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Product proprietary name: ZOLTERO  
Dosage form and strength: Concentrate for solution for infusion and 4 mg/5 ml  
APPROVED PROFESSIONAL INFORMATION FOR ZOLTERO  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
ZOLTERO 4 mg/ 5mL (concentrate for solution for infusion)  
2 QUALITATIIVE AND QUANTITATIVE COMPOSITION  
One vial with 5 mL concentrate contains 4 mg Zoledronic acid (anhydrous), corresponding to 4,264  
mg zoledronic acid monohydrate.  
Contains sodium citrate 4.8 mg  
For the full list of excipients, see section 6.1.  
3 PHARMACEUTICAL FORM  
Clear colourless solution free from visible particles.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
Treatment of tumour-induced hypercalcaemia (TIH).  
ZOLTERO slows progression of skeletal conditions in adult patients when used in conjunction with  
appropriate antineoplastic therapy in patients with advanced carcinoma of the breast, prostate,  
lung and myeloma.  
4.2 Posology and method of administration  
Posology  
Skeletal conditions in patients with advanced malignancies involving bone:  
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Adults and elderly:  
The recommended dose is 4 mg. The concentrate must be further diluted with 100 mL sterile 0,9 %  
w/v sodium chloride or 5 % w/v glucose solution, and given as an intravenous infusion lasting no less  
than 15 minutes every 3 to 4 weeks.  
Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D  
daily.  
The decision to treat patients with bone metastases for the prevention of skeletal related events  
should consider that the onset of treatment effect is 2 - 3 months.  
Treatment of Tumour-induced Hypercalcaemia (TIH):  
Adults and elderly:  
The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥ 12,0 mg/dL or 3,0  
mmol/L) is 4 mg. The concentrate must be diluted with 100 mL sterile 0,9 % w/v sodium chloride or 5  
% w/v glucose solution and given as a single intravenous infusion of no less than 15 minutes. Patients  
must be maintained well hydrated prior to and following administration of ZOLTERO.  
Special populations  
Renal impairment:  
Treatment of Tumour-induced Hypercalcaemia (HCM):  
ZOLTERO treatment in patients with hypercalcaemia of malignancy (HCM) and who also have severe  
renal impairment should be considered only after evaluating the risks and benefits of treatment. In the  
clinical studies, patients with serum creatinine > 400 micromol/L or > 4,5 mg/dL were excluded. No  
dose adjustment is necessary in HCM patients with serum creatinine < 400 micromol/L or < 4,5 mg/dL  
(see Section 4.4).  
Skeletal related events in patients with advanced malignancies involving bone:  
Skeletal-related events (SREs) are complications associated with bone metastases and may include  
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fractures, spinal cord compression, bone pain, and frequently hypercalcemia. They are associated  
with intractable bone pain, fractures, bladder and bowel disturbances, anxiety, depression, and  
decreased survival.  
When initiating treatment with ZOLTERO in patients with multiple myeloma or metastatic bone lesions  
from solid tumours, serum creatinine levels and creatinine clearance (CrCI) should be determined.  
CrCI is calculated from serum creatinine levels using the Cockcraft-Gault formula. ZOLTERO is not  
recommended for patients presenting with severe renal impairment prior to initiation of therapy, which  
is defined for this population as CrCI < 30 mL/min. In clinical trials with ZOLTERO, patients with  
serum creatinine > 265 micromol/L or > 3,0 mg/dL were excluded.  
In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation  
of therapy, which is defined for this population as CrCI 30 to 60 mL/mm, the following ZOLTERO dose  
is recommended (see also Section 4.4).  
Table 1:  
Baseline Creatinine Clearance (mL/ min)  
HETZOLE Recommended Dose  
> 60  
4,0 mg  
3,5 mg*  
3,3 mg*  
3,0 mg*  
50 to 60  
40 to 49  
30 to 39  
* Doses have been calculated assuming target AUC of 0,66 (mg.hr/L) (CrCI = 75 mL/min). The  
reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen  
m patients with creatinine clearance of 75 mL/min.  
