Consumer medicine information

APO-Zoledronic Acid Solution for Infusion

Zoledronic acid

BRAND INFORMATION

Brand name

APO-Zoledronic Acid

Active ingredient

Zoledronic acid

Schedule

What is in this leaflet

This leaflet answers some common questions about zoledronic acid 4mg/5mL. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Zoledronic acid is used to lower the amount of calcium in the blood when it becomes too high, as may happen in some forms of cancer.

Some cancers can speed up normal changes in bone so that the amount of calcium released from the bones into the blood is increased.

Zoledronic acid is also used to slow down the spread of cancers in bone, helping to prevent changes to the bones that may cause them to weaken. It is used in people with advanced cancer of the bone marrow (called multiple myeloma) and other advanced cancers that have spread to the bone. This medicine is used in addition to other standard cancer treatments.

How it works

Zoledronic acid belongs to a group of medicines called bisphosphonates, which strongly bind to bone. These medicines slow down the rate of bone change and help to restore the amount of calcium in the blood to normal.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

There is not enough information to recommend the use of this medicine in children.

Before you use this medicine

When you must not use it

Do not use this medicine if you have an allergy to:

zoledronic acid
any other bisphosphonates such as alendronate or risedronate
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

cough, shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue, throat or other parts of the body
rash, itching or hives on the skin
fainting
hayfever-like symptoms

Do not take this medicine if you are pregnant or plan to become pregnant. Zoledronic acid may affect your developing baby if you take it during pregnancy.

Do not take this medicine if you are breastfeeding. Zoledronic acid may pass into human breast milk and affect the baby.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

kidney or liver problems
heart conditions
asthma and you are allergic to aspirin
surgery on your thyroid
pain in the teeth, gums or jaw, swelling or numbness of the jaw or a 'heavy jaw feeling' or loosening of a tooth.

Tell your doctor if you have been treated with or are being treated with:

other medicines which contain zoledronic acid
other bisphosphonate medicines
diuretic therapy (commonly called 'fluid tablet')

Tell your doctor if you are receiving or are planning to receive dental treatment. A dental condition called jaw osteonecrosis has been reported in some patients being treated with zoledronic acid or other drugs in the same class as zoledronic acid. It is advisable to have a dental check-up before starting zoledronic acid. You may need to have dental treatment completed before starting this medicine. Tell your dentist you may be receiving zoledronic acid.

Tell your doctor if you are planning to have surgery or an anaesthetic.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and zoledronic acid may interfere with each other. These include:

medicines that may affect your kidneys, such as fluid tablets
aminoglycoside medicines, used to treat severe infections. This combination may cause the level of calcium in the blood to become too low
anti-angiogenic medicines as part of your cancer treatment, which may increase the risk of bone damage in the jaw (osteonecrosis)
any other medicine containing zoledronic acid, or other bisphosphonates such as risedronate, alendronate
thalidomide, used to treat multiple myeloma
loop diuretics, used to treat high blood pressure or oedema.

These medicines may be affected by this medicine or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Other medicines not listed above may also interact with zoledronic acid.

How this medicine is given

Zoledronic acid is given over at least 20 minutes via infusion into a vein. You may also be given an infusion of fluids to ensure that you do not become dehydrated.

You will have a blood test before each dose of zoledronic acid to make sure the medicine is not affecting your kidneys.

How much you will be given

Your doctor will tell you how much of this medicine you will be given. This will depend on your condition and whether you are taking any other medicines. Your doctor may give you a lower dose if you have a mild kidney problem.

To lower the amount of calcium in the blood, the usual dose of zoledronic acid is 4 mg, given as a single infusion.

To treat cancer in the bone, the usual dose is 4 mg, given as an infusion every 3 to 4 weeks.

Your doctor may also prescribe a daily calcium supplement and a multivitamin containing Vitamin D.

Make sure you drink enough fluids before and after the treatment with this medicine as directed by your doctor.

If you are given too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have had too much of this medicine.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include:

unusual light headedness, dizziness or faintness
numbness or tingling sensation
muscle cramps.

These symptoms may mean the level of calcium in your blood has fallen too far.

While you are being given this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor if you are going to have surgery or an anaesthetic or are going into hospital.

Tell your doctor if you are about to have any blood tests.

Tell your doctor if you have any dental symptoms, including pain or unusual feeling in your teeth of gums, or any dental infections.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. If you are returning home immediately after the infusion, arrange to have someone else drive.

