PLERIXAFOR ACCORD 20mg / ml injectible solution medication leaflet

Plerixafor Accord 20 mg/ml solution for injection

One ml of solution contains 20 mg of plerixafor.

Each vial contains 24 mg plerixafor in 1.2 ml solution.

For the full list of excipients, see section 6.1.

Solution for injection

Clear, colourless to pale yellow solution, with a pH of 6.0-7.5 and an osmolalityof 260 - 320 mOsm/kg.

Adult patients

Plerixafor Accord is indicated in combination with granulocyte-colony stimulating factor (G-CSF) toenhance mobilisation of haematopoietic stem cells to the peripheral blood for collection andsubsequent autologous transplantation in adult patients with lymphoma or multiple myeloma whosecells mobilise poorly (see section 4.2).

Paediatric patients (1 to less than 18 years)

Plerixafor Accord is indicated in combination with G-CSF to enhance mobilisation of haematopoieticstem cells to the peripheral blood for collection and subsequent autologous transplantation in childrenwith lymphoma or solid malignant tumours, either:

- pre-emptively, when circulating stem cell count on the predicted day of collection afteradequate mobilization with G-CSF (with or without chemotherapy) is expected to beinsufficient with regards to desired hematopoietic stem cells yield, or

- who previously failed to collect sufficient haematopoietic stem cells (see section 4.2).

Plerixafor Accord therapy should be initiated and supervised by a physician experienced in oncologyand/or haematology. The mobilisation and apheresis procedures should be performed in collaborationwith an oncology-haematology centre with acceptable experience in this field and where themonitoring of haematopoietic progenitor cells can be correctly performed.

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

Adult

The recommended daily dose of plerixafor by subcutaneous injection is:

* 20 mg fixed dose or 0.24 mg/kg of body weight for patients weighing ≤ 83 kg (seesection 5.2).

* 0.24 mg/kg of body weight for patients weighing > 83 kg.

Paediatric (1 to less than 18 years)

The recommended daily dose of plerixafor by subcutaneous injection is:

* 0.24 mg/kg of body weight (see section 5.1).

Each vial of plerixafor treatment is filled to deliver 1.2 ml of 20 mg/ml plerixafor aqueous solution forinjection containing 24 mg of plerixafor.

Plerixafor has to be drawn up into a syringe size type which should be selected according to the weightof the patient.

For low weight patients, up to 45 kg of body weight, 1 ml syringes for use in infant patients can beused. This type of syringe has major graduations for 0.1 ml and minor graduations for 0.01 ml andtherefore is suitable to administer plerixafor, at a dose of 240 μg/kg, to paediatric patients of at least9 kg body weight.

For patients of more than 45 kg, 1 ml or 2 ml syringe with graduations that allow a volume to 0.1 ml tobe measured can be used.

It should be administered by subcutaneous injection 6 to 11 hours prior to initiation of each apheresisfollowing 4 day pre-treatment with G-CSF. In clinical trials, plerixafor has been commonly used for2 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 firstdose of plerixafor. In clinical studies, the dose of plerixafor has been calculated based on body weightin patients up to 175% of ideal body weight. Plerixafor dose and treatment of patients weighing morethan 175% of ideal body weight have not been investigated. Ideal body weight can be determinedusing the following equations:

male (kg): 50 + 2.3 x ((Height (cm) x 0.394) - 60);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 notexceed 40 mg/day.

Recommended concomitant medicinal products

In pivotal clinical studies supporting the use of Plerixafor treatment, all patients received dailymorning doses of 10 μg/kg G-CSF for 4 consecutive days prior to the first dose of plerixafor and oneach morning prior to apheresis.

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 patientswith a creatinine clearance <20 ml/min, as well as to make posology recommendations for patients onhaemodialysis.

Based on increasing exposure with increasing body weight the dose should not exceed 27 mg/day ifthe creatinine clearance is lower than 50 ml/min.

The safety and efficacy of Plerixafor treatment in children (1 to less than 18 years) were studied in anopen label, multicenter, controlled study (see sections 4.8, 5.1 and 5.2).

Elderly patients (> 65 years old)

No dose modifications are necessary in elderly patients with normal renal function. Dose adjustmentin elderly patients with creatinine clearance ≤ 50 ml/min is recommended (see Renal impairmentabove). In general, care should be taken in dose selection for elderly patients due to the greaterfrequency of decreased renal function with advanced age.

