Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
FINAL PROFESSIONAL INFORMATION FOR FALOXERAN  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
FALOXERAN 50 mg/ vial (Powder for solution for injection/infusion)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan.  
Contains “no sugar”  
‘For full list of excipients, see section 6.1’.  
3 PHARMACEUTICAL FORM  
White to off-white freeze-dried powder or cake in a clear glass vial.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
FALOXERAN, at conventional intravenous dosage, may be used in the  
treatment of:  
Multiple myeloma: FALOXERAN, either alone or in combination with other cytotoxic medicines.  
Ovarian cancer: FALOXERAN, either alone or in combination with other cytotoxic medicines.  
FALOXERAN, at high intravenous dosage, may be used in the treatment of:  
Multiple myeloma: With or without autologous bone marrow rescue, either as first line treatment or to consolidate  
a response to conventional cytoreductive chemotherapy.  
25 June 2024  
Initial…MU…….  
Page 1 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Neuroblastoma in childhood: High-dose FALOXERAN with autologous bone marrow rescue has been used  
either alone or combined with radiotherapy and/or other cytotoxic medicines, to consolidate a response to  
conventional treatment.  
4.2 Posology and method of administration  
General  
FALOXERAN is a cytotoxic medicine, which falls into the general class of alkylating medicines. It should be  
prescribed only by medical practitioners experienced in the management of malignant disease with such  
medicines.  
Since FALOXERAN is myelosuppressive, frequent blood counts are essential during therapy and the dosage  
should be adjusted if necessary (see section 4.4).  
Posology  
Multiple myeloma  
FALOXERAN has been used on an intermittent basis alone, or in combination with other cytotoxic medicines, at  
doses varying between 8 mg/m2 body surface area and 30 mg/m2 body surface area, given at intervals of  
between 2 to 6 weeks. The literature should be consulted for details.  
When used as a single medicine, a typical intravenous dosage schedule is 0,4 mg/kg body mass (16 mg/m2  
body surface area) repeated at appropriate intervals (e.g., once every 4 weeks), provided there has been  
recovery of the peripheral blood count during this period.  
High-dose regimens generally employ single intravenous doses of between 100 mg/m2 and 200 mg/m2 body  
surface area (approximately 2,5 mg/kg to 5,0 mg/kg body mass), but autologous bone marrow rescue becomes  
essential following doses in excess of 140 mg/m2 body surface area. In cases of renal impairment, the dose  
should be reduced by fifty percent. In view of the severe myelosuppression induced by high-dose FALOXERAN,  
25 June 2024  
Initial…MU…….  
Page 2 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
treatment should be confined to specialist centers, with the appropriate facilities, and only be administered by  
experienced medical practitioners (see section 4.4).  
Advanced ovarian adenocarcinoma  
When used intravenously as a single medicine, a dose of 1 mg/kg body mass (approximately 40 mg/m2 body  
surface area) given at intervals of 4 weeks has often been used.  
When combined with other cytotoxic medicines, intravenous doses of between 0,3 mg/kg and 0,4 mg/kg body  
mass (12 mg/m2 to 16 mg/m2 body surface area) have been used at intervals of 4 to 6 weeks.  
Advanced malignant melanoma  
Hyperthermic regional perfusion with FALOXERAN has been used as palliative treatment for advanced but  
localised disease. The scientific literature should be consulted for details of perfusion technique and dosage  
used.  
Advanced neuroblastoma  
Doses of between 100 and 240 mg/m2 body surface area (sometimes divided equally over 3 consecutive days)  
together with autologous bone marrow rescue, have been used either alone or in combination with radiotherapy  
and/or other cytotoxic medicines.  
Special populations  
Use in the elderly  
Although FALOXERAN is frequently used at conventional dosage in the elderly, there is no specific information  
available relating to its administration to this patient sub-group.  
Experience in the use of high-dose FALOXERAN in elderly patients is limited.  
Consideration should therefore be given to ensure adequate performance status and organ function before using  
high-dose FALOXERAN in elderly patients.  
25 June 2024  
Initial…MU…….  
Page 3 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Dosage in renal impairment  
FALOXERAN clearance, though variable, is decreased in renal impairment. When FALOXERAN is used at  
conventional intravenous dosage (8 mg/m2 to 40 mg/m2 body surface area), it is recommended that the initial  
dose should be reduced by 50 % in patients with moderate to severe renal impairment and subsequent dosage  
determined according to the degree of hematological suppression.  