Practice good dental hygiene. Your routine dental hygiene should include:

brushing your teeth and tongue after every meal and at bedtime
gentle flossing once a day to remove plaque
keeping your mouth moist by drinking water (many cancer medicines can cause 'dry mouth' which can lead to decay and other dental problems)
avoiding use of mouthwash that contains alcohol

Use a mirror to check your teeth and gums regularly for any changes such as sores or bleeding gums. If you notice any problems, tell your doctor and dentist immediately.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking zoledronic acid.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

redness, swelling or pain where the needle for the infusion was inserted
stomach complaints, such as upset stomach, abdominal pain, loss of appetite, nausea (feeling sick) or vomiting, constipation or diarrhoea
increased weight
dry or sore mouth
anxiety, confusion, difficulty sleeping
headache, facial pain
changes in taste sensation
cough
increased sweating

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

irritated eyes, blurred vision, eye pain, sensitivity to light, runny, itchy or swollen eyes
tingling or numbness of the hands or feet
swollen aching joints or muscles, pain in the bones
slow or irregular heartbeat
swelling of fingers or lower legs due to fluid build up
short-lasting fever, sometimes with flu-like symptoms: such as chills; tiredness; fatigue; weakness; aches and pains, and joint pain and swelling
passing less urine than normal, blood in the urine

The above list includes serious side effects that may require medical attention.

If any of the following happen, the infusion must be stopped, and contact your doctor immediately or go to Accident and Emergency at your nearest hospital:

difficulty breathing with wheezing or coughing
signs that the level of calcium in your blood may have fallen too far, such as unusual light headedness, dizziness or faintness, numbness or tingling sensation, muscle cramps, convulsions or spasms.
constant "flu-like" symptoms (chills, fever, sore throat, sores in mouth, swollen glands, tiredness or lack of energy) that could be a sign of blood problems
chest pain
seizures
pain in the mouth, teeth or jaw, swelling or sores inside the mouth, numbness or a "heavy jaw feeling" or loosening of a tooth. These symptoms could be a sign of a jaw-bone problem known as jaw osteonecrosis
cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, or other parts of the body; rash, itching or hives on the skin; fainting; hayfever-like symptoms (signs of an allergic reaction)
pain, weakness or discomfort in your thigh, hip or groin, as this may be an early sign of a possible fracture of the thigh bone. Patients taking zoledronic acid may be at risk of unusual fracture of the thigh bone.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

It is unlikely that you will have to store zoledronic acid at home.

If you have to store it:

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of the vial it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C. Do not store your medicine or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or they have passed their expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Zoledronic Acid 4mg/5mL looks like

This medicine is packaged in plastic vials containing a clear, colourless, sterile solution.

AUST R 190337

Packs of 1, 4 or 10 vials

* Not all strengths, pack types and/or pack sizes may be available.

What APO-Zoledronic Acid 4 mg/100 mL looks like

This medicine is packaged in glass vials containing a clear, colourless, sterile solution.

AUST R 205927

Packs of 1, 4 or 5 vials

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each vial contains 4.264 mg of zoledronic acid (as monohydrate), equivalent to 4 mg of zoledronic acid in 5 mL, or 100 mL of solution, as the active ingredient.

It also contains the following:

mannitol
sodium citrate
water for injections

This medicine does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO and APOTEX are the registered trademarks of Apotex Inc.

This leaflet was prepared in October 2018.

Published by MIMS December 2018

BRAND INFORMATION

Brand name

APO-Zoledronic Acid

Active ingredient

Zoledronic acid

Schedule

1 Name of Medicine

Zoledronic acid (as monohydrate).

2 Qualitative and Quantitative Composition

Each vial contains zoledronic acid 4 mg calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

4 mg zoledronic acid is available in two forms: zoledronic acid 4 mg/100 mL injection solution for infusion and zoledronic acid 4 mg/5 mL concentrated injection for infusion.
Zoledronic acid 4 mg/100 mL injection solution for infusion and zoledronic acid 4 mg/5 mL concentrated injection for infusion are a clear, colourless sterile solution, practically free from visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Prevention of skeletal-related events (pathological fracture, spinal cord compression, radiation to bone or surgery to bone) in patients with advanced malignancies involving bone.
Treatment of tumour-induced hypercalcaemia.

4.2 Dose and Method of Administration

APO-Zoledronic Acid 4 mg/5 mL and APO-Zoledronic Acid 4 mg/100 mL are/is intended for injection by i.v. infusion.

Dosage.

For information on the dilution of zoledronic acid 4 mg/100 mL solution, see Instructions for use and handling.

Prevention of skeletal-related events in patients with advanced malignancies involving bone.

Dosage regimen for adults (including elderly patients). The recommended dose for the prevention of skeletal-related events in patients with advanced malignancies involving bone is 4 mg lasting no less than 20 minutes given as an intravenous infusion every 3 to 4 weeks. The zoledronic acid 4 mg/5 mL concentrated injection should be diluted before use, see Instructions for use and handling. The zoledronic acid 4 mg/100 mL injection solution requires no further dilution. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.

