Consumer medicine information

Zoledronic Acid Accord

Zoledronic acid

BRAND INFORMATION

Brand name

Zoledronic Acid Accord

Active ingredient

Zoledronic acid

Schedule

SUMMARY CMI

ZOLEDRONIC ACID ACCORD

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Zoledronic Acid Accord?

Zoledronic Acid Accord contains the active ingredient zoledronic acid. This medicine can be used:

To lower the amount of calcium in the blood when it becomes too high, as may happen in some forms of cancer.
To slow down the spread of cancers in bone, helping to prevent changes to the bones that may cause them to weaken.
As an additional treatment for women with early breast cancer, who are in established menopause.

For more information, see Section 1. Why am I using Zoledronic Acid Accord? in the full CMI.

2. What should I know before I'm given Zoledronic Acid Accord?

Do not use if you are allergic to zoledronic acid, any of the ingredients listed at the end of this leaflet or any other bisphosphonate medicine.

Talk to your doctor if you have any other medical conditions, take any other medicines, plan to have dental treatment, are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I'm given Zoledronic Acid Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zoledronic Acid Accord and affect how it works.

See Section 3. What if I am taking other medicines? in the full CMI.

4. How is Zoledronic Acid Accord given?

Zoledronic Acid Accord is an injection and will be given to you by your doctor.

More instructions can be found in Section 4. How is Zoledronic Acid Accord given? in the full CMI.

5. What should I know while being given Zoledronic Acid Accord?

Things you should do	Tell any other doctors, nurses or pharmacists who treat you that you are taking this medicine Tell your doctor immediately If you become pregnant while taking this medicine Tell your doctor if you experience any of the side effects listed in the CMI
Things you should not do	Do not receive Zoledronic Acid Accord if you are allergic to zoledronic acid, any of the ingredients listed at the end of this leaflet or any other bisphosphonate medicine.
Driving or using machines	Be careful driving or operating machinery until you know how Zoledronic Acid Accord affects you.

For more information, see Section 5. What should I know while being given Zoledronic Acid Accord? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Some of the common and serious side effects are included below in the CMI. Speak to your doctor if you have side effects and they worry you.

Symptoms of a serious allergic reaction are:

skin rash, itching or hives on the skin
shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue, throat or other parts of the body

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

ZOLEDRONIC ACID ACCORD

Active ingredient: zoledronic acid

Consumer Medicine Information (CMI)

This leaflet provides important information about using Zoledronic Acid Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Zoledronic Acid Accord.

Where to find information in this leaflet:

1. Why am I using Zoledronic Acid Accord?
2. What should I know before I'm given Zoledronic Acid Accord?
3. What if I am taking other medicines?
4. How is Zoledronic Acid Accord given?
5. What should I know while being given Zoledronic Acid Accord?
6. Are there any side effects?
7. Product details

1. Why am I using Zoledronic Acid Accord?

Zoledronic Acid Accord contains the active ingredient zoledronic acid. Zoledronic Acid Accord 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 reduce the amount of calcium in the blood.

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 Accord can be used to lower the amount of calcium in the blood when it becomes too high, as may happen in some forms of cancer.

Zoledronic Acid Accord can also be 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.

Zoledronic acid can be used as an additional treatment for women with early breast cancer who are in established menopause.

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

2. What should I know before I'm given Zoledronic Acid Accord?

Warnings

Do not receive Zoledronic Acid Accord if:

you are allergic to zoledronic acid, any of the ingredients listed at the end of this leaflet or any other bisphosphonate medicine

Check with your doctor if you have or have had:

a kidney or liver problem
a heart condition
asthma and are also allergic to aspirin
surgery on your thyroid
you take any other biphosphonates or other strengths of zoledronic acid
pain in the teeth, gums or jaw, swelling or numbness of the jaw or a "heavy jaw feeling" or loosening of a tooth or any other oral issues
joint stiffness, aches and pains and difficulty in movement (especially of the hip or thigh) or pain around the external ear canal
you take medication that may lower calcium levels in your blood and you may require calcium with Vitamin D supplements

Your doctor may want to take special precautions if you have any of the above conditions.