Plerixafor Accord 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 ordiscolouration. Since Plerixafor Accord is supplied as a sterile, preservative-free formulation, aseptictechnique should be followed when transferring the contents of the vial to a suitable syringe forsubcutaneous administration (see section 6.3).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Tumour cell mobilisation in patients with lymphoma and multiple myeloma

When Plerixafor treatment is used in conjunction with G-CSF for haematopoietic stem cellmobilisation in patients with lymphoma or multiple myeloma‚ tumour cells may be released from themarrow and subsequently collected in the leukapheresis product. Results showed that, in case tumourcells are mobilised, the number of tumour cells mobilised is not increased upon plerixafor plus G-CSFcompared to G-CSF alone.

Tumour cell mobilisation in leukaemia patients

In a compassionate use programme, Plerixafor treatment and G-CSF have been administered topatients with acute myelogenous leukaemia and plasma cell leukaemia. In some instances, thesepatients experienced an increase in the number of circulating leukaemia cells. For the purpose ofhaematopoietic stem cell mobilisation, plerixafor may cause mobilisation of leukaemic cells andsubsequent contamination of the apheresis product. Therefore, plerixafor is not recommended forhaematopoietic stem cell mobilisation and harvest in patients with leukaemia.

Hyperleukocytosis

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

Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving

Plerixafor treatment. Platelet counts should be monitored in all patients receiving Plerixafor treatmentand undergoing apheresis.

Plerixafor treatment has been uncommonly associated with potential systemic reactions related tosubcutaneous injection such as urticaria, periorbital swelling, dyspnoea, or hypoxia (see section 4.8).

Symptoms responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplementaloxygen) or resolved spontaneously. Cases of anaphylactic reactions, including anaphylactic shock,have been reported from world-wide post-marketing experience. Appropriate precautions should betaken because of the potential for these reactions.

Vasovagal reactions

Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneousinjections (see section 4.8). Appropriate precautions should be taken because of the potential for thesereactions.

Effect on the spleen

In preclinical studies, higher absolute and relative spleen weights associated with extramedullaryhaematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor subcutaneousadministration 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 clinicalstudies. Cases of splenic enlargement and/or rupture have been reported following the administrationof Plerixafor treatment in conjunction with growth factor G-CSF. Individuals receiving Plerixafortreatment in conjunction with G-CSF who report left upper abdominal pain and/or scapular or shoulderpain should be evaluated for splenic integrity.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose that is to say essentially‘sodium- free’.

No interaction studies have been performed. In vitro tests showed that plerixafor was not metabolisedby P450 CYP enzymes, did not inhibit or induce P450 CYP enzymes. Plerixafor did not act as asubstrate 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 amobilisation 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 congenitalmalformations when administered during pregnancy. Studies in animals have shown teratogenicity(see section 5.3). Plerixafor should not be used during pregnancy unless the clinical condition of thewoman requires treatment with plerixafor.

It is unknown whether plerixafor is excreted in human milk. A risk to the suckling child cannot beexcluded. Breast-feeding should be discontinued during treatment with Plerixafor Accord.

The effects of plerixafor on male and female fertility are not known (see section 5.3).

Plerixafor Accord has minor influence on the ability to drive and use machines. Some patients haveexperienced dizziness, fatigue or vasovagal reactions; therefore caution is advised when driving oroperating machines.

Safety data for plerixafor in conjunction with G-CSF in oncology patients with lymphoma andmultiple myeloma were obtained from 2 placebo-controlled Phase III studies (301 patients) and10 uncontrolled phase II studies (242 patients). Patients were primarily treated with daily doses of0.24 mg/kg plerixafor by subcutaneous injection. The exposure to plerixafor in these studies rangedfrom 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. Patientsreceived daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor orplacebo 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 patientswho received Plerixafor, during haematopoietic stem cell mobilisation and apheresis and prior tochemotherapy/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 acrosstreatment groups.

Adverse reactions are listed by System Organ Class and frequency. Frequencies are defined accordingto 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 beestimated from the available data).