Treatment of tumour-induced hypercalcaemia (TIH).

Dosage regimen for adults (including elderly patients). The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥ 3.0 mmol/L) is 4 mg given as a single intravenous infusion of no less than 20 minutes. The zoledronic acid 4 mg/5 mL concentrated injection should be diluted before use, see Instructions for use and handling. The zoledronic acid 4 mg/100 mL injection solution requires no further dilution. The hydration status of patients must be assessed prior to administration of zoledronic acid 4 mg to assure that patients are adequately hydrated prior to and following administration of zoledronic Acid 4 mg. Following an initial dose of 4 mg, the median time to relapse is 30 days.

Renal impairment.

The use of zoledronic acid 4 mg is not recommended in patients with severe renal impairment (calculated creatinine clearance by Cockcroft-Gault formula of < 30 mL/min) (see Section 4.4 Special Warnings and Precautions for Use and Section 5.2 Pharmacokinetic Properties).
Dose adjustments are not recommended in patients with TIH presenting with mild to moderate renal impairment prior to initiation of therapy (serum creatinine < 400 micromol/L or calculated creatinine clearance by Cockcroft-Gault formula of ≥ 30 mL/min) as there are insufficient data to support the efficacy of doses less than 4 mg.
When initiating treatment with zoledronic acid 4 mg in patients with advanced malignancies involving bone, serum creatinine levels and creatinine clearance (CrCl) should be determined. CrCl is calculated from serum creatinine levels using the Cockcroft-Gault formula.
In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for this population as CrCl 30-60 mL/min, the following zoledronic acid 4 mg dose is recommended (see Section 4.4 Special Warnings and Precautions for Use). See table 1.

Following initiation of therapy, patients who receive zoledronic acid 4 mg should have serum creatinine assessed prior to each dose (see Section 4.4 Special Warnings and Precautions for Use). Patients being treated for TIH who have evidence of deterioration in renal function should be appropriately evaluated, with consideration given as to whether the potential benefit of continued treatment with zoledronic acid 4 mg outweighs the possible risk. Patients being treated for bone metastases should have the dose of zoledronic acid 4 mg withheld if renal function has deteriorated. In the clinical studies, deterioration in renal function was defined as follows:
For patients with normal baseline creatinine (< 125 micromol/L), increase of > 44 micromol/L.
For patients with abnormal baseline creatinine (> 125 micromol/L), increase of > 88 micromol/L.
In the clinical studies, zoledronic acid 4 mg treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid 4 mg should be resumed at the same dose administered prior to treatment interruption.

Monitoring advice.

Instructions for use and handling.

Zoledronic acid 4 mg/5 mL concentrated injection for infusion and zoledronic acid 4 mg/100 mL injection solution for infusion contain no antimicrobial agent. The injection solution is for single use in one patient on one occasion only. Discard any remaining residue.
1. Zoledronic acid 4 mg/5 mL concentrate for intravenous injection. Zoledronic acid 4 mg/5 mL concentrate vial contains an overfill of 4% to permit the withdrawal of the labelled amount of zoledronic acid from the vial. Prior to administration, the required amount of concentrate from one vial must be further diluted with 100 mL of calcium-free infusion solution (0.9% w/v sodium chloride solution or 5% w/v glucose solution). If refrigerated, the solution must be allowed to reach room temperature before administration.
2. Zoledronic acid 4 mg/100 mL injection solution for infusion. Zoledronic acid 4 mg/100 mL injection solution is a "ready to use" presentation and must not be further diluted or mixed with other infusion solutions, except for patients with renal impairment.
3. Instructions on preparing reduced doses of zoledronic acid 4 mg/5 mL concentrated solution and 4 mg/100 mL solution. In patients with mild to moderate renal impairment, which is defined as CL_cr 30 to 60 mL/min, reduced zoledronic acid dosages are recommended, except in patients with TIH (see Section 4.2 Dose and Method of Administration, Renal impairment).
To prepare reduced doses from zoledronic acid 4 mg/5 mL concentrated solution, withdraw an appropriate volume of the concentrate 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.
To prepare reduced doses from zoledronic acid 4 mg/100 mL injection solution, remove the corresponding volume of the solution as indicated below and replace with an equal volume of sterile 0.9% w/v sodium chloride or sterile 5% w/v glucose solution. See Table 2.

Stability after dilution.

After addition of the solution to the infusion media, the infusion solution should be used as soon as practicable to reduce the risk of microbiological hazard. If storage of the infusion solution is necessary, hold at 25°C or between 2°-8°C for not more than 24 hours.

Incompatibilities.

