Consumer medicine information

Zometa

Zoledronic acid

BRAND INFORMATION

Brand name

Zometa

Active ingredient

Zoledronic acid

Schedule

What is in this leaflet

This leaflet answers some common questions about Zometa.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.medsafe.govt.nz (New Zealand).

Those updates may contain important information about the medicine and its use of which you should be aware.

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 having Zometa against the benefits they expect it will provide.

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

Keep this leaflet. You may need to read it again.

What Zometa is used for

Zometa 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. Zometa 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.
Zometa 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.

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

Zometa is only available with a doctor's prescription. It is not addictive.

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

Before you have Zometa

When you must not have it

Do not have Zometa if you have ever had an allergic reaction to:

zoledronic acid (the active ingredient in Zometa) or to any of the other ingredients listed at the end of this leaflet
any other bisphosphonate medicine

Some of the symptoms of an allergic reaction may include 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.

If you are not sure whether you are allergic to other bisphosphonate medicines, talk to your doctor.

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

Do not have Zometa if you are pregnant. There is no information on the use of this medicine in pregnancy.

Do not breast-feed while you are having treatment with Zometa. It is not known if the active ingredient, zoledronic acid, passes into the breast milk and could affect your baby.

If you are being treated with Zometa (zoledronic acid), you should not be treated with Aclasta concomitantly.

Do not have Zometa after the expiry date printed on the label or if the packaging is torn or shows signs of tampering. In that case, return the medicine to your pharmacist.

Before you start to have it

Tell your doctor if:

you have a kidney or liver problem
you have a heart condition
you have asthma and are also allergic to aspirin
you have had surgery on your thyroid
you take any other biphosphonates
you had or have 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
you had or have 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.

It is advisable to have a dental check-up before starting on Zometa and regular dental check-ups while on Zometa. Tell your dentist you may be receiving Zometa.

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 Zometa. A dental condition called jaw osteonecrosis has been reported in some patients being treated with Zometa or with other drugs in the same class as Zometa. 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.

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

Taking other medicines

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

Some medicines and Zometa 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)
Aclasta or any other bisphosphonates, such as Actonel, Fosamax
loop diuretics, medicines used to treat high blood pressure or oedema
calcitonin (a type of medicine used to treat post-menopausal osteoporosis and high calcium levels).

You may need to take different amounts of these medicines or you may need to take different medicines. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you have Zometa.

How Zometa is given

How it will be given

Zometa is given as a 15-minute infusion into a vein.

You may also be given an infusion of fluids to ensure that you do not become dehydrated.

How much you need

To lower the amount of calcium in the blood, the usual dose of Zometa 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 give you a lower dose if you have a mild kidney problem. Your doctor may also prescribe a daily calcium supplement and a multiple vitamin containing Vitamin D.

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

If you have too much

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

While you are having Zometa

Things you must do

Make sure you follow your doctor's instructions carefully and keep all appointments. 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 immediately if you become pregnant while having treatment with Zometa. Your doctor can discuss with you the risks of having it while you are pregnant.

Tell your doctor and dentist immediately about any dental symptoms including pain, swelling or unusual feeling in your teeth or gums, or non-healing of sores or discharge or any dental infections. A dental condition called jaw osteonecrosis has been reported in some patients being treated with Zometa or other drugs in the same class as Zometa.

Tell your dentist that you are being treated with Zometa. Your dentist may need to take special precautions.

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

Tell any other doctor or pharmacist who treats you that you are having Zometa.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are having Zometa until you know how it 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 or dentist immediately.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are having Zometa. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

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

Tell your doctor if you notice any of the following side effects and they worry you:

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, red 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.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled 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, sores or non-healing sores in the mouth or discharge, swelling, dry mouth, numbness or a feeling of heaviness in the jaw ("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).

The above side effects may be serious. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed here may happen 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.

After having Zometa

Storage

If you are keeping a supply of Zometa at home:

Store the medicine in a cool dry place below 30°C.
Do not store Zometa or any other medicine in the bathroom or near a sink.
Do not leave it in the car on hot days.

Keep the medicine where young 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 you no longer need Zometa or the expiry date has passed, return any unused medicine to your pharmacist.