Other bisphosphonate medicines can cause breathing difficulties in people with asthma who are allergic to aspirin. It is not known whether zoledronic acid can have this effect.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether Zoledronic Acid Accord passes into breast milk. You should not breastfeed during treatment with Zoledronic Acid Accord.

Your doctor will discuss the risks and benefits of using Zoledronic Acid Accord if you are pregnant or breast-feeding.

General

If you are being treated with Zoledronic Acid Accord you should not be treated with other strengths of zoledronic acid concomitantly.

It is advisable to have a dental check-up before starting on Zoledronic Acid Accord. Tell your dentist you may be receiving Zoledronic Acid Accord.

Tell your doctor if you need to have any dental treatment or dental surgery. If you are undergoing dental treatment or will undergo dental surgery, tell your dentist that you are being treated with Zoledronic Acid Accord.

A dental condition called jaw osteonecrosis has been reported in some patients being treated with Zoledronic Acid Accord or with other drugs in the same class as Zoledronic Acid Accord. You may need to have dental treatments completed before starting it.

Ensure sufficient intake of fluid (water) prior to infusions as directed by your doctor as this will help prevent dehydration.

3. What if I am taking other medicines?

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

Some medicines and Zoledronic Acid Accord may interfere with each other, these include:

medicines that may have side effects on your kidneys
aminoglycoside medicines, used to treat severe infections. The combination of aminoglycoside and bisphosphonate medicines may cause the level of calcium in the blood to become too low
anti-angiogenic medicines as part of your cancer treatment. The combination of these medicines and bisphosphonate medicines may increase the risk of bone damage in the jaw (osteonecrosis)
any other medicine containing zoledronic acid or other bisphosphonates, such as risedronate, alendronate
loop diuretics, medicines used to treat high blood pressure or oedema
thalidomide, use to treat multiple myeloma
calcitonin, a type of medicine used to treat post-menopausal osteoporosis and high calcium levels

You may need to use different amounts of your medicines or take different medicines. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Zoledronic Acid Accord.

4. How is Zoledronic Acid Accord given?

How it will be given

Treatment with Zoledronic Acid Accord will be under the supervision of a doctor. Your treatment with Zoledronic Acid Accord may be given to you by a doctor or nurse. Zoledronic Acid Accord solution is given as an infusion into your 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 Accord to make sure the medicine is not affecting your kidneys.

How much you will be given

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

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

When given as an additional treatment for women with early breast cancer, the recommended dose of 4 mg, given as an infusion every 6 months for 3 years or every 3 months for 2 years.

Your doctor may give you a lower dose if you have a mild kidney problem. Your doctor may also prescribe a daily calcium supplement and a multivitamin containing Vitamin D.

If you are given too much

As your doctor will be monitoring your condition carefully, it is unlikely that you will be given too much Zoledronic Acid Accord.

Tell your doctor if you have any of the following symptoms. They may mean that the level of calcium in your blood has fallen too far:

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

5. What should I know while being given Zoledronic Acid Accord?

Things you should do

Tell any other doctors, nurses or pharmacists who treat you that you are taking this medicine. If you are about to be started on any new medicine, remind your doctor and pharmacist that you are having Zoledronic Acid Accord.

If you become pregnant while taking this medicine, tell your doctor immediately. Your doctor can discuss with you the risks of continuing treatment while you are pregnant.

Keep all of your doctor's appointments so that your progress can be checked.

You will need regular blood tests to make sure the treatment is working. Regular blood tests can also find side effects before they become serious.

Tell your doctor and dentist immediately about any dental symptoms including pain or unusual feeling in your teeth or gums, or any dental infections.

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.

Tell your dentist that you are being treated with Zoledronic Acid Accord.

Your dentist may need to take special precautions.

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 or dentist immediately.

Driving or using machines

Be careful driving or operating machinery until you know how Zoledronic Acid Accord affects you.

If you are returning home immediately after the infusion, arrange to have someone else drive.