Studies with glass bottles, as well as several types of infusion bags and infusion lines made from polyvinylchloride, polyethylene and polypropylene (prefilled with 0.9% sodium chloride injection or 5% glucose injection), showed no incompatibility with zoledronic acid 4 mg/100 mL.
To avoid potential incompatibilities, zoledronic acid 4 mg solution is to be diluted with 0.9% sodium chloride injection or 5% glucose injection.
Zoledronic acid 4 mg/100 mL must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4.3 Contraindications

Hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of zoledronic acid; pregnancy and breast-feeding.

4.4 Special Warnings and Precautions for Use

Administration of zoledronic acid.

Zoledronic acid should be administered as a single intravenous solution in a line separate from all other drugs and should be administered over a period of no less than 20 minutes.

Rehydration.

Patients must be maintained in a well hydrated state prior to and following administration of zoledronic acid. Patients must be assessed prior to administration of zoledronic acid to ensure that they are adequately hydrated. It is essential in the initial treatment of tumour-induced hypercalcaemia that intravenous rehydration be instituted to restore urine output. Patients should be hydrated adequately throughout treatment but overhydration must be avoided. In patients with cardiac disease, especially in the elderly, additional saline overload may precipitate cardiac failure (left ventricular failure or congestive heart failure). Fever (influenza-like symptoms) may also contribute to this deterioration.

Monitoring of metabolic parameters.

Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium and potassium, as well as serum creatinine, should be carefully monitored after initiating zoledronic acid therapy. If hypocalcaemia, hypophosphataemia or hypomagnesaemia occurs, 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.
Zoledronic acid is also marketed in for indications related to decreased bone mineral density (e.g. osteoporosis in post-menopausal women, osteoporosis in men, treatment and prevention of osteoporosis caused by long-term glucocorticoid use) and for Paget's disease. Patients being treated with zoledronic acid for these conditions should not be treated with other strengths of zoledronic acid nor any other bisphosphonate concomitantly.
While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Occasional cases of mild, transient hypocalcaemia, usually asymptomatic, have been reported. Symptomatic hypocalcaemia occurs rarely and can be reversed with calcium gluconate. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcaemia due to relative hypoparathyroidism.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) has been reported predominantly in patients treated with bisphosphonates, including zoledronic acid 4 mg. Many of these patients were also receiving chemotherapy and corticosteroids. Many had signs of local infection including osteomyelitis. Presentation may include jaw pain, toothache, exposed bone, altered sensation and local infection, including osteomyelitis. The condition may result in chronic pain, may be resistant to treatment, and in serious cases may result in disfigurement.
Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).
Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. Patients and their dentists should be advised of the reports of osteonecrosis of the jaw so that dental symptoms developing during treatment can be fully assessed before commencing dental procedures.
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

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 zoledronic acid.

Atypical fractures of the femur.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving 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 zoledronic acid-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of zoledronic acid 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. Reports of atypical femoral fracture have been received in patients treated with zoledronic acid; however causality with zoledronic therapy has not been established.
During zoledronic acid 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.

Severe musculoskeletal pain.

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates. This category of drugs includes zoledronic acid (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Hypocalcaemia.

Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias 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 zoledronic acid is administered with other hypocalcaemia causing drugs, as they may have synergistic effect resulting in severe hypocalcaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Serum calcium should be measured and hypocalcaemia must be corrected before initiating zoledronic acid therapy. Patients should be adequately supplemented with calcium and vitamin D.

Use in hepatic impairment.

As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.

Monitoring of renal function.

Zoledronic acid, in common with other bisphosphonates has been associated with the development of renal impairment in some subjects, sometimes progressing to renal failure. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid 4 mg or other bisphosphonates, as well as the use of nephrotoxic drugs, or using a shorter infusion time than 15 minutes. Impairment of renal function may occur in patients with bone metastases receiving zoledronic acid for the prevention of skeletal related events, as well as those with TIH. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of zoledronic acid.
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.
Patients who receive zoledronic acid 4 mg should have serum creatinine assessed prior to each dose. Patients being treated for TIH who have a deterioration in renal function should be appropriately evaluated, with consideration given as to whether the potential benefit of continued treatment outweighs the possible risk. Patients being treated for bone metastases who have a deterioration in renal function should have the dose withheld, and have treatment resumed only when the creatinine level returns to within 10% of baseline.

Use in renal impairment.

Use in patients with pre-existing renal impairment.

Upon initiation of treatment of bone metastases in patients with mild to moderate renal impairment at baseline, dosage reductions are recommended (see Section 4.2 Dose and Method of Administration). The use of zoledronic acid is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Use in patients with severe renal impairment.