For high intravenous doses of FALOXERAN (100 mg/m2 to 240 mg/m2), the need for dose reduction depends  
upon the degree of renal impairment, whether autologous bone marrow stem cells are reinfused, and therapeutic  
need. As a guide, for moderate to severe impairment (EDTA clearance 30 ml/min to 50 ml/min) a dose reduction  
of 50 % is usual. Adequate hydration and forced diuresis are also necessary. High-dose FALOXERAN is not  
recommended in patients with more severe renal impairment.  
Use in Children  
High-dose FALOXERAN, in association with bone marrow rescue, has been administered to children and  
dosage guidelines based on body surface area, as for adults, may be used.  
Method of administration  
Parenteral administration  
Except in cases where regional arterial perfusion is indicated, FALOXERAN is for intravenous use only.  
It is recommended that FALOXERAN is injected slowly into a fast-running infusion solution via a swabbed  
injection port.  
If direct injection into a fast-running infusion is not appropriate, FALOXERAN may be administered diluted in an  
infusion bag.  
When further diluted in an infusion solution, FALOXERAN had reduced stability and the rate of degradation  
increases rapidly with increasing temperature.  
If FALOXERAN is infused at a room temperature of approximately 25 °C, the total time from preparation of the  
25 June 2024  
Initial…MU…….  
Page 4 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Injection solution to the completion of infusion should not exceed 1,5 hours.  
Should any visible turbidity or crystallization appear in the reconstituted or diluted solutions the preparation must  
be discarded.  
Care should be taken to avoid possible extravasation of FALOXERAN and in cases of poor peripheral venous  
access, consideration should be given to use of a central venous line.  
If high-dose FALOXERAN is administered with or without autologous bone marrow transplantation,  
administration via a central venous line is recommended.  
For regional arterial perfusion, the literature should be consulted for detailed methodology.  
4.3 Contraindications  
•
•
Hypersensitivity to the melphalan or to any of the excipients listed in section 6.1.  
FALOXERAN should not be given to patients who have suffered a previous allergic reaction to  
melphalan.  
•
•
•
•
Severe myelosuppression (leukocytes < 2000 / mm3, thrombocytes <50,000 / mm3).  
Pregnancy  
Breastfeeding (see section 4.6)  
Immunisation with live attenuated organism vaccines.  
4.4 Special warnings and precautions for use  
FALOXERAN IS AN ACTIVE CYTOTOXIC MEDICINE FOR USE ONLY UNDER THE DIRECTION OF  
MEDICAL PRACTITIONERS EXPERIENCED IN THE ADMINISTRATION OF SUCH MEDICINES.  
Precautions should be taken to prevent tumour lysis syndrome.  
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts.  
Therefore, immunisations with live organism vaccines are contraindicated (see section 4.3).  
25 June 2024  
Initial…MU…….  
Page 5 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
FALOXERAN solution can cause local tissue damage should extravasation occur and consequently it should not  
be administered by direct injection into a peripheral vein. It is recommended that FALOXERAN is administered  
by injecting slowly into a fast-running intravenous infusion via a swabbed injection port, or via a central venous  
line.  
In view of the hazards involved and the level of supportive care required, the administration of high dose  
FALOXERAN should be confined to specialist centres, with the appropriate facilities and only be conducted by  
experienced medical practitioners.  
In patients receiving high dose FALOXERAN, consideration should be given to the prophylactic administration of  
anti-infective medicines, the administration of blood products as required and the maintenance of a high renal  
output during the period immediately following the administration of FALOXERAN by the use of hydration and  
forced diuresis.  
Consideration should be given to ensure adequate performance status and organ function before using high  
dose FALOXERAN in elderly patients.  
FALOXERAN should not be given without haematopoietic stem cell rescue at doses of above140 mg/m2.  
Cyclophosphamide pretreatment has been shown to reduce the severity of the gastrointestinal damage induced  
by high-dose FALOXERAN; the literature should be consulted for details.  
Monitoring  
Since FALOXERAN is a potent myelosuppressive medicine, it is essential that careful attention should be paid to  
the monitoring of blood counts, to avoid the possibility of excessive myelosuppression and the risk of irreversible  
bone marrow aplasia.  
Blood counts may continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in  
leukocyte or platelet counts, treatment should be temporarily interrupted.  
25 June 2024  
Initial…MU…….  
Page 6 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
FALOXERAN should be used with caution in patients who have undergone recent radiotherapy or chemotherapy  
in view of increased bone marrow toxicity.  