Looking after your medicine

The hospital will store Zoledronic Acid Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Zoledronic Acid Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effects

What to do

short-lasting fever, sometimes with flu-like symptoms such as chills, tiredness, weakness and aches and pains
redness, swelling or pain where the needle for the infusion was inserted
tingling or numbness of the hands or feet
upset stomach, abdominal pain, loss of appetite
nausea (feeling sick) or vomiting
dry or sore mouth
constipation or diarrhoea
swollen aching joints or muscles, pain in the bones
swelling of fingers, hands, feet, ankles or lower legs due to fluid build up
anxiety, confusion, difficulty sleeping
headache, facial pain
irritated eyes, blurred vision, eye pain, sensitivity to light, runny, itchy or swollen eyes
changes in taste sensation
cough
slow heart beat
increased sweating
irregular heart beat
difficulty breathing with wheezing or coughing
lung disease
weight increased
pain, weakness or discomfort in your thigh, hip or groin. Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may occur. Contact your doctor if you experience this as it may be an early sign of a possible fracture of the thigh bone

Speak to your doctor if you have any of these common side effects and they worry you

Serious side effects

Serious side effects

What to do

signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue, throat or other part of the body; shortness of breath, wheezing or difficulty breathing
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
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
spasm and twitching
passing less urine than normal, blood in the urine
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)
passing large amount of urine (that can lead to dehydration), bone pain and muscle weakness (can be a problem with how the kidneys are working)

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Some of these (e.g. effects on kidney function and on the level of some chemicals in the blood) can only be found by laboratory testing.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

It is not addictive.

What Zoledronic Acid Accord contains

Active ingredient (main ingredient)	zoledronic acid
Other ingredients (inactive ingredients)	mannitol sodium citrate dihydrate water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Zoledronic Acid Accord looks like

Zoledronic Acid Accord is a clear colourless solution supplied in a plastic vial in packs of 1.

(4 mg/5 mL: AUST R 223405).

Who distributes Zoledronic Acid Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in October 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Zoledronic Acid Accord

Active ingredient

Zoledronic acid

Schedule

1 Name of Medicine

Zoledronic acid.

2 Qualitative and Quantitative Composition

1 mL contains 0.8 mg zoledronic acid.
1 vial of 5 mL concentrated injection contains 4 mg zoledronic acid (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

Zoledronic Acid Accord is a clear, colourless solution, practically free from visible particles and is available as a sterile liquid concentrate for injection.
After further dilution, Zoledronic Acid Accord is administered by intravenous (IV) infusion (see Section 4.2 Dose and Method of Administration). The concentrate for injection is for single use in one patient on one occasion only.

4 Clinical Particulars

4.1 Therapeutic Indications

Zoledronic Acid Accord is indicated:
For the prevention of skeletal-related events (pathological fracture, spinal cord compression, radiation to bone or surgery to bone) in patients with advanced malignancies involving bone.
For treatment of tumour-induced hypercalcaemia.
As an adjunct to adjuvant treatment for women with early breast cancer who are in established menopause.

4.2 Dose and Method of Administration

For information on the dilution of Zoledronic Acid Accord, 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, given as an intravenous infusion lasting no less than 15-minutes every 3 to 4 weeks. Zoledronic Acid Accord should be further diluted with 100 mL 0.9% w/v sodium chloride or 5% w/v glucose injection. 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 15 minutes (see Instructions for use and handling). Zoledronic Acid Accord should be further diluted with 100 mL 0.9% w/v sodium chloride or 5% w/v glucose injection. The hydration status of patients must be assessed prior to administration of Zoledronic Acid Accord to assure that patients are adequately hydrated prior to and following administration of Zoledronic Acid Accord. Following an initial dose of 4 mg, the median time to relapse is 30 days.

As an adjunct to adjuvant treatment for women with early breast cancer who are in established menopause.

Dosage regimen for adults (including elderly patients).

The recommended dose for is 4 mg, given as an intravenous infusion lasting no less than 20 minutes either: once every 6 months for 3 years or once every 3 months for 2 years (the optimal dose has not been established). Zoledronic Acid Accord should be further diluted with 100 mL 0.9% w/v sodium chloride or 5% w/v glucose injection. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.

Patients with impaired renal function.

The use of Zoledronic Acid Accord 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; 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 Accord 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 Accord 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 Accord IV Infusion 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 Accord outweighs the possible risk. Patients being treated for bone metastases should have the dose of Zoledronic Acid Accord 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 treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Accord should be resumed at the same dose administered prior to treatment interruption.