Following initiation of therapy, serum creatinine should be measured prior to each dose of ZOLTERO  
and treatment should be withheld, if renal function has deteriorated. In the clinical trials, renal  
deterioration was defined as follows:  
•
For patients with normal baseline serum creatinine (< 1,4 mg/dL or 123,76 mmol/L), an  
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increase of ≥ 0,5 mg/dL or 44,2 mmol/L.  
•
For patients with an abnormal baseline creatinine (> 1,4 mg/dL or 123,76 mmol/L), an  
increase of ≥ 1,0 mg/dL or 88,4 mmol/L.  
In the clinical studies, ZOLTERO treatment was resumed only when the creatinine level returned to  
within 10 % of the baseline value (see Section 4.4). ZOLTERO should be resumed at the same dose  
as that prior to treatment interruption.  
Paediatric population  
The safety and efficacy of ZOLTERO in paediatric patients have not been established.  
Method of administration  
Instructions on preparing reduced doses of ZOLTERO:  
Withdraw an appropriate volume of the reconstituted solution (4 mg/5 mL) as needed:  
4,4 mL for 3,5 mg dose  
4,1 mL for 3,3 mg dose  
3,8 mL for 3,0 mg dose  
For information on the reconstitution and dilution of ZOLTERO, see Instructions for use and  
handling.  
The withdrawn amount of liquid concentrate must be further diluted in 100 mL of sterile 0,9 % w/v  
sodium chloride solution or 5 % w/v glucose solution. The dose must be given as a single  
intravenous infusion of no less than 15 minutes.  
4.3 Contraindications  
•
•
•
Hypersensitivity to Zoledronic acid or any of the ingredients of ZOLTERO.  
Hypersensitivity the other bisphosphonates.  
Pregnancy and breastfeeding (see section 4.6).  
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•
Severe renal impairment.  
4.4 Special warnings and precautions for use  
Patients must be assessed prior to administration of ZOLTERO to assure that they are adequately  
hydrated.  
Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate,  
magnesium as well as serum creatinine should be carefully monitored after initiating ZOLTERO  
therapy. If hypocalcaemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental  
therapy may be necessary.  
Untreated hypercalcaemia patients generally have some degree of renal function impairment;  
therefore, careful renal function monitoring should be considered.  
Renal impairment:  
Patients with HCM with evidence of deterioration in renal function should be appropriately evaluated  
with consideration given as to whether the potential benefit of continued treatment with ZOLTERO  
outweighs the possible risk.  
Bisphosphonates as a class, including ZOLTERO, have been associated with reports of renal  
dysfunction. Factors that may increase the potential for deterioration in renal function include  
dehydration, pre-existing renal impairment, multiple cycles of ZOLTERO or other bisphosphonates as  
well as use of nephrotoxic drugs or using a shorter infusion time than currently recommended. While  
the risk is reduced with a dose of ZOLTERO 4 mg administered over no less than 15 minutes,  
deterioration in renal function may still occur. Increases in serum creatinine also occur in some  
patients with chronic administration of ZOLTERO at recommended doses for prevention of skeletal  
related events, although less frequently.  
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Patients should have their serum creatinine levels assessed prior to each dose of ZOLTERO. Upon  
initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower  
doses of ZOLTERO are recommended. In patients who show evidence of renal deterioration during  
treatment ZOLTERO should only be resumed when the creatinine level returns to within 10 % of the  
baseline value (see Section 4.2).  
In view of the potential impact of bisphosphonates, including ZOLTERO on renal function, the lack of  
extensive clinical safety data in patients with severe renal impairment (in clinical trials defined as  
serum creatinine ≥ 400 micromol/L or ≥ 4,5 mg/dL for patients with HCM and ≥ 265 micromol/L or ≥  
3,0 mg/dL for patients with cancer and bone metastases, respectively) at baseline and only limited  
pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance < 30  
mL/min), the use of ZOLTERO is not recommended in patients with severe renal impairment (see  
Section 4.3).  