Limited clinical data are available in patients with pre-existing renal impairment. Zoledronic acid is excreted exclusively via the kidney and the risk of renal deterioration may be greater in patients with pre-existing impairment of renal function. Patients with severe renal impairment were excluded from the pivotal clinical studies. The use of zoledronic acid is not recommended in patients with severe renal impairment because there are limited clinical safety and pharmacokinetic data in this population, and there is a risk of renal function deterioration in patients treated with bisphosphonates, including zoledronic acid. In clinical trials, patients with severe renal impairment were defined as those with baseline serum creatinine > 400 micromol/L for patients with TIH and > 265 micromol/L for premenopausal patients with EBC and patients with bone metastases, respectively. In pharmacokinetic studies, patients with severe renal impairment were defined as those with baseline creatinine clearance < 30 mL/min.

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of zoledronic acid 4 mg in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Absence of interactions.

In clinical studies, zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics (except for loop diuretics, see Anticipated interactions to be considered), antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows moderate binding to plasma proteins and human P450 enzymes in vitro (see Section 5.2 Pharmacokinetic Properties), but no formal clinical interaction studies have been performed.
In multiple myeloma patients, the risk of renal dysfunction may be increased when intravenous bisphosphonates are used in combination with thalidomide.

Anticipated interactions to be considered.

Caution is advised when bisphosphonates are administered with aminoglycosides and 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 zoledronic acid is used in combination with other potentially nephrotoxic drugs.

Observed interactions to be considered.

Caution is advised when zoledronic acid is administered with anti-angiogenic drugs as an increase in incidence of ONJ have been observed in patients treated concomitantly with these drugs.

4.6 Fertility, Pregnancy and Lactation

Effect on fertility.

The fertility was decreased in rats dosed SC with 0.1 mg/kg/day zoledronic acid (0.1 times the maximum human exposure of 8 mg, based on BSA), and pre-implantation loss was increased at 0.01 mg/kg/day. Reversible testicular atrophy occurred in rats at 0.003 mg/kg/day SC for 12 months (0.004 times the maximum human exposure of 8 mg, based on BSA). In dogs, testicular and prostatic atrophy and oligospermia were observed at 0.2 mg/kg/day IV for 3 months (0.6 times the maximum human exposure of 8 mg, based on BSA), and testicular atrophy and/or mineralisation at 0.03 mg/kg IV dosed every 2-3 days for 6 months (0.1 times the maximum human exposure of 8 mg, based on BSA). Female dogs had decreased weights of ovaries and uterus, correlated with anoestrus and, in some animals, with vaginal epithelial degeneration at 0.01 mg/kg/day IV (0.03 times the maximum human exposure of 8 mg, based on BSA).
(Category B3)
Zoledronic acid was administered subcutaneously to rats and rabbits during the foetal organogenesis period. In rats, increased malformations were seen at 0.2 mg/kg/day (1.5 times the expected human exposure at 8 mg, based on AUC), and increased postimplantation loss occurred at 0.4 mg/kg/day (3 times the human exposure). No embryofoetal effects were observed at 0.1 mg/kg/day (0.7 times the human exposure). In rabbits, zoledronic acid increased late resorptions at 0.03 mg/kg/day and above (0.07 times the highest clinical dose, based on body surface area [BSA]). Maternal toxicity was apparent in rabbits at these doses. In the absence of adequate available experience in human pregnancy, zoledronic acid should not be used during pregnancy.

Women of child-bearing potential.

Women of child-bearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the foetus while receiving zoledronic acid. There may be risk of foetal harm (e.g. skeletal and other abnormalities) if a woman becomes pregnant while receiving bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established.
Studies have not been performed in lactating animals, and the transfer of zoledronic acid into milk is unknown. Because many drugs are excreted in human milk, breast-feeding should be discontinued before administration.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Overview of clinical trial data.

The most serious adverse drug reactions reported in patients receiving zoledronic acid in the approved indications are: anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal function impairment, acute phase reaction, and hypocalcaemia. The frequencies of these adverse reactions are shown in Table 3 or shown as adverse reactions from 'Spontaneous reports and literature cases' with 'not known' frequency.
Frequencies of adverse reactions to zoledronic acid 4 mg are mainly based on data collected from chronic treatment. Adverse reactions to zoledronic acid 4 mg are usually mild and transient and similar to those reported for other bisphosphonates. These reactions can be expected to occur in approximately one third of patients who receive either zoledronic acid 4 mg or pamidronate 90 mg.
Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including pyrexia, fatigue, bone pain, rigors, influenza-like illness, arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see subsection Description of selected adverse reactions). Arthralgia and myalgia have been reported in approximately 3% of patients. In most cases no specific treatment is required and the symptoms subside after a couple of hours/days.
Frequently, the reduction in renal calcium excretion is accompanied by a fall in serum phosphate levels in approximately 20% of patients, which is asymptomatic and does not require treatment. The serum calcium may fall to asymptomatic hypocalcaemic levels in approximately 3% of patients.
Gastrointestinal reactions such as nausea (5.8%) and vomiting (2.6%) have been reported following intravenous infusion of zoledronic acid 4 mg. Anorexia was reported in 1.5% of patients treated with zoledronic acid 4 mg.
Local reactions at the infusion site such as redness or swelling and/or pain were also observed in less than 1% of patients.
Some cases of rash, pruritus and chest pain have been observed.
As with other bisphosphonates, cases of conjunctivitis in approximately 1% of patients and cases of hypomagnesaemia have been reported.
In clinical trials of patients with tumour-induced hypercalcaemia, Grade 3 (NCI Common Toxicity Criteria [CTC]) elevations of serum creatinine were seen in 2.3%, 3.1% and 3.0% of patients receiving zoledronic acid 4 mg, zoledronic acid 8 mg and pamidronate 90 mg, respectively, as expected in this disease state and with this class of compounds. However, other risk factors in this severely ill patient population may have contributed as well.
The following adverse drug reactions have been accumulated from clinical studies following predominantly chronic treatment with zoledronic acid:
Adverse reactions are ranked under headings of frequency, using the following convention: Very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), including isolated reports.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse reactions have been reported during post approval use of zoledronic acid 4 mg via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency (which is therefore categorised as not known) or establish a causal relationship to drug exposure.