Monitoring advice.

Instructions for use and handling.

Zoledronic Acid Accord contains no antimicrobial agent and is for single use in one patient on one occasion only. Discard any remaining residue.
Zoledronic Acid Accord is available as a 4 mg/5 mL liquid concentrate (the liquid concentrate vial contains an overfill 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 injection or 5 % w/v glucose injection). If refrigerated, the solution must be allowed to reach room temperature before administration.

Instructions on preparing reduced doses of Zoledronic Acid Accord.

In patients with mild to moderate renal impairment, which is defined as CrCl 30 to 60 mL/min, reduced Zoledronic Acid Accord dosages are recommended, except in patients with TIH (see Section 4.2 Dose and Method of Administration, Patients with impaired renal function).
To prepare reduced doses of Zoledronic Acid Accord withdraw an appropriate volume of the liquid concentrate (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.

Stability after dilution.

To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2‐8°C for not more than 24 hours.
Also see Section 6.2 Incompatibilities.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Administration of Zoledronic Acid Accord.

Zoledronic Acid Accord 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 15 minutes.

Rehydration.

Patients must be maintained in a well hydrated state prior to and following administration of Zoledronic Acid Accord. Patients must be assessed prior to administration of Zoledronic Acid Accord 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 Accord 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.
Zolendronic acid is also marketed in 5 mg/100 mL 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. When receiving zoledronic acid for one indication, patients should not receive additional zoledronic acid at any dose for any other indication, 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.

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 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 Accord 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.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) has been reported predominantly in patients treated with bisphosphonates, including zoledronic acid. 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 (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 Accord-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of 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 acid therapy has not been established.
During Zoledronic Acid Accord 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 has 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.

Hypocalcemia.

Hypocalcemia 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 hypocalcemia. In some instances, the hypocalcemia may be life-threatening. Caution is advised when Zoledronic Acid Accord is administered with other hypocalcemia causing drugs, as they may have synergistic effect resulting in severe hypocalcemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Serum calcium should be measured and hypocalcemia must be corrected before initiating zoledronic acid therapy. Provide calcium and vitamin D supplementation to patients during treatment (unless the indication for use is hypercalcaemia).

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 zolendronic 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 (see Section 4.2 Dose and Method of Administration). 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 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.

Use in the elderly.

The postmenopausal osteoporosis trial included 3868 patients treated with 5 mg zoledronic acid who were at least 65 years of age, while 1497 patients were at least 75 years old. No overall differences in efficacy or safety were observed between patients under 75 years of age with those at least 75 years of age, except that the acute phase reactions occurred less frequently in the older patients.
The prevention of clinical fractures after hip fracture trial included 893 patients treated with 5 mg zoledronic acid who were at least 65 years of age, while 586 patients were at least 75 years old. Those who were 65 years and older had the same reduction in clinical fractures (35%) as those less than 65 years of age. Those 75 years and older had a 42% reduction in clinical fractures. No overall differences in safety were observed between these patients and younger patients.
However, because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

Paediatric use.

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

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

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 like zoledronic acid are administered with aminoglycosides or calcitonin or and loop diuretics, since these 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

Effects on fertility.

The fertility was decreased in rats dosed with 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 fetal 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 post implantation loss occurred at 0.4 mg/kg/day (3 times the human exposure). No embryofetal 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 a 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 zoledronic acid 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 following is an overview of safety data from clinical trials conducted in patients receiving zoledronic acid for the prevention of skeletal-related events in the setting of advanced malignancies involving bone, or for tumour-induced hypercalcaemia.
The most serious adverse drug reactions reported in these patients were: 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 2 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. Similar adverse reactions to zoledronic acid have been observed in literature. Adverse reactions to zoledronic acid 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 Description of selected adverse reaction). 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. 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 drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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). See Table 2.

Literature publications regarding safety in patients with early breast cancer receiving bisphosphonates in the adjuvant setting.

