Pleditex 24,0 mg SOLUTION FOR INJECTION

PLEDITEX is indicated to enhance mobilisation of hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma (MM).

Posology
The recommended dose of PLEDITEX is 0,24 mg/kg body weight by subcutaneous injection. PLEDITEX should be administered 6 to 11 hours prior to initiation of apheresis following 4 days of treatment with G-CSF. PLEDITEX has been commonly used for 2 to 4 consecutive days. It has been used for up to 7 consecutive days in a clinical setting. The patientu2019s actual body weight will be used to calculate the volume of PLEDITEX to be administered. Each vial delivers 1,2 ml of 20 mg/mL solution, and the volume to be administered to patients will be calculated from the following equation: 0,012 x patientu2019s actual body weight (in kg) = dose to be administered (in mL). In clinical studies, PLEDITEX dose has been calculated based on actual body weight in patients up to 175 % of ideal body weight. PLEDITEX dose and treatment of patients weighing more than 175 % of ideal body weight have not been investigated. The weight used to calculate the volume of PLEDITEX should be obtained within 1 week of the first dose of [PRODUCT NAME].
Recommended concomitant medications: In pivotal clinical studies supporting the use of [PRODUCT NAME], all patients received daily morning doses of granulocyte-colony stimulating factor (G-CSF) 10 u03bcg/kg for 4 days prior to the first dose of PLEDITEX and on each morning prior to apheresis.
Special Populations
Patients with renal impairment: Patients with moderate and severe renal insufficiency (creatinine clearance (CrCl) u2264 50 mL/min) should have their dose of PLEDITEX reduced by one-third to 0,16 mg/kg. Similar systemic exposure is expected if the dose is reduced by one-third in patients with moderate and severe renal impairment compared with subjects with normal renal function. Clinical data with this dose adjustment in patients with renal impairment are limited. The following (Cockroft-Gault) formula may be used to estimate CrCl: Males: Creatinine clearance (mL/min) = [weight (kg) x (140 - age in years)] / [72 x serum creatinine (mg/dL)]. Females: Creatinine clearance (mL/min) = 0,85 x value calculated for males. There is insufficient information to make dosage recommendations in patients on haemodialysis.
Elderly patients: In the two placebo-controlled clinical studies of [PRODUCT NAME], 24 % of patients were u2265 65 years old. No notable differences in the incidence of adverse drug reactions were observed in elderly and younger patients. Since the active ingredient of [PRODUCT NAME], plerixafor, is mainly excreted by the kidney, no dose modifications are necessary in elderly individuals with normal renal function. In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Dosage adjustment in elderly patients with CrCl u2264 50 ml/min is recommended.
Paediatric population: The safety and efficacy of PLEDITEX in paediatric patients has not been established in controlled clinical studies.
Method of administration
PLEDITEX is administered as a subcutaneous injection. PLEDITEX should be administered by a nurse, physician, or other healthcare professional.

Hypersensitivity to plerixafor or to any of the ingredients of PLEDITEX (see section 6.1). Pregnancy and lactation (see section 4.6).

Tumour cell mobilisation in leukaemia patients
In a compassionate use programme, PLEDITEX 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, [PRODUCT NAME] may cause mobilisation of leukaemic cells and subsequent contamination of the apheresis product. Therefore, PLEDITEX is not recommended for haematopoietic stem cell mobilisation and harvest in patients with leukaemia.
Hematologic effects
Leukocytosis: Administration of PLEDITEX in conjunction with G-CSF increases circulating leukocytes as well as HSC populations. White blood cell counts should be monitored during PLEDITEX use. Clinical judgment should be exercised when administering PLEDITEX to patients with peripheral blood neutrophil counts above 50 000 cells/u03bcl.
Thrombocytopenia: Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving [PRODUCT NAME]. Platelet counts should be monitored in all patients who receive PLEDITEX and then undergo apheresis.
Potential for tumour cell mobilisation in lymphoma and multiple myeloma patients
When PLEDITEX is used in conjunction with G-CSF for HSC mobilisation in patients with lymphoma or MM, tumour cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumour cells has not been well-studied.
Systemic reactions
In PLEDITEX oncology clinical studies, less than 1 % of patients experienced mild or moderate systemic reactions within approximately 30 minutes after PLEDITEX administration. Events included one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnoea (n = 1) or hypoxia (n = 1). Symptoms generally 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 SC injections. In PLEDITEX oncology and healthy volunteer clinical studies, less than 1 % of subjects experienced vasovagal reactions (orthostatic hypotension and/or syncope) following SC administration of PLEDITEX doses u2264 0,24 mg/kg. The majority of these events occurred within 1 hour of PLEDITEX administration. Appropriate precautions should be taken because of the potential for these reactions.
Potential effect on spleen size
Higher absolute and relative spleen weights associated with extramedullary haematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4 fold higher than the recommended human dose. The effect of PLEDITEX on spleen size in patients has not been specifically evaluated in clinical studies. The possibility that PLEDITEX in conjunction with the growth factor G-CSF can cause splenic enlargement cannot be excluded.
Due to the rare occurrence of splenic rupture following G-CSF administration, individuals receiving PLEDITEX in conjunction with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity.
Useful laboratory tests for monitoring patients
White blood cell and platelet counts should be monitored during PLEDITEX use and apheresis. PLEDITEX has not been shown to interfere with any routine clinical laboratory tests. This medicinal product contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per effervescent tablet, that is to say essentially u2018sodium-freeu2019.