Immune system disorders.

Anaphylactic reaction/shock.

Nervous system disorders.

Somnolence.

Eye disorders.

Uveitis, episcleritis, scleritis and orbital inflammation.

Cardiac disorders.

Atrial fibrillation.

Vascular disorders.

Hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors.

Respiratory, thoracic and mediastinal disorders.

Bronchospasm, interstitial lung disease (ILD).

Skin and subcutaneous tissue disorders.

Urticaria.

Musculoskeletal and connective tissue disorders.

Severe and occasionally incapacitating bone, joint, and/or muscle pain, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction, including zoledronic acid).

Description of selected adverse reactions.

Renal function impairment.

Zoledronic acid has been associated with reports of renal function impairment.
In a pooled analysis of safety data from zoledronic 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 zoledronic acid (adverse reactions) was as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung and other solid tumours (3.2%).
Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid 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, has been reported in patients after the initial dose or a single dose of zoledronic acid (see Section 4.4 Special Warnings and Precautions for Use).

Osteonecrosis.

Cases of osteonecrosis (primarily of the jaw but also of other anatomical sites including the hip, femur and external auditory canal) have been reported predominantly in cancer patients treated with bisphosphonates, including zoledronic acid. Many patients with osteonecrosis of the jaw had signs of local infection including osteomyelitis, and 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, anti-angiogenic drugs, radiotherapy, corticosteroids) and comorbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see Section 4.4 Special Warnings and Precautions for Use). Data suggests a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).

Acute phase reaction.

This adverse drug reaction consists of a constellation of symptoms that includes pyrexia, fatigue, bone pain, chills, influenza-like illness arthritis with subsequent joint swelling. The on-set is < 3 days post zoledronic acid 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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Clinical experience with acute overdosage of zoledronic acid 4 mg/100 mL is limited. Patients who have received doses higher than those recommended should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Zoledronic acid is a bisphosphonate, potently inhibiting osteoclastic bone resorption. Bisphosphonates have a high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term studies in adult animals, zoledronic acid inhibits bone resorption and increases bone mineralisation without adversely affecting the formation or mechanical properties of bone.
Clinical studies in tumour-induced hypercalcaemia demonstrated that the effect of zoledronic acid is characterised by decreases in serum calcium and urinary calcium excretion. Preclinical studies demonstrated that, in addition to its inhibitory activity against bone resorption, zoledronic acid possesses the following properties that could contribute to its overall efficacy in the treatment of metastatic bone disease:
In vivo: anti-tumour activity in some animal models, anti-angiogenic activity, anti-pain activity.
In vitro: inhibition of osteoclast proliferation, cytostatic and pro-apoptotic activity on tumour cells at concentrations greater than the clinical C_max, synergistic cytostatic effect with other anti- cancer drugs.

Clinical trials.

Prevention of skeletal-related events in patients with advanced malignancies involving bone.

Three randomised, double-blind studies (039, 010, 011) were conducted to assess the efficacy of zoledronic acid in preventing skeletal-related events (SREs) in patients with advanced malignancies involving bone. The primary efficacy variable was the proportion of patients experiencing at least one SRE, defined as radiation therapy to bone, surgery to bone, pathological bone fracture or spinal cord compression.
In Study 039, zoledronic acid 4 mg/5 mL was compared to placebo for the prevention of skeletal related events (SREs) in prostate cancer patients with 214 men receiving zoledronic acid 4 mg IV infusion every 3 weeks versus 208 receiving placebo (IV infusion of saline). After the initial 15 months of treatment, 186 patients continued for up to an additional 9 months, giving a total duration of double-blind therapy up to 24 months. Zoledronic acid 4 mg significantly reduced the proportion of patients with SRE (p=0.028) and delayed the time to first SRE (p=0.009). Multiple event analysis showed 36% relative risk reduction in developing skeletal related events in the zoledronic acid group compared with placebo (p=0.002). Pain was measured at baseline and periodically throughout the trial. Patients receiving zoledronic acid reported less increase in pain than those receiving placebo, and the differences reached significance at months 21 (p=0.014) and 24 (p=0.024). The treatment effects were less pronounced in patients with blastic lesions. Efficacy results are summarised in Table 4.

