Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
APPROVED PROFESSIONAL INFORMATION FOR HETERIX 24  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
HETERIX 24 (Solution for injection)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL).  
Each mL solution for injection contains approximately 5 mg sodium.  
No excipient with known pharmacological effect.  
For full list of excipients, see section 6.1.  
HETERIX 24 is sugar free  
3 PHARMACEUTICAL FORM  
HETERIX 24 is a sterile, clear, colourless to pale yellow, isotonic solution, free from visible  
particles.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
HETERIX 24 is indicated to enhance mobilisation of hematopoietic stem cells (HSCs) to the  
peripheral blood for collection and subsequent autologous transplantation in patients with  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
lymphoma and multiple myeloma (MM).  
4.2 Posology and method of administration  
HETERIX 24 should be administered by a nurse, medical practitioner, or other healthcare  
professional.  
The recommended dose of HETERIX 24 is 0,24 mg/kg body weight by subcutaneous injection.  
HETERIX 24 should be administered 6 to 11 hours prior to initiation of apheresis following 4 days  
of treatment with G-CSF.  
HETERIX 24 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 patient’s actual body weight will be used to calculate the volume of HETERIX 24 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 patient’s actual body weight (in kg) = dose to be administered (in mL).  
In clinical studies, HETERIX 24 dose has been calculated based on actual body weight in patients  
up to 175 % of ideal body weight. HETERIX 24 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 HETERIX 24 should be obtained within 1 week of the  
first dose of HETERIX 24.  
Patients with renal impairment  
Patients with moderate and severe renal insufficiency (creatinine clearance (CrCL) ≤ 50 mL/min)  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
should have their dose of HETERIX 24 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.  
Method of administration  
The recommended dose of HETERIX 24 is 0,24 mg/kg body weight by subcutaneous injection.  
4.3 Contraindications  
•
Hypersensitivity to any of the ingredients of HETERIX 24, including the excipients (see Section  
6.1).  
•
Pregnancy and lactation (see Section 4.6).  
4.4 Special warnings and precautions for use  
HETERIX 24 contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free’.  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
Tumour cell mobilisation in leukaemia patients  
HETERIX 24 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 HSC mobilisation, plerixafor may cause  
mobilisation of leukemic cells and subsequent contamination of the apheresis product. Therefore,  
HETERIX 24 is not intended for HSC mobilisation and harvest in patients with leukaemia.  
Hematologic effects  
Leukocytosis:  
Administration of plerixafor in conjunction with G-CSF increases circulating leukocytes as well as  
HSC populations. White blood cell counts should be monitored during HETERIX 24 use. Clinical  
judgment should be exercised when administering HETERIX 24 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 plerixafor. Platelet counts should be monitored in all patients who receive HETERIX 24  
and then undergo apheresis.  
Potential for tumour cell mobilisation in lymphoma and multiple myeloma patients  
When HETERIX 24 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. In clinical studies of patients with non-Hodgkin’s lymphoma (NHL) and MM, mobilisation of  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
tumour cells has not been observed with plerixafor.  
Systemic reactions  
In plerixafor oncology clinical studies, less than 1 % of patients experienced mild or moderate  
systemic reactions within approximately 30 minutes after plerixafor administration. Events included  
one or more of the following: urticaria, periorbital swelling, dyspnoea or hypoxia. 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  
plerixafor oncology and healthy volunteer clinical studies, less than 1 % of subjects experienced  
vasovagal reactions (orthostatic hypotension and/or syncope) following SC administration of  
HETERIX 24 doses ≤ 0,24 mg/kg. The majority of these events occurred within 1 hour of plerixafor  
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 HETERIX 24 on  
spleen size in patients has not been specifically evaluated in clinical studies. The possibility that  
HETERIX 24 in conjunction with the growth factor G-CSF can cause splenic enlargement cannot  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
be excluded. Due to the rare occurrence of splenic rupture following G-CSF administration,  
individuals receiving HETERIX 24 in conjunction with G-CSF who report left upper abdominal pain  
and/or scapular or shoulder pain should be evaluated for splenic integrity.  