Renal Impairment  
Impaired renal function has been described in bone marrow transplant patients who were preconditioned with  
high dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host  
disease.  
Melphalan clearance may be reduced in patients with renal impairment who may also have uraemic marrow  
suppression. Dose reduction may therefore be necessary (see Section 4.2). See section 4.8 for elevation of  
blood urea. In patients with renal impairment who are treated with melphalan a 50 mg i.v blood urea levels may  
be transiently elevated and may cause bone marrow suppression. Therefore, blood urea levels should be  
carefully monitored in these patients.  
Mutagenicity  
FALOXERAN is mutagenic in animals and chromosome aberrations have been observed in patients being  
treated with the medicine.  
Carcinogenicity (secondary primary malignancy)  
Acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS)  
Melphalan can cause leukemia especially in elderly patients after long combination therapy and radiation  
therapy.  
Before starting the treatment, the leukemogenic risk (AML and MDS) should be weighed against the possible  
therapeutic benefit when the use of melphalan in combination with thalidomide or lenalidomide and prednisone is  
considered, as it has been demonstrated that these combinations lead to an elevated leukemic risk.  
Before and during the treatment, the medical practitioners must therefore carefully examine the patients in the  
context of the usual measurement procedures for early cancer detection and, if necessary, initiate therapy.  
25 June 2024  
Initial…MU…….  
Page 7 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
In patients with ovarian carcinoma who were treated with alkylating medicines including melphalan, acute  
leukemia significantly increased with respect to a treatment group that did not receive such medicines.  
Solid tumors  
The use of alkylating medicines has been implicated in the development of secondary primary malignancies  
(SPM). In particular, melphalan in combination with lenalidomide and prednisone and, to a lesser extent,  
thalidomide and prednisone are associated with an increased risk of solid SPM in elderly patients with newly  
diagnosed multiple myeloma.  
The characteristics of the patient (e.g., age, ethnicity), primary indication and treatment modalities (e.g., radiation  
therapy, transplantation) as well as environmental risk factors (e.g., tobacco use) should be assessed prior to the  
administration of melphalan.  
Contraception  
Adequate contraceptive precautions should be advised when either partner is receiving FALOXERAN and for at  
least a year after cessation of treatment. Due to the increased risk of venous thromboembolism in patients with  
multiple myeloma, combination oral contraceptives are not recommended. If a patient is currently taking a  
combination oral contraceptive, she should switch to another reliable contraceptive method. The risk of venous  
thromboembolism persists for 4-6 weeks after discontinuation of a combined oral contraceptive. For males  
treated with melphalan 50 mg i.v. it is recommended to avoid conception during treatment with melphalan and up  
to 6 months thereafter, and be counseled as to sperm conservation prior to initiation of therapy due to the  
possibility of therapy induced irreversible infertility.  
4.5 Interaction with other medicines and other forms of interaction  
Vaccinations with live organism vaccines are contraindicated in immunocompromised individuals (see sections  
4.3 and 4.4).  
Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic  
enterocolitis.  
25 June 2024  
Initial…MU…….  
Page 8 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
In children and adolescents, treated with busulfan-melphalan regimen, there were reports that the administration  
of melphalan may have an influence on the development of toxicities within 24 hours after the last oral  
administration of busulfan.  
Impaired renal function has been described in bone marrow transplant patients who received high-dose  
intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.  
4.6 Fertility, pregnancy and lactation  
Women of childbearing potential / Contraception in males and females  
Appropriate contraceptive measures must be taken when one of the partners receive FALOXERAN. If pregnancy  
occurs during treatment, the possibility of genetic counseling should be used.  
Pregnancy  
The use of FALOXERAN is contraindicated during pregnancy (see section 4.3)  
Teratogenicity:  
The teratogenic potential of FALOXERAN has not been studied. In view of its Mutagenic properties and  
structural similarity to known teratogenic compounds, melphalan could cause congenital defects in the offspring  
of patients treated with the medicine.  
Breastfeeding  
Mothers receiving FALOXERAN should not breastfeed.  
Fertility  
FALOXERAN causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a  
significant number of patients. Melphalan has a mutagenic effect in animal models; in patients treated with the  
medicine, chromosomal aberrations were observed. Therefore, men treated are advised not to produce a child  
25 June 2024  
Initial…MU…….  
Page 9 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
during treatment with melphalan and up to 6 months afterwards, and to consult a sperm reserve before the start  
of treatment because of the possibility of an irreversible infertility caused by the treatment.  