Based on In vitro studies done 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-Hodgkinu2019s lymphoma, the addition of rituximab to a mobilisation regimen of PLEDITEX and G-CSF did not impact patient safety or CD34+ cell yield.

Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment.
Pregnancy
PLEDITEX is contraindicated during pregnancy. (see section 4.3) PLEDITEX may cause foetal harm when administered to a pregnant woman. Studies in animals have shown teratogenicity. There are no adequate and well-controlled studies in pregnant women using [PRODUCT NAME]. If the patient becomes pregnant while taking [PRODUCT NAME], the patient should be informed of the potential hazard to the foetus.
Lactation
It is not known whether plerixafor is excreted in human milk. Patients should not breastfeed their baby whilst on treatment with [PRODUCT NAME]. (see section 4.3).
Fertility
The effects of PLEDITEX on male and female fertility are not known (see section 5.3).

PLEDITEX 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.

a. Tabulated list of adverse reactions
Table 1
MedDRA System Organ Class Frequency MedDRA preferred term
Blood and lymphatic system disorders Frequency unknown Splenomegaly, splenic rupture
Immune system disorders Less frequent Allergic reaction Anaphylactic reactions, including anaphylactic
Psychiatric disorders Frequent Insomnia Less frequent Abnormal dreams, nightmares, anticipatory anxiety, anxiety
Nervous system disorders Frequent Dizziness, headache Less frequent Dysgeusia
Gastrointestinal disorders Frequent Diarrhoea, nausea Frequent Vomiting, abdominal pain, stomach discomfort, dyspepsia, abdominal distention, constipation, flatulence, hypoaesthesia oral, dry mouth Less frequent Abdominal discomfort, eructation, retching, stomatitis
Skin and subcutaneous tissue disorders Frequent Hyperhidrosis, erythema Less frequent Cold sweat, ecchymosis, hypoaesthesia facial, night sweats, urticaria, urticaria localised
Musculoskeletal, connective tissue and bone disorders Frequent Arthralgia, musculoskeletal pain Less frequent Muscular weakness, musculoskeletal stiffness, neck pain
General disorders and administration site conditions Frequent Injection and infusion site reactions Frequent Fatigue, malaise Less frequent Asthenia, influenza like illness, irritability
Cardiac disorders Less frequent Extrasystoles
Ear and labyrinth disorders Less frequent Vertigo
Eye disorders Less frequent Eye swelling
Injury, poisoning and procedural complications Less frequent Procedural hypertension, procedural nausea
Investigations Less frequent Aspartate aminotransferase increased
Metabolism and nutrition disorders Less frequent Decreased appetite, hypocalcaemia, hyponatraemia, hypophosphataemia
Renal and urinary disorders Less frequent Pollakiuria
Respiratory, thoracic and mediastinal disorders Less frequent Sinus congestion
Vascular disorders Less frequent Flushing, hot flush, hypotension
The adverse reactions reported in patients with lymphoma and multiple myeloma who received PLEDITEX in the conducted controlled Phase III studies and uncontrolled studies, including a Phase II study of PLEDITEX 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.
c. Description of selected adverse reactions
Myocardial infarction
Based on conducted clinical studies, 7 of 679 oncology patients experienced myocardial infarctions after haematopoietic stem cell mobilisation with PLEDITEX and G-CSF. All events occurred at least 14 days after last PLEDITEX administration. Additionally, two female oncology patients in the compassionate use programme experienced myocardial infarction following haematopoietic stem cell mobilisation with PLEDITEX and G-CSF. One of these events occurred 4 days after last PLEDITEX administration. Lack of temporal relationship in 8 of 9 patients coupled with the risk profile of patients with myocardial infarction does not suggest PLEDITEX confers an independent risk for myocardial infarction 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 of apheresis, in 7 % patients receiving PLEDITEX and in 1 % patients receiving placebo in the Phase III studies. No complications or clinical symptoms of leukostasis were observed.
Vasovagal reactions
Based on PLEDITEX conducted 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 u2264 0,24 mg/kg. The majority of these events occurred within 1 hour of PLEDITEX administration.
Gastrointestinal disorders
Based on PLEDITEX conducted clinical studies of oncology patients, there have been rare reports of severe gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.
Paraesthesia
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 PLEDITEX and placebo groups, respectively.
Elderly patients
Based on the two placebo-controlled conducted clinical studies of [PRODUCT NAME], 24 % of patients were u2265 65 years old. No notable differences in the incidence of adverse reactions were observed in these elderly patients when compared with younger ones.
Reporting of suspected adverse reactions
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 to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019. Found under SAHPRAu2019s publications: https://www/sahpra.org.za/Publications/Index/8.

Symptoms
Based on limited data at doses above the recommended dose of 0,24 mg/kg SC and up to 0,48 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.
Treatment
Treatment is symptomatic and supportive.