Paediatric population  
The safety and efficacy of HETERIX 24 in paediatric patients have not been established in  
controlled clinical studies.  
Use in elderly  
In the two placebo-controlled clinical studies of plerixafor, 24 % of patients were ≥ 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 HETERIX 24, 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 ≤ 50  
ml/min is recommended (see Section 4.2).  
Renal impairment  
Dosage adjustment in patients with CrCL ≤ 50 mL/min is recommended (see Section 4.2).  
Useful laboratory tests for monitoring patients  
White blood cell and platelet counts should be monitored during HETERIX 24 use and apheresis.  
Plerixafor has not been shown to interfere with any routine clinical laboratory tests.  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
4.5 Interaction with other medicines and other forms of interaction  
Based on in vitro studies, plerixafor is not a substrate, inhibitor, or inducer of human cytochrome  
P450 enzymes. Formal medicine interaction studies have not been conducted (see Section 5.2). In  
clinical studies of patients with NHL, the addition of rituximab to a mobilisation regimen of  
HETERIX 24 and G-CSF did not impact patient safety or CD34+ cell yield.  
Food  
HETERIX 24 is not a substrate, an inducer or an inhibitor of cytochrome P450 (CYP450) enzymes  
(see Section 5.2). Therefore CYP450 mediated medicine-food interactions are unlikely to occur  
with HETERIX 24.  
Paediatric population  
Interaction studies have only been performed in adults.  
4.6 Fertility, pregnancy and lactation  
Safety and efficacy of HETERIX 24 in pregnancy and lactation has not been established.  
Women of childbearing potential  
Women of childbearing potential must be advised to use effective contraception during treatment  
(see Section 4.3).  
Pregnancy  
HETERIX 24 may cause foetal harm when administered to a pregnant woman. Studies with  
plerixafor in animals have shown teratogenicity. There are no adequate and well-controlled studies  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
in pregnant women using plerixafor. If HETERIX 24 is used during pregnancy, or if the patient  
becomes pregnant while taking HETERIX 24, the patient should be informed of the potential  
hazard to the foetus.  
Breastfeeding  
It is not known whether HETERIX 24 is excreted in human breast milk. Patients should be advised  
not to breastfeed the baby whilst on treatment with HETERIX 24.  
4.7 Effects on ability to drive and use machines  
HETERIX 24 may cause side effects such as dizziness, fatigue or vasovagal reactions. Patients  
should be advised not to drive or operate machines until it is established that their ability to perform  
such activities is not affected.  
4.8 Undesirable effects  
a. Summary of the safety profile  
In the two Phase 3 studies in patients with NHL and MM (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 solution for injection or placebo and  
on each morning prior to apheresis. Adverse events that occurred more frequently with plerixafor  
solution for injection than placebo and were reported as related in ≥ 1 % of the patients who  
received plerixafor solution for injection during HSC mobilisation and apheresis and prior to  
chemotherapy/ablative treatment in preparation for transplantation are shown below. From  
chemotherapy/ablative treatment in preparation of transplantation through 12 months post-  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
transplantation, no notable differences in the incidence of adverse events were observed across  
treatment groups.  