There is evidence from some animal studies that melphalan can have an undesirable effect on spermatogenesis.  
Therefore, it is possible that FALOXERAN may cause temporary or permanent sterility in male patients.  
4.7 Effects on ability to drive and use machines  
Melphalan has no or negligible influence on the ability to drive and use machines.  
Patients should not drive, use machinery or perform any tasks that require concentration until they are certain  
that FALOXERAN does not adversely affect their ability to do so safely (see section 4.8).  
4.8 Undesirable effects  
Tabulated summary of adverse reactions  
SYSTEM ORGAN CLASS  
FREQUENCY  
Frequent  
ADVERSE REACTION  
Neoplasms benign,  
malignant and unspecified  
(including cysts and  
polyps)  
Acute leukemia  
Frequency unknown  
Acute Myeloid Leukaemia (AML) and  
myelodysplastic syndromes (MDS)  
Blood and lymphatic  
system disorders  
Frequent  
Bone marrow depression, which  
manifests as leukocytopenia,  
thrombocytopenia and anaemia.  
Less frequent  
Less frequent  
Less frequent  
Hemolytic anaemia  
Allergic reactions  
Immune system disorders  
Respiratory, thoracic and  
mediastinal disorders  
Interstitial pneumonia and pulmonary  
fibrosis (including fatal cases).  
25 June 2024  
Initial…MU…….  
Page 10 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Gastrointestinal disorders  
Hepato-biliary disorders  
Frequent  
Nausea, diarrhoea and vomiting,  
stomatitis at high doses.  
Less frequent  
Less frequent  
Stomatitis with conventional dose.  
Hepatic impairment from pathological liver  
function to clinical manifestations such as  
hepatitis and jaundice; liver vein  
occlusions after high-dose therapy.  
Skin and subcutaneous  
tissue disorders  
Frequent  
Hair loss with high dose, hair loss at  
conventional dose  
Less frequent  
Frequent  
Maculopapular exanthemia and itching  
(see also immune system disorders).  
Musculoskeletal and  
connective tissue disorders  
(After parenteral  
Muscular atrophy, muscle fibrosis,  
myalgia, increase in creatinine  
phosphokinase in the blood,  
Compartment Syndrome  
administration for regional  
perfusion of the  
Frequency unknown  
Frequent  
Muscle necrosis, rhabdomyolysis.  
extremities)  
Renal and urinary  
disorders  
Transient, markedly increased blood urea  
levels under a melphalan treatment during  
the first cycles of patients with renal  
impairment with multiple myeloma.  
Reproductive system and  
breast disorders  
Frequent  
Azoospermia and Amenorrhoea (see  
section 4.4)  
25 June 2024  
Initial…MU…….  
Page 11 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Vascular disorders  
Frequency unknown  
Frequent  
Deep vein thrombosis, pulmonary  
embolus  
General disorders and  
administration site  
conditions  
Subjective and transient heat sensation  
and / or tingling after administration of  
high doses of melphalan via a central  
venous catheter.  
Description of selected adverse reactions  
Allergic reactions  
Allergic reactions of FALOXERAN such as urticaria, oedema, skin rashes and anaphylaxis have been  
reported following initial or subsequent dosing, particularly after intravenous administration in patients who  
were treated over several months. Cardiac arrest has occurred in association with such events.  
Gastrointestinal disorders  
The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high  
i.v. doses of FALOXERAN in association with haemopoietic stem cell rescue. Cyclophosphamide pre-  
treatment has been shown to reduce the severity of the gastrointestinal damage induced by high-dose  
FALOXERAN; the literature should be consulted for details.  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of FALOXERAN is important. It allows continued  
monitoring of the benefit/risk balance of the FALOXERAN. Healthcare professionals are asked to report any  
suspected adverse to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug  
Reactions  
Reporting  
Form”,  
found  
online  
under  
SAHPRA’s  
publications:  
https://www.sahpra.org.za/publications/Index/8 or to the Holder of certificate of registration through the mail:  
pvg.cdma@heterogroups.com  
25 June 2024  
Initial…MU…….  
Page 12 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
4.9 Overdose  
Symptoms  
The immediate effects of acute intravenous overdosage are nausea and vomiting. Damage to the  
gastrointestinal mucosa may also ensue, and diarrhoea, sometimes haemorrhagic, has been reported after  
overdosage. The principal toxic effect is bone marrow suppression, leading to leucopaenia, thrombocytopaenia  
and anaemia.  