Table 1: Adverse reactions occurring more frequently with plerixafor than placebo andconsidered related to plerixafor during mobilisation and apheresis in phaseIII studies

Not known Splenomegaly, splenic rupture (see section 4.4)**

Uncommon Allergic reaction*

Anaphylactic reactions, including anaphylacticshock (see section 4.4) **

Common Insomnia

Uncommon Abnormal dreams, nightmares

Common Dizziness, headache

Very common Diarrhoea, nausea

Common Vomiting, abdominal pain, stomachdiscomfort, 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 minafter 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 significantdifferences 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 afterhaematopoieticstem cell mobilisation with plerixafor and G-CSF. All events occurred at least 14 daysafter last plerixafor administration. Additionally, two female oncology patients in the compassionateuse programme experienced myocardial infarction following haematopoietic stem cell mobilisationwith plerixafor and G-CSF. One of these events occurred 4 days after last plerixafor administration.

Lack of temporal relationship in 8 of 9 patients coupled with the risk profile of patients withmyocardial infarction does not suggest Plerixafor confers an independent risk for myocardialinfarction in patients who also receive G-CSF.

Hyperleukocytosis

White blood cell counts of 100 x 109/L or greater were observed, on the day prior to or any day ofapheresis, in 7% patients receiving Plerixafor and in 1% patients receiving placebo in the Phase IIIstudies. No complications or clinical symptoms of leukostasis were observed.

Vasovagal reactions

In Plerixafor oncology and healthy volunteer clinical studies, less than 1% of subjects experiencedvasovagal reactions (orthostatic hypotension and/or syncope) following subcutaneous administrationof plerixafor doses ≤0.24 mg/kg. The majority of these events occurred within 1 hour of plerixaforadministration.

In Plerixafor clinical studies of oncology patients, there have been rare reports of severegastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.

Paraesthesia

Paraesthesia is commonly observed in oncology patients undergoing autologous transplantationfollowing multiple disease interventions. In the placebo-controlled phase III studies, the incidence ofparaesthesia 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. Nonotable differences in the incidence of adverse reactions were observed in these elderly patients whencompared with younger ones.

Thirty patients were treated with 0.24 mg/kg of plerixafor in an open label, multicenter, controlledstudy (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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported. Based on limited data at doses above the recommended doseand up to 0.48 mg/kg the frequency of gastrointestinal disorders, vasovagal reactions, orthostatichypotension, and/or syncope may be higher.

Pharmacotherapeutic group: Immunostimulants, other immunostimulants; ATC code: L03AX16

Plerixafor is a bicyclam derivative, a selective reversible antagonist of the CXCR4 chemokine receptorand 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 celllevels are thought to result from a disruption of CXCR4 binding to its cognate ligand, resulting in theappearance of both mature and pluripotent cells in the systemic circulation. CD34+ cells mobilised byplerixafor are functional and capable of engraftment with long-term repopulating capacity.

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 healthyvolunteers of plerixafor in conjunction with G-CSF administered at identical dose regimen to that instudies in patients, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to18 hours after plerixafor administration with peak response between 10 and 14 hours.

In order to compare the pharmacokinetics and pharmacodynamics of plerixafor following 0.24 mg/kgbased and fixed (20 mg) doses, a trial was conducted in adult patients with NHL (N=61) who weretreated with 0.24 mg/kg or 20 mg of plerixafor. The trial was conducted in patients weighing 70 kg orless (median: 63.7 kg, min: 34.2 kg, max: 70 kg). The fixed 20 mg dose showed 1.43-fold higherexposure (AUC0-10h) than the 0.24 mg/kg dose (Table 2). The fixed 20 mg dose also showednumerically higher response rate (5.2% [60.0% vs 54.8%] based on the local lab data and 11.7%[63.3% vs 51.6%] based on the central lab data) in attaining the target of ≥ 5 × 106 CD34+ cells/kgthan the mg/kg-based dose. The median time to reach ≥ 5 × 106 CD34+ cells/kg was 3 days for bothtreatment groups, and the safety profile between the groups was similar. Body weight of 83 kg wasselected as the cut-off point to transition patients from fixed to weight based dosing (83 kg x 0.24 mg= 19.92 mg/kg).