A three-arm, open label, randomised study was conducted to assess the risk factors for bisphosphonate-related osteonecrosis of the jaw as result of adjuvant bisphosphonates therapy in early-stage breast cancer (Kizub et al., 2021). The study randomised women with Stage I-III breast cancer to receive zoledronic acid, clodronate, or ibandronate for three years, implemented bisphosphonate-related osteonecrosis of the jaw prevention guidelines, and collected information about dental health and development of bisphosphonate-related osteonecrosis of the jaw. All statistical tests were two-sided. Of 6018 women, 48 developed bisphosphonate-related osteonecrosis of the jaw. Infection was present in 44%. Median time to bisphosphonate-related osteonecrosis of the jaw was 2.1 years for zoledronic acid, 2.0 years for ibandronate and 3.4 years for clodronate (p=0.04). Bisphosphonate-related osteonecrosis of the jaw was associated with bisphosphonate type (28/2231 (1.26%) for zoledronic acid, 8/2235 (0.36%) for clodronate, 12/1552 (0.77%) for ibandronate), dental calculus (odds ratio [OR] 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, bisphosphonate-related osteonecrosis of the jaw occurred spontaneously in 20 (35%) and was provoked by dental extraction in 20 (35%), periodontal disease in 14 (25%), denture trauma in 6 (11%), dental surgery in 2 (4%). Spontaneous bisphosphonate-related osteonecrosis of the jaw occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked bisphosphonate-related osteonecrosis of the jaw.
A systematic review and meta-analysis of randomised controlled trials of neoadjuvant, adjuvant and metastatic treatment of breast cancer, where at least one of the treatments was a bisphosphonate was conducted to identify and quantify the adverse effects of bisphosphonates (Jackson et al., 2021). Primary outcomes were adverse events of any type or severity (excluding death). Individual patient-level data was additionally sought from the AZURE trial to ascertain whether adverse effects differed by individual factors such as age or interacted with other common adjuvant breast cancer treatments. The authors identified 56 trials that reported adverse event data, which included a total of 29,248 patients (18,301 receiving bisphosphonate drugs versus 10,947 not). Out of 103 different adverse outcomes analysed, 24 showed a statistically and practically significant increase in patients receiving a bisphosphonate drug compared with those not (2 additional outcomes that appeared statistically significant came only from small studies with low event counts and no clinical suspicion so are likely artifacts). Most of these 24 are already clinically recognised: flu-like symptoms, fever, headache and chills, increased bone pain, arthralgia, myalgia, back pain, cardiac events, thromboembolic events, hypocalcaemia and osteonecrosis of the jaw, as well as possibly stiffness and nausea. Four additional potential adverse effects emerged for bisphosphonate drugs in this analysis which have not classically been recognised: fatigue, neurosensory problems, hypertonia/muscle spasms and possibly dysgeusia. Several symptoms previously reported as potential side effects in the literature were not significantly increased in this analysis: constipation, insomnia, respiratory problems, oedema or thirst/dry mouth. Individual patient-level data and subgroup analysis revealed little variation in side effects between women of different ages or menopausal status, those with metastatic versus non-metastatic cancer, or between women receiving different concurrent breast cancer therapies.

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

The following adverse reactions have been reported during post-marketing experience with zoledronic acid 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.

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.

Bronchospasms.

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 acid 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, preexisting 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 have 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 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 co-morbid 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 (breast cancer, multiple myeloma). In patients with early breast cancer receiving zoledronic acid as an adjunct to adjuvant treatment in the SWOG 0307 study, the rate of ONJ was approximately 1.3% despite implementation of osteonecrosis prevention guidelines (Kizub et al., 2021; see Literature publications regarding safety in patients with early breast cancer receiving bisphosphonates in the adjuvant setting).

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 onset time 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.

4.9 Overdose

Clinical experience with acute overdosage of zoledronic acid 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 13 11 26 (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.
The precise mechanism of action in reducing recurrence and mortality in early breast cancer is unknown.

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 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 3.

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 4.

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 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 5.

Zoledronic acid 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 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 4 mg zoledronic acid or placebo every four weeks for one year. Patients were evenly distributed between zoledronic acid-treated and placebo groups.
The SRE rate ratio at one year was 0.61, indicating that treatment with zoledronic acid 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-treated group versus 49.6% in the placebo group (p = 0.003). Zoledronic acid significantly delayed the time of onset of the first SRE compared with placebo (median not reached versus 364 days; p = 0.007). Zoledronic acid 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-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 was consistently below baseline.