Treatment  
General supportive measures, together with appropriate blood transfusion, should be instituted if necessary.  
There is no specific antidote. The blood picture should be closely monitored for at least four weeks following  
overdosage until there is evidence of recovery and consideration given to hospitalisation, antibiotic cover, and  
the use of haemotological growth factors.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
CATEGORY AND CLASS  
A 26 Cytostatic agents  
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents,  
Antineoplastic agents. Alkylating agents. Nitrogen mustard analogues; ATC code: L01AA03  
Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-  
chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-  
linking two DNA strands and thereby preventing cell replication.  
5.2 Pharmacokinetic properties  
Intravenous administration can be used to avoid variability in absorption associated with myeloablative  
treatment.  
25 June 2024  
Initial…MU…….  
Page 13 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Distribution  
Melphalan is moderately bound to plasma proteins with reported percent binding ranging from 69% to 78%.  
There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved in  
standard dose therapy, but that the binding may become concentration-dependent at the concentrations  
observed in high-dose therapy. Serum albumin is the major binding protein, accounting for about 55 to 60% the  
binding, and 20% is bound to α1-acidglycoprotein. In addition, melphalan binding studies have revealed the  
existence of an irreversible component attributable to the alkylation reaction with plasma proteins.  
Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m2 body surface area  
(approximately0.1 to 0.6 mg/kg bodyweight) to 10 patients with ovarian cancer or multiple myeloma, the mean  
volumes of distribution at steady state and central compartment were 29.1 ± 13.6 litres and 12.2 ± 6.5 litres,  
respectively.  
In 28 patients with various malignancies who were given doses of between 70 and 200 mg/m2 body surface area  
as a 2-to 20-min infusion, the mean volumes of distribution at steady state and central compartment were,  
respectively, 40.2 ±18.3 litres and 18.2 ± 11.7 litres.  
After hyperthermic (39 °C) lower limb perfusion with melphalan at 1.75 mg / kg body weight in 11 patients with  
another tumor disease (advanced malignant melanoma), mean volumes for steady state and central  
compartment distribution were 2.87 ± 0.8 liters and 1.01 ± 0.28 liters, respectively.  
Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled  
cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed  
in a single high-dose study in children.  
Biotransformation  
In vivo and in vitro data suggest that spontaneous degradation rather than enzymatic metabolism is the major  
determinant of the drug's half-life in man.  
25 June 2024  
Initial…MU…….  
Page 14 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Elimination  
In 8 patients given a single bolus dose of 0.5 to 0.6 mg/kg bodyweight, the composite initial and terminal half-  
lives were reported to be 7.7 ± 3.3 min and 108 ± 20.8 min, respectively. Following injection of melphalan,  
monohydroxymelphalan and dihydroxymelphalan were detected in the patients' plasma, reaching peak levels at  
approximately 60 min and 105min, respectively. A similar half-life of 126 ± 6 min was seen when melphalan was  
added to the patients' serum in vitro (37°C), suggesting that spontaneous degradation rather than enzymic  
metabolism may be the major determinant of the medicine's half-life in man.  
Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m2 body surface area  
(approximately0.1 to 0.6 mg/kg bodyweight) to 10 patients with ovarian cancer or multiple myeloma, the pooled  
initial and terminal half-lives were, respectively, 8.1 ± 6.6 min and 76.9 ± 40.7 min. A mean clearance of 342.7 ±  
96.8 ml/min was recorded.  
In 15 children and 11 adults given high-dose intravenous melphalan (140 mg/m2 body surface area) with forced  
diuresis, the mean initial and terminal half-lives were found to be 6.5 ± 3.6 min and 41.4 ± 16.5 min, respectively.  
Mean initial and terminal half-lives of 8.8 ± 6.6 min and 73.1 ± 45.9 min, respectively, were recorded in 28  
patients with various malignancies who were given doses of between 70 and 200 mg/m2 body surface area as a  
2- to 20-min infusion. The mean clearance was 564.6 ± 159.1 ml/min.  
Following hyperthermic (39°C) perfusion of the lower limb with 1.75 mg/kg bodyweight, mean initial and terminal  
half-lives of 3.6 ± 1.5 min and 46.5 ± 17.2 min, respectively, were recorded in 11 patients with advanced  
malignant melanoma. A mean clearance of 55.0 ± 9.4 ml/min was recorded.  
Special Populations  
Elderly  
No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination  
half-life.  