Hepatic impairment  
Only limited clinical data are available in patients with severe hepatic insufficiency, no specific  
recommendations can be given for this patient population (see Section 4.3). Overhydration should be  
avoided in patients at risk of cardiac failure.  
Osteonecrosis of the jaw  
Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving treatment  
regimens including bisphosphonates such as ZOLTERO. Many of these patients were also receiving  
chemotherapy and corticosteroids. The majority of reported cases have been associated with dental  
procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.  
A dental examination with appropriate dentistry should be considered prior to treatment with  
bisphosphonates, such as ZOLTERO, in patients with concomitant risk factors (e.g. cancer,  
chemotherapy, corticosteroids, poor oral hygiene).  
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While on treatment, these patients should avoid invasive dental procedures if possible. For patients  
who develop osteonecrosis of the jaw while on bisphosphonate (e.g. ZOLTERO) therapy, dental  
surgery may exacerbate the condition. For patients requiring dental procedures, there are no data  
available to suggest whether discontinuation of bisphosphonate (e.g. ZOLTERO) treatment reduces  
the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the  
management plan of each patient based on individual benefit/risk assessment.  
Atypical fractures of the femur:  
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate  
therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or  
short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to  
just above the supracondylar flare. These fractures occur after minimal or no trauma and some  
patients experience thigh or groin pain, often associated with imaging features of stress fractures,  
weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral;  
therefore the contralateral femur should be examined in ZOLTERO-treated patients, who have  
sustained a femoral shaft fracture. Poor healing of these fractures has also been reported.  
Discontinuation of ZOLTERO therapy in patients suspected to have an atypical femur fracture should  
be considered pending evaluation of the patient, based on an individual benefit risk assessment.  
During ZOLTERO treatment patients should be advised to report any thigh, hip or groin pain and any  
patient presenting with such symptoms should be evaluated for an incomplete femur fracture.  
Musculoskeletal pain:  
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain  
have been reported in patients taking bisphosphonates, including ZOLTERO. However, such reports  
have been infrequent. The time to onset of symptoms varied from one day to several months after  
starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had  
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recurrence of symptoms when re-challenged with the same drug or another bisphosphonate.  
Hypocalcaemia:  
Hypocalcaemia has been reported in patients treated with ZOLTERO. Cardiac dysrhythmias and  
neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases  
of severe hypocalcaemia. In some instances, the hypocalcaemia may be life-threatening. Caution is  
advised when ZOLTERO is administered with other hypocalcaemia causing medicines, as they may  
have a synergistic effect resulting in severe hypocalcaemia (see section 4.5). Serum calcium should  
be measured and hypocalcaemia must be corrected before initiating ZOLTERO therapy. Patients  
should be adequately supplemented with calcium and vitamin D.  
While not observed with ZOLTERO, administration of bisphosphonates as a class has been  
associated with bronchoconstriction in acetylsalicylic acid-sensitive asthmatic patients.  
ZOLTERO contains 24 mg sodium per 4 mg/ 5ml, equivalent to 1.2% of the WHO recommended  
maximum daily intake of 2 g sodium for an adult.”  
Paediatric population  
The safety and efficacy of ZOLTERO in paediatric patients have not been established.  
Elderly population  
Clinical studies of zoledronic acid as contained in ZOLTERO in hypercalcemia of malignancy, multiple  
myeloma and bone metastases included patients who were 65 years of age or older. No significant  
differences in response rate or adverse reactions were seen in elderly patients receiving ZOLTERO  
as compared to younger adult patients. Because decreased renal function occurs with  
bisphosphonates including ZOLTERO more commonly in the elderly, special care should be taken to  
monitor renal function.  
