clinical studies, Plerixafor dose has been calculated based on actual 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:

Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day.

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 table below). 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.

Recommended Dosage of Plerixafor in Patients with Renal Impairment

There is insufficient information to make dosage recommendations in patients on hemodialysis.

Paediatric population

The safety and efficacy of Plerixafor in pediatric 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

Plerixafor is for subcutaneous injection. Each vial 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 Plerixafor 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.

Tumour cell mobilisation in patients with lymphoma and multiple myeloma

When Plerixafor 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. 

Since in clinical studies mobilization with Plerixafor is achieved in combination with GSF, based on the limited experience, it is not possible to conclude on increase in mobilization of tumour cells from lymphoma or multiple myeloma because of Plerixafor over and above that from G-CSF. Further, the effect of potential reinfusion of tumor cells has not been well studied. 

Tumour cell mobilisation in leukaemia patients

In a compassionate use programme, Plerixafor 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.

Haematological effects

Hyperleukocytosis

Administration of Plerixafor in conjunction with G-CSF increases circulating leukocytes as well as haematopoietic stem cell populations. White blood cell counts should be monitored during Plerixafor therapy. Clinical judgment should be exercised when administering Plerixafor to patients with peripheral blood neutrophil counts above 50 x 109/L.

Thrombocytopenia

Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving Plerixafor. Platelet counts should be monitored in all patients receiving Plerixafor and undergoing apheresis.

Allergic reactions

Plerixafor has been uncommonly associated with potential systemic reactions related to subcutaneous injection such as urticaria, periorbital swelling, dyspnoea, or hypoxia. 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

Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. Appropriate precautions should be taken because of the potential for these reactions.

Effect on the spleen

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 Plerixafor in conjunction with growth factor G-CSF. Individuals receiving Plerixafor in conjunction with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity.

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment.

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. Plerixafor should not be used during pregnancy unless the clinical condition of the woman requires treatment with plerixafor.

Breast-feeding

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 Plerixafor.

Fertility

The effects of plerixafor on male and female fertility are not known.

Summary of the safety profile

Safety data for Plerixafor 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 Plerixafor 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 Plerixafor and G-CSF than placebo and G-CSF and were reported as related in ≥1% of the patients who received Plerixafor, 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.

Tabulated list of adverse reactions

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 Plerixafor than placebo and considered related to Plerixafor during mobilisation and apheresis in phase III studies.

* 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 Plerixafor administration.

** From post-marketing experience

The adverse reactions reported in patients with lymphoma and multiple myeloma who received Plerixafor in the controlled Phase III studies and uncontrolled studies, including a Phase II study of Plerixafor 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.

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.

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.

CONTRAINDICATIONS 

Plerixafor is contraindicated in patients having hypersensitivity to the active substance or to any of the excipients of the formulation.

Store at 250 C (770F); excursions permitted to 15 to 300 C (590– 860 F).

Carton containing single use vial.