25 June 2024  
Initial…MU…….  
Page 15 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
Renal impairment  
Melphalan clearance may be decreased in renal impairment.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
•
•
Melphalan Hydrochloride  
Povidone  
Hydrochloric acid  
Water for injection  
Nitrogen gas  
6.2 Incompatibilities  
FALOXERAN is not compatible with infusion solutions containing dextrose and it is recommended that only  
Sodium Chloride Intravenous Infusion 0,9 % m/v is used.  
6.3 Shelf life  
24 months  
6.4 Special precautions for storage  
Store at or below 25 °C. Protect from light and moisture.  
Keep in the carton until required for use  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
FALOXERAN 50 mg/ vial (Powder for solution for injection/infusion) 10 ml clear tubular glass vials, type I with 20  
mm neck with 20 mm serum rubber GCB stopper with a white flip off seals 20 mm matte top finish.  
Pack size: 1 x 10 ml  
25 June 2024  
Initial…MU…….  
Page 16 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
FALOXERAN Diluent solution for injection/infusion 10 ml clear blow back Lyo bottom tubular vial, type I with 20  
mm neck with 20 mm serum rubber igloo GCB flurotec stopper with a white flip off seals 20 mm matte top finish.  
Pack size: 1 x 10 ml  
6.6 Special precautions for disposal and other handling  
Procedures for proper handling and disposal of cytotoxic medicinal products should be observed:  
-The employees are to be instructed in the reconstitution of the medicine.  
-Pregnant women should be excluded from handling this medicine.  
-The personnel should wear suitable protective clothing with face masks, safety goggles and gloves when  
reconstituting the preparation.  
-Any items used for administration or cleaning, including gloves, should be disposed of in waste containers for  
contaminated material to high-temperature combustion. Liquid waste can be discharged with plenty of water.  
In case of accidental eye contact with Melphalan immediately rinse with sodium chloride eyewash or plenty of  
water and immediately consult a doctor. The spilled solution should be immediately wiped with a damp paper  
towel, which must then be disposed of safely. The contaminated surfaces must be washed with plenty of water.  
Preparation of melphalan powder and solvent for solution for injection/infusion:  
It is important that both the powder and the solvent provided are at a temperature (approximately 25°C) before  
starting reconstitution. Melphalan should be prepared at a temperature (approximately 25°C), by reconstituting  
the powder with the solvent-diluent provided.  
10 ml of the solvent should be added quickly, as a single quantity into the vial containing the powder using a  
sterile needle ('21 gauge or higher gauge size needle' should be used for piercing of vial stopper during  
reconstitution, for smooth and effective penetration, not too fast or too rough, and nicely perpendicular to the  
stopper without twisting of the needle) and syringe. Immediately shake the vial vigorously (for approximately 5  
minutes) until a clear solution, without visible particles, is obtained. Rapid addition of diluent followed by  
immediate vigorous shaking is important for proper dissolution.  
25 June 2024  
Initial…MU…….  
Page 17 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
It should also be noted that shaking of the formulation leads to a significant amount of very small air bubbles.  
These bubbles can stay in place and it can take another 2 to 3 minutes before they dissolve, as the resulting  
solution is quite viscous. This can make it difficult to assess the clarity of the solution.  
Each vial must be reconstituted individually in this manner. The resulting solution contains the equivalent of 5 mg  
per ml anhydrous melphalan at approximately pH 6.5. Failure to follow above mentioned preparation steps may  
result in incomplete dissolution of Melphalan.  
Melphalan solution has limited stability and should be prepared immediately before use. Any reconstituted  
solution unused after 30 minutes should be discarded according to standard guidelines for handling and disposal  
of cytotoxic medicines.  
If visible turbidity or crystallization occurs in the diluted solution for infusion, this solution should be discarded.  
Any unused medicines or waste material should be disposed of in accordance with local requirements for  
cytotoxic medicines.  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd.,  
Waterfall Corporate Campus,  
Building 2, First Floor,  
74 Waterfall Drive,  
Midrand,  
2066  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@heterodrugs.com  
8 REGISTRATION NUMBER  
56/26/0931  
9 DATE OF FIRST AUTHORISATION  
25 June 2024  
Initial…MU…….  
Page 18 of 19  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: FALOXERAN  
Dosage form and strength: Injection, each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan  
25 June 2024  
10 DATE OF REVISION OF THE TEXT  
25 June 2024  
Initial…MU…….  
Page 19 of 19