Product description

What it looks like

Zometa concentrated injection is packaged in plastic vials containing the active ingredient, zoledronic acid, in 5 mL solution.

Zometa ready to use injection solution is packaged in a plastic vial containing the active ingredient, zoledronic acid, in 100 mL solution. (Not supplied in New Zealand)

Ingredients

Contains sodium and sulfites.

Each vial of Zometa concentrated injection contains 4 mg of zoledronic acid. The vials also contain mannitol, sodium citrate and water for injections.

Each vial of Zometa injection solution contains 4 mg of zoledronic acid. The vials also contain mannitol, sodium citrate and water for injections. (Not supplied in New Zealand)

Sponsor

Zometa is supplied in Australia by:

SciGen (Australia) Pty Ltd
4/9 Mogo Place, Billinudgel,
NSW 2483 Australia

® = Registered Trademark

This leaflet was prepared in June 2021

Australian Registration Number:

Zometa concentrated injection 4 mg/5 mL AUST R 90882

Zometa injection solution 4 mg/100 mL AUST R 192265

Based on PI version (revision date): 15 June 2021

Published by MIMS October 2021

BRAND INFORMATION

Brand name

Zometa

Active ingredient

Zoledronic acid

Schedule

1 Name of Medicine

Zoledronic acid.

2 Qualitative and Quantitative Composition

Zometa powder for injection contains 4 mg zoledronic acid (calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate) as a lyophilised powder.
Zometa concentrated injection contains 4 mg zoledronic acid (calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate) as a liquid concentrate.
Zometa injection solution contains 4 mg zoledronic acid (calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate) as a ready to use injection solution.
Contains sodium and sulfites.
For the full list of excipients, Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zometa powder for injection.

White to off white lyophilised powder in glass vials. Diluent: Clear, colourless liquid in glass ampoules.

Zometa concentrated injection.

Clear, colourless solution in plastic vials.

Zometa injection solution.

Clear, colourless solution in plastic vials.

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 hypercalcemia.

4.2 Dose and Method of Administration

For information on the reconstitution and dilution of Zometa, 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. The Zometa 4 mg/5 mL concentrate should be reconstituted and further diluted with 100 mL 0.9% w/v sodium chloride or 5% w/v glucose solution. The 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 hypercalcemia (TIH).

Dosage regimen for adults (including elderly patients).

The recommended dose in hypercalcemia (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). The Zometa 4 mg/5 mL concentrate should be reconstituted and further diluted with 100 mL 0.9% w/v sodium chloride or 5% w/v glucose solution. The 4 mg/100 mL injection solution requires no further dilution. The hydration status of patients must be assessed prior to administration of Zometa to assure that patients are adequately hydrated prior to and following administration of Zometa. Following an initial dose of 4 mg, the median time to relapse is 30 days.

Patients with impaired renal function.

The use of Zometa 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 Zometa 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 Zometa dose is recommended (see Table 1; see Section 4.4 Special Warnings and Precautions for Use).

Following initiation of therapy, patients who receive Zometa 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 Zometa outweighs the possible risk. Patients being treated for bone metastases should have the dose of Zometa 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, Zometa treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zometa should be resumed at the same dose administered prior to treatment interruption.

Monitoring advice.

Instructions for use and handling.

Zometa powder for injection and Zometa liquid concentrate for injection contain no antimicrobial agent. Zometa is for single use in one patient only. Discard any remaining residue.
1. Zometa powder for intravenous injection. Each vial contains 4 mg zoledronic acid (anhydrous) as a sterile lyophilised powder (the vial contains an overfill of 4% to permit the withdrawal of the labelled amount of zoledronic acid from the vial). The powder must first be reconstituted in the vial using 5 mL water for injections from the ampoule supplied (the ampoule contains a 6.2% overfill to permit the withdrawal of the nominal dose from the ampoule). Dissolution must be complete before the solution is withdrawn. The required amount of the reconstituted solution is then further diluted with 100 mL of calcium free infusion solution (0.9% sodium chloride solution or 5% glucose solution). If refrigerated, the solution must be allowed to reach room temperature before administration.

Stability after reconstitution and dilution.