Tumour-induced hypercalcaemia (TIH).

Two identical multicenter, 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 multicenter 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 6.

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 7.

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).

Adjunct to adjuvant treatment for women with early breast cancer who are in established menopause.

Approval of this indication was based two key literature publications (Early Breast Cancer Trialists' Collaborative Group (EBCTCG), 2015 and O'Carrigan et al., 2017).

Early breast cancer trialists' collaborative group (EBCTCG), 2015.

A meta-analysis was conducted using individual patient data for 18,766 women who received bisphosphonates (97% for 2 to 5 years) across 26 randomised controlled clinical trials (EBCTCG, 2015). Trials were eligible for inclusion if they began before 2008 and randomly assigned women between a bisphosphonate of any type, dose, and schedule versus a control group (open label or placebo) with no bisphosphonate, all other treatments being similar in both groups.
The primary outcomes were recurrence, distant recurrence and breast cancer mortality. Pre-planned subgroup analyses were conducted based on site of first distant recurrence (bone versus other), menopausal status (postmenopausal [combining natural and artifical] or not) and bisphosphonate class (aminobisphosphonate [including zoledronic acid] or other). Intention-to-treat log-rank methods were used to generate bisphosphonate versus control first-event rate ratios, reported as RR [95% confidence interval], with 2-sided p-value.
Among premenopausal women, treatment had no apparent effect on any outcome. Among 11,767 postmenopausal women significant reductions were demonstrated in the RR for recurrence (0.86 [0.78, 0.94], p=0.002), distant recurrence (0.82 [0.74, 0.92], p=0.0003), bone recurrence (0.72 [0.60, 0.86], p=0.0002), and breast cancer mortality (0.82 [0.73, 0.93], p=0.002). The 2-sided p-value associated with heterogeneity of benefit was 0.06 for trend with menopausal status and 0.03 for trend with age, and was non-significant for bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality.

O'Carrigan et al., 2017.

A systematic review was conducted to assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: in women with early breast cancer, in women with advanced breast cancer without bone metastases, and in women with metastatic breast cancer and bone metastases (O'Carrigan et al., 2017). The review included 44 randomised controlled trials involving 37,302 women.
In women with early breast cancer, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI): 0.75 to 0.99, p=0.03, 11 studies, 15,005 women, moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit for women with early breast cancer overall (HR 0.91, 95% CI: 0.83 to 0.99, p=0.04, 9 studies, 13,949 women, high-quality evidence with evidence of heterogeneity), however, subgroup analysis by menopausal status showed this was attributable to survival benefit for postmenopausal women only (HR 0.77, 95% CI: 0.66 to 0.90, p=0.001, 4 studies, 6048 women, high-quality evidence with no evidence of heterogeneity). No survival benefit was seen in the subgroup analysis of OS for premenopausal women (HR 1.03, 95% CI: 0.86 to 1.22, p=0.78, 2 studies, 3501 women, high-quality evidence with no heterogeneity). A disease-free survival benefit from bisphosphonates was also only demonstrated for the postmenopausal subgroup (HR 0.82, 95% CI: 0.74 to 0.91, p < 0.001, 7 studies, 8314 women, high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI: 0.54 to 1.08, p=0.13, 6 studies, 7602 women, moderate-quality evidence due to wide confidence intervals).

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 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 in both species at all doses.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, sodium citrate dihydrate, water for injections.

6.2 Incompatibilities

Studies with polyethylene bottles, as well as polyethylene infusion bags and infusion lines made from polyethylene (prefilled with 0.9% sodium chloride injection or 5% glucose injection), are compatible with Zoledronic Acid Accord.
To avoid potential incompatibilities, Zoledronic Acid Accord solution is to be diluted with 0.9% sodium chloride injection or 5% glucose injection.
Zoledronic Acid Accord 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

Zoledronic Acid Accord contains 4 mg zoledronic acid (calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate) as a liquid concentrate in plastic vials. Zoledronic Acid Accord is provided as single plastic vials.

6.6 Special Precautions for Disposal

Discard any remaining residue. In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

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 structure.

CAS number.

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

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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