Table 2. Systemic Exposure (AUC0-10h) comparisons of fixed and weight based regimens

Regimen Geometric mean AUC

Fixed 20 mg (n=30) 3991.20.24 mg/kg (n=31) 2792.7

Ratio (90% CI) 1.43 (1.32,1.54)

In two phase III randomised-controlled studies patients with non-Hodgkin’s lymphoma or multiplemyeloma received plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patientsreceived daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor orplacebo and on each morning prior to apheresis. Optimal (5 or 6 x 106 cells/kg) and minimal(2 x 106 cells/kg) numbers of CD34+ cells/kg within a given number of days, as well as the primarycomposite endpoints which incorporated successful engraftment are presented in Tables 3 and 5; theproportion of patients reaching optimal numbers of CD34+ cells/kg by apheresis day are presented in

Tables 4 and 6.

Table 3. Study AMD3100-3101 efficacy results - CD34+ cell mobilisation in non-Hodgkin’slymphoma patients

Efficacy endpointb Plerixafor and Placebo and p-value a

G-CSF (n = 150) G-CSF (n = 148)

Patients achieving ≥ 5 x 106 cells/kg in ≤ 86 (57.3%) 28 (18.9%) <0.0014 apheresis days and successfulengraftment

Patients achieving ≥ 2 x 106cells/kg in ≤ 126 (84.0%) 64 (43.2%) < 0.0014 apheresis days and successfulengraftmenta p-value calculated using Pearson’s Chi-Squared testbStatistically significantly more patients achieved ≥ 5 x 106 cells/kg in ≤ 4 apheresis days with Plerixafor 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 106 cells/kg in ≤ 4 apheresis days with Plerixafor and G-CSF (n=130; 86.7%) than with placebo and G-CSF (n=70;47.3%), p<0.001.

Table 4. Study AMD3100-3101 - Proportion of patients who achieved ≥ 5 x 106

CD34+ cells/kgby apheresis day in non-Hodgkin’s lymphoma patients

Days Proportiona Proportionain Plerixafor and G-CSF in Placebo and G-CSF(n=147b) (n=142b)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 methodb n includes all patients who received at least one day of apheresis

Table 5. Study AMD3100-3102 efficacy results - CD34+ cell mobilisation in multiple myelomapatients

Efficacy endpointb Plerixafor and Placebo and p-value a

G-CSF G-CSF(n = 148) (n = 154)

Patients achieving ≥ 6 x 106 cells/kg 104 (70.3%) 53 (34.4%) <0.001in ≤ 2 apheresis days and successfulengraftmentap-value calculated using Cochran-Mantel-Haenszel statistic blocked by baseline platelet countbStatistically significantly more patients achieved ≥ 6 x 106 cells/kg in ≤ 2 apheresis days with Plerixafor 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 106 cells/kg in ≤ 4 apheresis days with Plerixafor 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 106 cells/kg in ≤ 4 apheresis days with Plerixafor and

G-CSF (n=141; 95.3%) than with placebo and G-CSF (n=136; 88.3%), p=0.031.

Table 6. Study AMD3100-3102 - Proportion of patients who achieved ≥ 6 x 106 CD34+ cells/kgby apheresis day in multiple myeloma patients

Days Proportiona Proportionain plerixafor and G-CSF in placebo and G-CSF(n=144b) (n=150b)1 54.2% 17.3%2 77.9% 35.3%3 86.8% 48.9%4 86.8% 55.9%aPercents determined by Kaplan Meier methodb n includes all patients who received at least one day of apheresis

Rescue patients

In study AMD3100-3101, 62 patients (10 in the plerixafor + G-CSF group and 52 in the placebo +

GCSFgroup), who could not mobilise sufficient numbers of CD34+ cells and thus could not proceed totransplantation, entered into an open-label Rescue procedure with Plerixafor and G-CSF. Of thesepatients, 55 % (34 out of 62) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment. Instudy 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 x106/kg CD34+ cells and had successfulengraftment.

The dose of haematopoietic stem cells used for each transplant was determined by the investigator andall haematopoietic stem cells that were collected were not necessarily transplanted. For transplantedpatients in the phase III studies, median time to neutrophil engraftment (10-11 days), median time toplatelet engraftment (18-20 days) and graft durability up to 12 months post-transplantation weresimilar across the Plerixafor and placebo groups.

Mobilisation and engraftment data from supportive Phase II studies (plerixafor 0.24 mg/kg dosed onthe evening or morning prior to apheresis) in patients with non-Hodgkin’s lymphoma, Hodgkin’sdisease, 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) overthe 24-hour period from the day prior to the first apheresis to just before the first apheresis wasevaluated (Table 7). During that 24-hour period, the first dose of plerixafor 0.24 mg/kg or placebo wasadministered 10-11 hours prior to apheresis.