The reconstituted solution should be used immediately or as soon as practicable after preparation. If storage is necessary hold at 2-8°C.
After subsequent aseptic addition of the reconstituted solution to the infusion media, the infusion solution should also be used as soon as practicable to reduce the risk of microbiological hazard. If storage of the solution is necessary, hold at 2°-8°C. The total storage time from reconstitution of the powder to administration of the Zometa infusion solution should not be longer than 24 hours.
2. Zometa liquid concentrate for intravenous injection. Zometa is also available as a 4 mg/5 mL liquid concentrate (the liquid concentrate vial contains an overfill of 6% 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.
3. Zometa injection solution. Zometa is also available as a 4 mg/100 mL injection solution. The Zometa 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.
4. Instructions on preparing reduced doses of Zometa. In patients with mild to moderate renal impairment, which is defined as CrCl 30 to 60 mL/min, reduced Zometa 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 Zometa 4 mg powder for injection or Zometa 4 mg/5 mL concentrate, withdraw an appropriate volume of the reconstituted solution or 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.
To prepare reduced doses of Zometa 4 mg/100 mL injection solution remove the corresponding volume of Zometa solution as indicated in Table 2 and replace it with an equal volume of sterile 0.9% w/v sodium chloride solution or 5% w/v glucose solution.

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 2°-8°C for not more than 24 hours.

4.3 Contraindications

Hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of Zometa; pregnancy and breastfeeding.

4.4 Special Warnings and Precautions for Use

Administration of Zometa.

Zometa 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 Zometa. Patients must be assessed prior to administration of Zometa to ensure that they are adequately hydrated. It is essential in the initial treatment of tumour induced hypercalcemia 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 hypercalcemia related metabolic parameters, such as serum levels of calcium, phosphate, magnesium and potassium, as well as serum creatinine, should be carefully monitored after initiating Zometa therapy. If hypocalcemia, hypophosphatemia or hypomagnesemia occurs, short-term supplemental therapy may be necessary. Untreated hypercalcemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
Zometa contains the same active ingredient as in Aclasta (zoledronic acid). Patients being treated with Zometa should not be treated with Aclasta concomitantly. Patients treated with Zometa should also not be treated with any other bisphosphonate concomitantly.
While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Occasional cases of mild, transient hypocalcemia, usually asymptomatic, have been reported. Symptomatic hypocalcemia 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 Zometa 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 Zometa 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 Zometa.
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 Zometa 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 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 Zometa 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. Zometa 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 Zometa 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 Zometa. 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 (see Section 4.2 Dose and Method of Administration).

Use in patients with 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.

Osteonecrosis.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) has been reported predominantly in patients treated with bisphosphonates, including Zometa. 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.
Postmarketing 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 Zometa.

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 Zometa treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Zometa 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 Zometa; however causality with Zometa therapy has not been established.
During Zometa 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 postmarketing experience, severe and occasionally incapacitating bone, joint and/or muscle pain have been reported in patients taking bisphosphonates. This category of drugs includes Zometa (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 Zometa. 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 Zometa 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 Zometa therapy. Patients should be adequately supplemented with calcium and vitamin D.

Paediatric use.

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

Use in the elderly.

The postmenopausal osteoporosis trial included 3868 Aclasta-treated patients 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 Aclasta-treated patients 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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Absence of interactions.

In clinical studies, Zometa 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 Zometa are administered with aminoglycosides or calcitonin or 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 Zometa is used in combination with other potentially nephrotoxic drugs.

Observed interactions to be considered.

Caution is advised when Zometa is administered with antiangiogenic 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 SC with 0.1 mg/kg/day zoledronic acid (0.1 times the maximum human exposure of 8 mg, based on BSA), and preimplantation 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).

Women of childbearing potential.

Women of childbearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the fetus while receiving Zometa. There may be a risk of fetal 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.
(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 postimplantation 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, Zometa should not be used during pregnancy.
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, breastfeeding should be discontinued before Zometa 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 Zometa 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 hypocalcemia. 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 Zometa 4 mg are mainly based on data collected from chronic treatment. Adverse reactions to Zometa 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 Zometa 4 mg or pamidronate 90 mg.
Within three days after Zometa 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 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 Zometa. Anorexia was reported in 1.5% of patients treated with Zometa 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 hypercalcemia, grade 3 (NCI Common Toxicity Criteria [CTC]) elevations of serum creatinine were seen in 2.3%, 3.1% and 3.0% of patients receiving Zometa 4 mg, Zometa 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).