b. Tabulated list of adverse reactions  
Blood and lymphatic system disorders  
Frequency unknown:  
Immune system disorders  
Frequency unknown: Anaphylactic reactions, systemic reactions including urticaria, periorbital  
swelling, dyspnoea, hypoxia  
Metabolism and nutrition disorders  
Splenomegaly, splenic rupture  
Less frequent:  
Psychiatric disorders  
Frequent:  
Decreased appetite, hypocalcaemia, hyponatraemia, hypophosphataemia  
Insomnia  
Less frequent:  
Anticipatory anxiety, anxiety, nightmares  
Nervous system disorders  
Frequent:  
Headache, dizziness  
Less frequent:  
Frequency unknown:  
Eye disorders  
Less frequent:  
Dysgeusia  
Vasovagal reactions  
Eye swelling  
Ear and labyrinth disorders  
Less frequent:  
Vertigo  
Cardiac disorders  
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Product proprietary name: HETERIX 24  
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Frequency unknown:  
Vascular disorders  
Less frequent:  
Extrasystoles, myocardial infarction  
Flushing, hot flush, hypotension  
Respiratory, thoracic and mediastinal disorders  
Less frequent: Sinus congestion  
Gastrointestinal disorders  
Frequent:  
Diarrhoea, nausea, flatulence, abdominal pain, vomiting, abdominal  
distension, dry mouth, stomach discomfort, constipation, dyspepsia,  
hypoaesthesia oral  
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 and connective tissue disorders  
Frequent:  
Arthralgia, musculoskeletal pain  
Less frequent:  
Muscular weakness, musculoskeletal stiffness, neck pain  
Renal and urinary disorders  
Less frequent:  
Pollakiuria  
General disorders and administrative site conditions  
Frequent:  
Injection site reactions, fatigue, malaise  
Asthenia, influenza like illness, irritability  
Less frequent:  
Investigations  
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Product proprietary name: HETERIX 24  
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Less frequent:  
Increased aspartate aminotransferase  
Surgical and medical procedures  
Frequent:  
Procedural hypertension, procedural nausea  
c. Description of selected adverse 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 HETERIX 24 on  
spleen size in patients has not been specifically evaluated in clinical studies. The possibility that  
HETERIX 24 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 HETERIX 24 in conjunction with G-CSF who report left upper abdominal pain  
and/or scapular or shoulder pain should be evaluated for splenic integrity.  
Myocardial infarction  
In clinical studies, 7 of 679 oncology patients experienced myocardial infarctions after HSC  
mobilisation with plerixafor and G-CSF. All events occurred at least 14 days after last plerixafor  
administration. Additionally, two female oncology patients in the compassionate use program  
experienced myocardial infarctions following HSC mobilisation with 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 risk profile of patients with myocardial infarction does not suggest  
plerixafor confers an independent risk for myocardial infarction in patients who also receive G-  
CSF.  
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Product proprietary name: HETERIX 24  
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Gastrointestinal disorders  
In plerixafor clinical studies of oncology patients, there have been rare reports of severe  
gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.  
Paraesthesias  
Paraesthesias are commonly observed in oncology patients undergoing autologous transplantation  
following multiple disease interventions. In the placebo-controlled Phase 3 studies, the incidence of  
paraesthesias was 20,6 % and 21,2 % in the plerixafor and placebo groups, respectively.  
e. Other special populations  
Gender/age  
There was no apparent difference in the safety profile of plerixafor with respect to gender and age.  
Post marketing surveillance  
Not applicable  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows  
continued monitoring of the risk/benefit ratio of the medicine. Healthcare providers are asked to  
report any suspected adverse reactions to SAHPRA via ‘6.04 Adverse Drug Reaction reporting  
Form’  
available  
online  
under  
SAHPRA’s  
publications  
at  
https://www.sahpra.org.za/publications/Index/8/ or to the Holder of Certificate of Registration  
through the mail, pvg.cdma@heterodrugs.com. By reporting adverse reactions you can help  
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Product proprietary name: HETERIX 24  
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provide more information on the safety of HETERIX 24.  
4.9 Overdose  
Based on limited data at doses above the recommended dose of 0,24 mg/kg subcutaneous and up  
to 0,48 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic  
hypotension, and/or syncope may be higher. Treatment is symptomatic and supportive.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
A 32.2 Other substances (immunostimulant)  
Mechanism of action  
Plerixafor is a selective antagonist of the CXCR4 chemokine receptor and blocks binding of its  
cognate ligand, stromal cell-derived factor-1α (SDF-1α), also known as CXCL12. SDF-1α and  
CXCR4 are recognized to play key regulatory roles in the trafficking and homing of human  
hematopoietic stem cells (HSCs) to the marrow compartment. Stem cells express CXCR4 and are  
known to migrate to the bone marrow through a chemo-attractant effect of SDF-1α that is produced  
locally by bone marrow stromal cells. Once in the marrow, it is postulated that stem cell CXCR4  
can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the  
induction of other adhesion molecules. Plerixafor-induced leukocytosis and elevations in circulating  
hematopoietic 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  
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repopulating capacity.  