In a second phase III randomised, double-blind trial (Study 010) comparing zoledronic acid 4 mg to pamidronate 90 mg, 1,116 patients (561 zoledronic acid 4 mg, 555 pamidronate 90 mg) with multiple myeloma or breast cancer with at least one bone lesion were treated with 4 mg zoledronic acid IV infusion every 3 to 4 weeks or 90 mg pamidronate IV infusion every 3 to 4 weeks. 606 patients entered the 12-month, double-blind extension phase. Total therapy lasted up to 24 months. The results demonstrated that zoledronic acid 4 mg showed comparable efficacy to 90 mg pamidronate in the prevention of skeletal related events. The multiple event analysis did not reveal a significant difference between the two treatments (p=0.059). Efficacy results are provided in Table 5.

In the third trial (Study 011), zoledronic acid 4 mg IV infusion every 3 weeks (n=257) was compared with placebo (IV infusion of saline; n=250) in patients with other solid tumours involving bone. The tumours included non-small cell lung cancer (approximately 50% of subjects), renal cell cancer, thyroid cancer, head and neck cancer and other solid tumours. These patients had a median survival of only 6 months. After initial 9 months of treatment, 101 patients entered the 12 month double-blind extension study, and 26 completed the full 21 months. Zoledronic acid 4 mg showed a trend to reduce the proportion of patients with SRE (p=0.127) and significantly delayed the time to first SRE (p=0.03). Multiple event analysis showed 28% relative risk reduction in developing skeletal related events in the zoledronic acid 4 mg group compared with placebo (p=0.01). The treatment effect in non-small cell lung cancer patients appeared to be smaller than in patients with other solid tumours. Efficacy results are provided in Table 6.

Zoledronic acid 4 mg was also studied in a double-blind, randomised, placebo-controlled trial in 228 Japanese patients with documented bone metastases from breast cancer. This study evaluated the effect of zoledronic acid 4 mg on the skeletal related event (SRE) rate ratio, calculated as the total number of SRE events (adjusted for the presence of prior pathological fracture), divided by the total risk period. Patients received either zoledronic acid 4 mg or placebo every four weeks for one year. Patients were evenly distributed between zoledronic acid 4 mg-treated and placebo groups.
The SRE rate ratio at one year was 0.61, indicating that treatment with zoledronic acid 4 mg reduced the rate of occurrence of SREs by 39% compared with placebo (p=0.027). The proportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the zoledronic acid 4 mg-treated group versus 49.6% in the placebo group (p=0.003). Zoledronic acid 4 mg significantly delayed the time of onset of the first SRE compared with placebo (median not reached versus 364 days; p=0.007). Zoledronic acid 4 mg reduced the risk of SREs by 41% in a multiple event analysis (risk ratio=0.59, p=0.019) compared with placebo.
In the zoledronic acid 4 mg-treated group, statistically significant improvement (p < 0.05) in pain scores, a complication of bone metastases, (using the Brief Pain Inventory, BPI) was seen at 4 weeks and at every subsequent time point during the study, when compared to placebo. The pain score for zoledronic acid 4 mg was consistently below baseline.

Tumour-induced hypercalcaemia (TIH).

Two identical multicentre, randomised, double-blind, double-dummy studies of zoledronic acid 4 mg or 8 mg given as a 5-minute infusion or pamidronate 90 mg given as a 2-hour infusion were conducted in patients with tumour-induced hypercalcaemia (TIH). TIH was defined as corrected serum calcium (CSC) concentration of ≥ 3.00 mmol/L. The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to ≤ 2.70 mmol/L within ten days after drug infusion. Each treatment group was considered efficacious if the lower bound of the 95% confidence interval for the proportion of complete responders was > 70%. This was achieved for the zoledronic acid 4 mg and 8 mg groups in each study, but not for the pamidronate 90 mg group. To assess the effects of zoledronic acid versus those of pamidronate, the two multicentre TIH studies were combined in a pre-planned analysis. The results showed that zoledronic acid 4 mg and 8 mg were statistically superior to pamidronate 90 mg for the proportion of complete responders at day 7 and day 10. The results also demonstrated a faster normalisation of CSC by day 4 for zoledronic acid 8 mg and by day 7 for zoledronic acid 4 and 8 mg doses.
The following response rates were observed, see Table 7.