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Contains mannitol and may have a laxative effect.  
4.5 Interaction with other medicines and other forms of interaction  
•
•
•
•
In clinical studies, ZOLTERO has been administered concomitantly with commonly used  
anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions  
occurring.  
ZOLTERO shows no appreciable binding to plasma proteins and does not inhibit human  
P450 enzymes in vitro (see Pharmacokinetics), but no formal clinical interaction studies have  
been performed.  
Caution is advised when ZOLTERO is administered with aminoglycosides, calcitonin or loop  
diuretics, since both agents may have an additive effect, resulting in a lower serum calcium  
level for longer periods than required.  
Caution is indicated when bisphosphonates, like ZOLTERO is used with other potentially  
nephrotoxic drugs. Attention should also be paid to the possibility of hypomagnesaemia  
developing during treatment.  
•
•
In multiple myeloma patients, the risk of renal dysfunction may be increased when  
intravenous bisphosphonates, like ZOLTERO, are used in combination with thalidomide.  
No dose adjustment for ZOLTERO is needed when co-administered with thalidomide, except  
in patients with mild to moderate renal impairment at baseline (see section 4.2). Co-  
administration of thalidomide (100 or 200 mg once daily) with ZOLTERO (4 mg given as a 15  
minute infusion) did not significantly change the pharmacokinetics of zoledronic acid and the  
creatinine clearance of patients with multiple myeloma.  
•
Caution is advised when ZOLTERO is administered with antiangiogenic drugs as an increase  
in incidence of ONJ has been observed in patients treated concomitantly with these drugs.  
4.6 Fertility, pregnancy and lactation  
Women of childbearing potential / Contraception in males and females  
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Women of child-bearing potential should be advised to avoid becoming pregnant and advised of the  
potential hazard to the foetus while receiving ZOLTERO. There may be a risk of foetal harm (e.g.  
skeletal and other abnormalities) if a woman becomes pregnant (see section 4.3) while receiving  
bisphosphonate therapy.  
Pregnancy  
The safety of ZOLTERO in pregnant and lactating women has not been established.  
Breastfeeding  
It is not known whether ZOLTERO is excreted into human milk (see Section 4.3).  
In animal reproduction studies zoledronic acid was administered subcutaneously to rats and rabbits. It  
was found to be teratogenic at doses ≥ 0,2 mg/kg bodyweight in rats. In rabbits, there was no  
teratogenicity or foetotoxicity but maternotoxicity was found. In the absence of adequate available  
experience in human pregnancy, ZOLTERO should not be used during pregnancy (see Section 4.3).  
Fertility  
No information available  
4.7 Effects on ability to drive and use machines  
ZOLTERO might cause dizziness or blurred vision and somnolence. Do not drive, operate machinery,  
or do anything else that could be dangerous until you know how ZOLTERO affects you.  
4.8 Undesirable effects  
Summary of the safety profile  
Within three days after ZOLTERO administration, an acute phase reaction has commonly been  
reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis  
with subsequent joint swelling; these symptoms usually resolve within a few days (see description of  
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selected adverse reactions).  
The following are the important identified risks with ZOLTERO in the approved indications:  
Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial  
fibrillation, anaphylaxis, interstitial lung disease.  
Tabulated summary of adverse reactions  
Undesirable effects are tabulated below as less frequent, frequent & frequency unknown.  