Pharmacodynamics:  
Fold increase in peripheral blood CD34+ cell count (cells/µL) by apheresis day was evaluated in  
two placebo-controlled clinical studies in patients with lymphoma and multiple myeloma  
(AMD3100-3101 and AMD3100-3102, respectively). Fold increase over the 24-hour period from  
the day prior to the first apheresis to just before the first apheresis is summarised in Table 1.  
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 1: Fold increase in peripheral blood CD34+ cell count following plerixafor  
administration  
Plerixafor and G-CSF  
Placebo and G-CSF  
Study  
Median  
5,0  
Mean (SD)  
Median  
1,4  
Mean (SD)  
AMD3100-3101  
AMD3100-3102  
6,2 (5,4)  
6,4 (6,8)  
1,9 (1,5)  
2,4 (7,3)  
4,8  
1,7  
In pharmacodynamic studies in healthy volunteers of plerixafor, 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, 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. A study in healthy volunteers at single doses of 0,24 and 0,40 mg/kg  
showed that plerixafor had no effects on QT interval, heart rate, PR interval, QRS interval duration,  
or ECG morphology.  
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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 SC injection with peak concentrations reached in  
approximately 30 – 60 minutes.  
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 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 interactions.  
Elimination  
The major route of elimination of plerixafor is urinary. Following a 0,24 mg/kg dose in healthy  
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volunteers with normal renal function, approximately 70 % of the dose was excreted in the urine as  
the parent drug during the first 24 hours following administration. The half-life in plasma is 3 – 5  
hours.  
Renal impairment  
Following a single 0,24 mg/kg dose of plerixafor clearance was reduced in subjects with varying  
degrees of renal dysfunction and was positively correlated with CrCL. Mean values of AUC0-24 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 x h/mL, respectively,  
which were higher than the exposure observed in healthy patients with normal renal function (5070  
ng x h/mL). Renal impairment had no effect on Cmax (see Section 4.2).  
Gender  
A population pharmacokinetic analysis showed no effect of gender on plerixafor pharmacokinetics.  
Age  
A population pharmacokinetic analysis showed no effect of age on plerixafor pharmacokinetics.  
Paediatric population  
No pharmacokinetic studies were done on the paediatric population for plerixafor.  
5.3 Preclinical safety data  
Not applicable  
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Environmental Risk Assessment  
Not applicable  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
Hydrochloric acid  
Sodium chloride  
Sodium hydroxide  
Water for injection  
6.2 Incompatibilities  
In the absence of compatibility studies, HETERIX 24 should not be mixed with other medicinal  
products in the same injection.  
6.3 Shelf life  
36 months  
6.4 Special precautions for storage  
•
•
•
•
Store at or below 25 °C.  
Keep the vial in the outer carton until required for use.  
For single use only. Discard any unused portion.  
From a microbiological point of view, once drawn into a syringe, 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.  
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Product proprietary name: HETERIX 24  
Dosage form and strength: Solution for injection; Each 1,2 mL vial contains 24,0 mg plerixafor (20 mg/mL)  
•
Do not refrigerate.  
6.5 Nature and contents of the container  
2 mL clear tubular, Type 1 glass vials with grey coloured rubber stopper and a rust coloured plastic  
flip off aluminium seal.  
Pack size is 1 vial. Each vial is packed in an outer carton box.  
6.6 Special precautions for disposal and other handling  
No special requirements  
7 HOLDER OF CERTIFICAE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus, Building 2, First Floor  
74 Waterfall Drive  
Midrand, 2066  
8 REGISTRATION NUMBER(S)  
51/32.2/0297  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION  
06 October 2020  
10 DATE OF REVISION OF THE TEXT  
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