Table 7. Fold increase in peripheral blood CD34+ cell count following plerixafor administration

Study Plerixafor and G-CSF Placebo and G-CSF

Median Mean Median Mean(SD) (SD)

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)

The European Medicines Agency has waived the obligation to submit the results of studies withplerixafor in children aged 0 to 1 year in myelosuppression caused by chemotherapy to treat malignantdisorders, which requires an autologous haematopoietic stem cell transplant (see section 4.2 forinformation on paediatric use).

The efficacy and safety of plerixafor were evaluated in an open label, multi-center, controlled study inpaediatric patients with solid tumors (including neuroblastoma, sarcoma, Ewing sarcoma) orlymphoma who were eligible for autologous hematopoietic stem cell transplantation (DFI12860).

Patients with leukemia, persistent high percentage marrow involvement prior to mobilization, orprevious stem cell transplantation were excluded.

Forty-five paediatric patients (1 to less than 18 years) were randomised, 2:1, using 0.24 mg/kg ofplerixafor plus standard mobilisation (G-CSF plus or minus chemotherapy) versus control (standardmobilisation alone). Median age was 5.3 years (min: max 1:18) in the plerixafor arm versus 4.7 years(min:max 1:17) in the control arm.

Only one patient aged less than 2 years old was randomised to the plerixafor treatment arm. There wasan imbalance between treatment arms in peripheral blood CD34+ counts on the day prior to firstapheresis (i.e. prior to administration of plerixafor), with less circulating PB CD34+ in the plerixaforarm. The median PB CD34+ cell counts at baseline were 15 cells/μl in the plerixafor arm versus35 cells/μl in control arm. The primary analysis showed that 80% of patients in the plerixafor armexperienced at least a doubling of the PB CD34+ count, observed from the morning of the daypreceding the first planned apheresis to the morning prior to apheresis, versus, 28.6% of patients in thecontrol arm (p=0.0019). The median increase in PB CD34+ cell counts from baseline to the day ofapheresis was by 3.2 fold in the plerixafor arm versus by 1.4 fold in the control arm.

The pharmacokinetics of plerixafor have been evaluated in lymphoma and multiple myeloma patientsat the clinical dose level of 0.24 mg/kg following pre-treatment with G-CSF (10 μg/kg once daily for4 consecutive days).

Plerixafor is rapidly absorbed following subcutaneous injection, reaching peak concentrations inapproximately 30-60 minutes (tmax). Following subcutaneous administration of a 0.24 mg/kg dose topatients after receiving 4-days of G-CSF pre-treatment, the maximal plasma concentration (Cmax) andsystemic exposure (AUC0-24) of plerixafor were 887 ± 217 ng/ml and 4337 ± 922 ng·hr/ml,respectively.

Plerixafor is moderately bound to human plasma proteins up to 58%. The apparent volume ofdistribution of plerixafor in humans is 0.3 l/kg demonstrating that plerixafor is largely confined to, butnot limited to, the extravascular fluid space.

Plerixafor is not metabolised in vitro using human liver microsomes or human primary hepatocytesand 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 thatplerixafor has a low potential for involvement in P450-dependent drug-drug interactions.

The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthyvolunteers with normal renal function, approximately 70% of the dose was excreted unchanged inurine during the first 24 hours following administration. The elimination half-life (t1/2) in plasma is3-5 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.

Following a single dose of 0.24 mg/kg plerixafor, clearance was reduced in subjects with varyingdegrees of renal impairment and was positively correlated with creatinine clearance (CrCl). Meanvalues of AUC0-24 of plerixafor in subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31-50ml/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 renalfunction (5070 ng·hr/ml). Renal impairment had no effect on Cmax.

A population pharmacokinetic analysis showed no effect of gender on pharmacokinetics of plerixafor.

A population pharmacokinetic analysis showed no effect of age on pharmacokinetics of plerixafor.