Organ system  
frequent  
Less frequent  
Frequency  
unknown  
---  
Blood  
and  
the Anaemia  
Thrombocytopenia,  
leukopenia,  
lymphatic  
disorders  
Immune  
system  
pancytopenia  
Hypersensitivity  
reaction,  
system ---  
---  
disorders  
angioedema  
Psychiatric  
disorders  
---  
Anxiety,  
sleep ---  
disturbance,  
confusion  
Dizziness,  
Nervous  
system Headache  
Convulsions,  
disorders  
paraesthesia, taste hypoaesthesia  
disturbance,  
and tetany  
hypoaesthesia,  
hyperaesthesia,  
tremor, somnolence  
(secondary to  
hypocalcaemia)  
Eye disorders  
Conjunctivitis  
Blurred  
vision, ---  
orbital  
scleritis,  
inflammation,  
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uveitis, episcleritis  
Hypertension,  
Cardiac disorders  
---  
---  
hypotension  
scleritis, orbital  
inflammation,  
bradycardia, chest  
pain  
Vascular disorders  
Respiratory,  
---  
---  
---  
Thrombophlebitis  
---  
Dyspnoea, cough  
thoracic  
and  
mediastinal  
disorders  
Gastrointestinal  
disorders  
Nausea,  
anorexia  
vomiting, Diarrhoea,  
---  
constipation,  
abdominal  
dyspepsia,  
stomatitis,  
mouth  
pain,  
dry  
Skin  
and ---  
Pruritus,  
rash ---  
subcutaneous  
tissue disorders  
(including  
erythematous and  
macular rash),  
increased sweating  
Musculoskeletal,  
Bone pain, myalgia, Muscle cramps  
Osteonecrosis of  
the jaw  
connective  
tissue arthralgia  
and bone disorders  
Renal and urinary Renal impairment  
Acute renal failure, ---  
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disorders  
haematuria,  
proteinuria  
General disorders Pain, fever, flu-like Asthenia, peripheral ---  
and administrative syndrome  
site conditions (including:  
rigors, malaise and (including:  
flushing) irritation,  
oedema,  
injection  
reactions  
pain,  
fatigue, site  
swelling,  
induration), weight  
increase  
Investigations  
Hypophosphataemia, Hypomagnesaemia, ---  
blood creatinine and hypokalaemia,  
blood urea  
hyperkalaemia,  
hypernatraemia  
increased,  
hypocalcaemia  
Description of selected adverse reactions  
Renal function impairment:  
ZOLTERO has been associated with reports of renal function impairment. In a pooled analysis of  
safety data from ZOLTERO registration trials for the prevention of skeletal-related events in patients  
with advanced malignancy involving bone, the frequency of renal function impairment adverse events  
suspected to be related to ZOLTERO (adverse reactions) was as follows: multiple myeloma (3,2 %),  
prostate cancer (3,1 %), breast cancer (4,3 %), lung and other solid tumors (3,2 %). Factors that may  
increase the potential for deterioration in renal function include dehydration, pre-existing renal  
impairment, multiple cycles of ZOLTERO or other bisphosphonates, as well as concomitant use of  
nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Renal  
deterioration, progression to renal failure and dialysis have been reported in patients after the initial  
dose or a single dose of ZOLTERO (see section 4.4).  
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Osteonecrosis of the jaw:  
Cases of osteonecrosis (primarily of the jaws) have been reported predominantly in cancer patients  
treated with bisphosphonates, such as ZOLTERO. Many of these patients had signs of local infection  
including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions  
or other dental surgeries. Osteonecrosis of the jaws has multiple well documented risk factors  
including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy,  
corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral  
disease). Although causality cannot be determined, it is prudent to avoid dental surgery as recovery  
may be prolonged (see section 4.4).  
Osteonecrosis of other anatomical sites:  
Cases of osteonecrosis of other anatomical sites including the hip, femur and external auditory canal  
have been reported predominantly in adult cancer patients treated with bisphosphonates, including  
ZOLTERO.  
Acute phase reaction:  
This adverse drug reaction consists of a constellation of symptoms that includes fever, fatigue, bone  
pain, chills, myalgia, headache, extremity pain, nausea, vomiting, diarrhoea, arthralgia and arthritis  
with subsequent joint swelling. The onset time is ≤ 3 days post-Zoltero infusion, and the reaction is  
also referred to using the terms “flu-like” or “post-dose” symptoms. These symptoms usually resolve  
within a few days.  