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

The following adverse reactions have been reported during postmarketing experience with Zometa 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 Zometa).

Description of selected adverse reactions.

Renal function impairment.

Zometa has been associated with reports of renal function impairment.
In a pooled analysis of safety data from Zometa 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 Zometa (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 Zometa 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 Zometa (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 Zometa. 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, antiangiogenic 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 onset time is ≤ 3 days post-Zometa infusion, and the reaction is also referred to using the terms flu-like or postdose 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical experience with acute overdosage of Zometa 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 hypocalcemia, calcium gluconate infusions should be administered as clinically indicated.
For information on the management of overdose, contact the Poison 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 hypercalcemia 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: antitumour activity in some animal models, antiangiogenic activity, anti-pain activity.
In vitro: inhibition of osteoclast proliferation, cytostatic and proapoptotic activity on tumour cells at concentrations greater than the clinical C_max, synergistic cytostatic effect with other anticancer 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, Zometa was compared to placebo for the prevention of skeletal related events (SREs) in prostate cancer patients with 214 men receiving Zometa 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. Zometa 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 Zometa group compared with placebo (p = 0.002). Pain was measured at baseline and periodically throughout the trial. Patients receiving Zometa 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 Zometa 4 mg to pamidronate 90 mg, 1,116 patients (561 Zometa 4 mg, 555 pamidronate 90 mg) with multiple myeloma or breast cancer with at least one bone lesion were treated with 4 mg Zometa 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 Zometa 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), Zometa 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. Zometa 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 Zometa 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.

Zometa 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 Zometa 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 Zometa or placebo every four weeks for one year. Patients were evenly distributed between Zometa treated and placebo groups.
The SRE rate ratio at one year was 0.61, indicating that treatment with Zometa 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 hypercalcemia) was 29.8% in the Zometa treated group versus 49.6% in the placebo group (p = 0.003). Zometa significantly delayed the time of onset of the first SRE compared with placebo (median not reached versus 364 days; p = 0.007). Zometa reduced the risk of SREs by 41% in a multiple event analysis (risk ratio = 0.59, p = 0.019) compared with placebo.
In the Zometa 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 Zometa was consistently below baseline.

Tumour induced hypercalcemia (TIH).

Two identical multicenter, randomised, double blind, double dummy studies of Zometa 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 hypercalcemia (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 Zometa 4 mg and 8 mg groups in each study, but not for the pamidronate 90 mg group. To assess the effects of Zometa versus those of pamidronate, the two multicentre TIH studies were combined in a preplanned analysis. The results showed that Zometa 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 Zometa 8 mg and by day 7 for Zometa 4 and 8 mg doses. The following response rates were observed (see Table 7).

There were no statistically significant differences between the two Zometa doses.
Secondary efficacy variables, time to relapse and duration of complete response were also assessed (see Table 8). 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 Zometa doses had a statistically longer time to relapse than pamidronate. There was no statistically significant difference between the Zometa doses.

Retreatment with Zometa 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 Zometa for hypercalcemia. 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 Zometa 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 bodyweight. 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 hypercalcemia 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

Carcinogenicity.

In carcinogenicity studies, Zometa 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 Zometa in both species at all doses.

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.

Long term studies.

In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralisation or the mechanical properties of bone. Histomorphometric data from long-term rat and monkey experiments showed the typical response of bone to an anti-resorptive agent with a dose-dependent reduction in osteoclast activity and activation frequency of new remodelling sites in both trabecular and Haversian bone. Continuing bone remodelling was observed in bone samples from all animals treated with zoledronic acid. There was no evidence of a mineralising defect, no aberrant accumulation of osteoid and no woven bone in treated animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, sodium citrate dihydrate, 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 solution or 5% glucose solution), showed no incompatibility with Zometa.
To avoid potential incompatibilities, Zometa solution is to be diluted with 0.9% sodium chloride solution or 5% glucose solution.
Zometa 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 30 degrees C. Medicines should be kept out of the reach of children.