The pharmacokinetics of plerixafor were evaluated in 48 paediatric patients (1 to less than 18 years)with solid tumours at subcutaneous doses of 0.16, 0.24 and 0.32 mg/kg with standard mobilisation(GCSF plus or minus chemotherapy). Based on population pharmacokinetic modeling and similar toadults, μg/kg-based dosage results in increase in plerixafor exposure with increasing body weight inpaediatric patients. At the same weight-based dosing regimen of 240 μg/kg, the plerixafor meanexposure (AUC0-24h) is lower in paediatric patients aged 2 to <6 years (1410 ng.h/mL), 6 to<12 years(2318 ng.h/mL), and 12 to <18 years (2981 ng.h/mL) than in adults (4337 ng.h/mL). Based onpopulation pharmacokinetic modeling, the plerixafor mean exposures (AUC0-24h) in paediatric patientsaged 2 to <6 years (1905 ng.h/mL), 6 to <12 years (3063 ng.h/mL), and 12 to <18 years(4015 ng.h/mL), at the dose of 320 μg/kg are closer to the exposure in adults receiving 240 μg/kg.

However, mobilization of PB CD34+ count was observed in stage 2 of the trial.

The results from single dose subcutaneous studies in rats and mice showed plerixafor can inducetransient but severe neuromuscular effects (uncoordinated movement), sedative-like effects(hypoactivity), dyspnoea, ventral or lateral recumbency, and/or muscle spasms. Additional effects ofplerixafor consistently noted in repeated dose animal studies included increased levels of circulatingwhite blood cells and increased urinary excretion of calcium and magnesium in rats and dogs, slightlyhigher spleen weights in rats, and diarrhoea and tachycardia in dogs. Histopathology findings ofextramedullary haematopoiesis were observed in the liver and spleen of rats and/or dogs. One or moreof these findings were usually observed at systemic exposures in the same order of magnitude orslightly higher than the human clinical exposure.

The results of the dose range-finding study in juvenile miniature pigs and the range-finding anddefinitive studies in juvenile rats were similar to those observed in adult mice, rats, and dogs.

Exposure margins in the juvenile rat study at the maximum tolerated dose (MTD) were ≥18 fold whencompared with the highest clinical paediatric dose in children up to 18 years of age.

An in vitro general receptor activity screen showed that plerixafor, at a concentration (5 μg/ml) severalfold higher than the maximum human systemic level, has moderate or strong binding affinity for anumber of different receptors predominantly located on pre-synaptic nerve endings in the centralnervous system (CNS) and/or the peripheral nervous system (PNS) (N-type calcium channel,potassium channel SKCA, histamine H3, acetylcholine muscarinic M1 and M2, adrenergic α1B andα2C, neuropeptide Y/Y1 and glutamate NMDA polyamine receptors). The clinical relevance of thesefindings is not known.

Safety pharmacology studies with intravenously administered plerixafor in rats showed respiratory andcardiac depressant effects at systemic exposure slightly above the human clinical exposure, whilstsubcutaneous administration elicited respiratory and cardiovascular effects only at higher systemiclevels.

SDF-1α and CXCR4 play major roles in embryo-foetal development. Plerixafor has been shown tocause increased resorptions, decreased foetal weights, retarded skeletal development and increasedfoetal abnormalities in rats and rabbits. Data from animal models also suggest modulation of foetalhaematopoiesis, vascularisation, and cerebellar development by SDF-1α and CXCR4. Systemicexposure at No Observed Adverse Effect Level for teratogenic effects in rats and rabbits was of thesame magnitude or lower as found at therapeutic doses in patients. This teratogenic potential is likelydue to its pharmacodynamic mechanism of action.

In rat distribution studies concentrations of radiolabelled plerixafor was detected in reproductiveorgans (testes, ovaria, uterus) two weeks after single or 7 daily repeated doses in males and after7 daily repeated doses in females. The elimination rate from tissues was slow.

The potential effects of plerixafor on male fertility and postnatal development have not been evaluatedin non-clinical studies.

Carcinogenicity studies with plerixafor have not been conducted. Plerixafor was not genotoxic in anadequate 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 durationof dosing plerixafor in humans.

Sodium chloride

Hydrochloric acid, concentrated (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial24 months.

From a microbiological point of view, the product should be used immediately. If not usedmmediately, in-use storage times and conditions prior to use are the responsibility of the user.

This medicinal product does not require any special storage conditions.

2 ml type I clear glass vial with a chlorobutyl rubber stopper and aluminium flip-off seal with PPplastic blue mate top. Each vial contains 1.2 ml solution.

Pack size of 1 vial.

For single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/22/1701/001

Date of first authorisation: 16 December 2022.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.