Atypical fractures of the femur:  
During post-marketing experience the following reactions have been reported (frequency rare):  
Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).  
Post-marketing experience: Cases of osteonecrosis (primarily of the jaws) have been reported  
predominantly in cancer patients treated with bisphosphonates, such as ZOLTERO. Many of these  
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patients had signs of local infection including osteomyelitis. The majority of the reports refer to cancer  
patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaws has multiple  
well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g.  
chemotherapy,  
radiotherapy,  
corticosteroids)  
and  
co-morbid  
conditions  
(e.g.  
anaemia,  
coagulopathies, infection, pre-existing oral disease). Although causality cannot be determined, it is  
prudent to avoid dental surgery as recovery may be prolonged (see Warnings). In very rare cases,  
hypotension led to syncope or circulatory collapse, primarily in patients with underlying risk factors.  
Hypocalcaemia-related ADRs:  
Hypocalcaemia is an important identified risk with ZOLTERO in the approved indications. Based on  
the review of both clinical trial and post-marketing cases, there is sufficient evidence to support an  
association between ZOLTERO therapy, the reported event of hypocalcaemia, and the secondary  
development of cardiac dysrhythmia. Furthermore, there is evidence of an association between  
hypocalcaemia and secondary neurological events reported in these cases including; convulsions,  
hypoaesthesia and tetany (see section 4.4).  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of ZOLTERO is important. It allows  
continued monitoring of the benefit/risk balance of ZOLTERO. Health care providers are requested to  
report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X  
SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website 8 or to the Holder of  
certificate of registration through the mail: pvg.cdma@heterogroups.com.  
4.9 Overdose  
Overdosage:  
There is no experience of acute intoxication with ZOLTERO. Patients who have received doses  
higher than those recommended should be carefully monitored.  
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Treatment:  
In the event of clinically significant hypocalcaemia, reversal may be achieved with an infusion of  
calcium gluconate.  
Treatment should be supportive and symptomatic.  
5. PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates; ATC-code M05  
BA08.  
Category and class: A 34 Other  
Mechanism of action  
Zoledronic acid is a bisphosphonate which acts primarily on bone. It is an inhibitor of osteoclastic  
bone resorption.  
In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the  
formation, mineralisation or mechanical properties of bone.  
In addition to inhibiting osteoclastic bone resorption, zoledronic acid exerts direct anti-tumour effects  
on cultured human myeloma and breast cancer cells, inhibiting proliferation and inducing apoptosis. It  
also inhibits human endothelial cell proliferation in vitro and is anti-angiogenic in animals. Moreover,  
the observation that zoledronic acid reduces the invasion of human breast cancer cells through  
extracellular matrix in vitro indicates that it may have anti-metastatic properties.  
Pharmacokinetic properties  
Absorption & Distribution:  
Single and multiple 5- and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients with  
bone metastases yielded the following pharmacokinetic data, which were found to be dose  
independent.  
After initiating the infusion of zoledronic acid, the plasma concentrations of drug increased, achieving  
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their peak at the end of the infusion period, followed by a decline to < 10 % of peak after 4 hours and  
< 1 % of peak after 24 hours, with a subsequent prolonged period of very low concentrations not  
exceeding 0,1 % of peak prior to the second infusion of drug on day 28.  
Biotransformation & Elimination:  
Intravenously administered zoledronic acid is eliminated in two stages: rapid biphasic disappearance  
from the systemic circulation, with half- lives of 0,24 and 1,87 hours, followed by a long elimination  
phase with a terminal elimination half-life of T1/2y 146 hours. There was no accumulation of drug in  
plasma after multiple doses of the drug given every 28 days. Zoledronic acid is not metabolised and is  
excreted unchanged via the kidneys. Over the first 24 hours, 39 ± 16 % of the administered dose is  
recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue it  
is released very slowly back into the systemic circulation and eliminated via the kidney with a half-life  
of at least 167 hours. The total body clearance is 5,04 ± 2,5 L/h, independent of dose, and  
unaffected by gender, age, race, and body weight.  