There were no statistically significant differences between the two zoledronic acid doses.
Secondary efficacy variables, time to relapse and duration of complete response, were also assessed. Time to relapse was defined as the duration (in days) from study infusion until the last CSC value ≤ 2.90 mmol/L. Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤ 2.70 mmol/L. The results showed that both zoledronic acid doses had a statistically longer time to relapse than pamidronate. There was no statistically significant difference between the zoledronic acid doses. See Table 8.

Retreatment with zoledronic acid 8 mg was allowed for patients in any of the treatment arms whose serum calcium did not return to normal or remain normal after initial treatment. A minimum of 7 days was allowed to elapse before retreatment to allow for full response to the initial dose. In clinical studies, 69 patients have received a second infusion of 8 mg zoledronic acid for hypercalcaemia. The complete response rate observed in these retreated patients was 52%.
Although these studies used doses of 8 mg and an infusion time of 5 minutes, subsequent safety data have indicated that such dosage regimens are associated with an increased risk of renal impairment. Therefore, doses of zoledronic acid should not exceed 4 mg and should not be administered over less than 15 minutes (see Section 4.4 Special Warnings and Precautions for Use).

5.2 Pharmacokinetic Properties

Single 5- and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 32 patients with bone metastases yielded the following pharmacokinetic data, which were found to be dose independent.

Absorption.

Zoledronic acid is administered by intravenous infusion. By definition, absorption is complete at the end of the infusion.

Distribution.

Zoledronic acid shows no affinity for the cellular components of blood. Protein binding is dependent on calcium ions and, possibly, other cations present in plasma. Plasma protein binding in heparinised plasma from healthy subjects is moderate (approximately 60%) and independent of the concentration of zoledronic acid.

Excretion.

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of 0.23 and 1.75 hours, followed by a long elimination phase with a terminal elimination half-life of 167 hours. Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 to 46% 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 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 3.7-4.7 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.
Special patient populations. 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.

Renal insufficiency.

The renal clearance of zoledronic acid was significantly positively correlated with creatinine clearance, 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) (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Zoledronic acid was not mutagenic in bacterial reverse mutation tests in Salmonella typhimurium and Escherichia coli or in cultured V79 Chinese hamster lung cells. Zoledronic acid did not induce chromosome aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo micronucleus test in rats.

Carcinogenicity.

In carcinogenicity studies, zoledronic acid 4 mg was administered orally by gavage to rats and mice at daily doses of 0.1, 0.5 and 2.0 mg/kg and 0.1, 0.3 and 1.0 mg/kg, respectively, for at least 104 weeks without evidence of carcinogenic potential. Chronic parenteral administration was not feasible given the potential of the compound to cause severe local irritation. The pharmacological bone changes typically observed following long-term bisphosphonate administration to young animals with growing skeletons gave clear evidence of systemic exposure to zoledronic acid 4 mg in both species at all doses.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, sodium citrate, water for injections.

6.2 Incompatibilities

Studies with glass bottles, as well as several types of infusion bags and infusion lines made from polyvinylchloride, polyethylene and polypropylene (prefilled with 0.9% sodium chloride injection or 5% glucose injection), showed no incompatibility with zoledronic acid 4 mg/100 mL.
To avoid potential incompatibilities, zoledronic acid 4 mg solution is to be diluted with 0.9% sodium chloride injection or 5% glucose injection.
Zoledronic acid 4 mg/100 mL must not be mixed with calcium or other divalent cation containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APO-Zoledronic Acid 4 mg/5 mL concentrated injection for infusion.

Clear plastic vials, rubber stoppers and aluminium seals with polypropylene flip off caps of 1, 4 or 10 vials*.
(AUST R 190337).

APO-Zoledronic Acid 4 mg/100 mL injection solution for infusion.

Clear glass vials, rubber stoppers and aluminium seals with polypropylene flip off caps of 1, 4 or 5 vials.*
(AUST R 205927).
*Not all strengths and pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Zoledronic acid monohydrate is a white, crystalline powder. It is soluble in water, most soluble at neutral pH (> 290 mg/mL; pH = 6.8) and practically insoluble in organic solvents.
Chemical Name: 1-hydroxy-2- (1H-imidazol- 1-yl)ethane- 1,1-diphosphonic acid monohydrate. Molecular Formula: C₅H₁₀N₂O₇P₂H₂O. Molecular Weight: 290.11.

Chemical structure.

CAS number.

165800-06-6 (zoledronic acid monohydrate), 118072-93-8 (zoledronic acid anhydrous).

7 Medicine Schedule (Poisons Standard)

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