Increasing the infusion time from 5 to 15 minutes caused a 30 % decrease in zoledronic acid  
concentration at the end of the infusion but had no effect on the area under the plasma concentration  
versus time curve.  
The interpatient variability in pharmacokinetic parameters for zoledronic acid was high.  
Characteristics in specific groups of subjects or patients  
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in  
patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes in vitro,  
shows no biotransformation and in animal studies < 3 % of the administered dose was recovered in  
the faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.  
The renal clearance of zoledronic acid was significantly positively correlated with creatinine clearance,  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: ZOLTERO  
Dosage form and strength: Concentrate for solution for infusion and 4 mg/5 ml  
renal clearance representing 75 ± 33 % of the creatinine clearance, which showed a mean of 84 ± 29  
mL/min (range 22 to 143 mL/min) in the 64 cancer patients studied. Population analysis showed that  
for a patient with creatinine clearance of 20 mL/min (severe renal impairment), or 50 mL/min  
(moderate impairment), the corresponding predicted clearance of zoledronic acid  
would be 37 % or 72 % respectively, of that of a patient showing creatinine clearance of 84 mL/min.  
Only limited pharmacokinetic data are available in patients with severe renal insufficiency (creatinine  
clearance < 30 mL/min).  
Zoledronic acid shows no affinity for the cellular components of blood and plasma protein binding is  
approximately 56 % and independent of the concentration of zoledronic acid.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
Mannitol (Perlitol PF)  
Sodium citrate anhydrous  
Sodium hydroxide  
Anhydr citricacid  
Water for injection  
Nitrogen.  
6.2 Incompatibilities  
Studies with glass bottles, as well as several types of infusion bags and infusion lines made from  
polyvinylchloride, polyethylene and polypropylene (pre-fil led with 0,9 % sodium chloride solution or 5  
% glucose solution), showed no incompatibility with ZOLTERO.  
To avoid potential incompatibilities, ZOLTERO concentrate is to be diluted with 0,9 % sodium chloride  
solution or 5 % glucose solution. ZOLTERO concentrate must not be mixed with calcium-containing  
solutions such as Ringer's solution.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: ZOLTERO  
Dosage form and strength: Concentrate for solution for infusion and 4 mg/5 ml  
6.3 Shelf life  
24 months  
6.4 Special precautions for storage  
Store at or below 25 °C, Excursion permitted to 15 – 30ºC. Protect from light and moisture.  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
Zoledronic acid injection 4 mg/5 mL.  
Clear colourless solution free from visible particles, packed in a 5 mL vial with a rubber stopper, with a  
pink flip off seal.  
Clear colourless solution free from visible particles, packed in a 10 mL vial with a rubber stopper, with  
a blue flip off seal.  
6.6 Special precautions for disposal and other handling  
ZOLTERO 4 mg/ 5 mL concentrate for solution for infusion is for intravenous use only. Prior to  
administration, 5,0 mL concentrate from one vial or the volume of the concentrate withdrawn as  
required must be further diluted with 100 mL of calcium-free infusion solution (0,9 % w/v sodium  
chloride or 5 % w/v glucose solution). If refrigerated, the solution must be allowed to reach room  
temperature before administration (see Section 4.2).  
7. HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd.  
Waterfall Corporate Campus  
Building No. 2, First floor  
74 Waterfall Drive  
Midrand, 2066  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: ZOLTERO  
Dosage form and strength: Concentrate for solution for infusion and 4 mg/5 ml  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@hetero.com  
8. REGISTRATION NUMBER  
51/34/0202  
9. DATE OF FIRST AUTHORISATION  
30 August 2022  
10.DATE OF REVISION OF THE TEXT  
30 August 2022  
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