Consumer medicine information

DBL Zoledronic Acid IV Infusion

Zoledronic acid

BRAND INFORMATION

Brand name

DBL Zoledronic Acid IV Infusion

Active ingredient

Zoledronic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Zoledronic Acid IV Infusion.

What is in this leaflet

This leaflet answers some common questions about DBL™ Zoledronic Acid IV Infusion.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using DBL™ Zoledronic Acid IV Infusion against the benefits they expect it will have for you.

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

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

What DBL™ Zoledronic Acid IV Infusion is used for

DBL™ Zoledronic Acid IV Infusion contains the active ingredient zoledronic acid. It belongs to a group of medicines called bisphosphonates which work by stopping the breakdown of bone which can occur in some forms of cancer.

In people with advanced cancer involving the bone, DBL™ Zoledronic Acid IV Infusion is used prevent unwanted bone-related events such as fractures, severe back pain and the need for radiation or surgery to the bones.

DBL™ Zoledronic Acid IV Infusion can also be used to lower high levels of calcium in the blood due to cancer.

Your doctor may have prescribed DBL™ Zoledronic Acid IV Infusion for another purpose.

Ask your doctor if you have any questions regarding why DBL™ Zoledronic Acid IV Infusion has been prescribed for you.

DBL™ Zoledronic Acid IV Infusion is not addictive.

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

Before you are given DBL™ Zoledronic Acid IV Infusion

When you must not have it

Do not take or receive DBL™ Zoledronic Acid IV Infusion if:

you have had an allergic reaction to:

  • zoledronic acid or any of the 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.

you are pregnant
There is no information on the use of this medicine in pregnancy and therefore should not be used during pregnancy.

you are breast feeding
It is not known whether the active ingredient, zoledronic acid, passes into the breast milk and could affect your baby and therefore breast feeding should be discontinued before you are given DBL™ Zoledronic Acid IV Infusion.

the package is torn or shows signs of tampering

the expiry date (EXP) printed on the pack has passed.
If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be receiving DBL™ Zoledronic Acid IV Infusion, talk to your doctor.

Before you start to take or receive it

Tell your doctor if:

you have any other health problems, especially if:

  • you have a kidney or liver problem
  • you have a heart condition
  • you have asthma and are also allergic to aspirin
  • you are allergic to any other medicines, foods, dyes or preservatives
  • you have had surgery on your thyroid
  • 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

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

Tell your doctor if you need to have any dental treatment or dental surgery. A dental condition called jaw osteonecrosis has been reported in some patients being treated with zoledronic acid or with other drugs in the same class as DBL™ Zoledronic Acid IV Infusion. You may need to have dental treatments completed before starting it.

If you have not told your doctor about any of the above, tell them before you start receiving DBL™ Zoledronic Acid IV Infusion.

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 any that you have bought without a prescription from a pharmacy, supermarket or healthfood shop.

Some medicines may interfere with DBL™ Zoledronic Acid IV Infusion. These medicines include:

  • medicines that may have side effects on your kidneys (e.g. Diuretics or ‘water’ tablets)
  • aminoglycoside medicines, used to treat severe infections. The combination of an aminoglycoside and bisphosphonate medicine may cause the level of calcium in the blood to become too low.
  • Thalidomide, a medicine which may be used to treat some forms of cancer

These medicines may be affected by DBL™ Zoledronic Acid IV Infusion, or may affect how well it works. You may need to receive different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while receiving DBL™ Zoledronic Acid IV Infusion.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How DBL™ Zoledronic Acid IV Infusion is given

DBL™ Zoledronic Acid IV Infusion is prepared by a healthcare professional in a hospital setting. It is given as a ‘drip’ into a vein, usually over a period of 15 minutes.

Your doctor will decide what dose of DBL™ Zoledronic Acid IV Infusion you will receive, depending on your condition.

Make sure you drink enough fluids before and after the treatment as directed by your doctor. Two glasses of fluid (such as water) before and after the infusion are usually enough. This will help to prevent dehydration.

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

If you receive too much

As DBL™ Zoledronic Acid IV Infusion is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

Tell your doctor if you have any of the following symptoms. This may mean that the level of calcium in your blood is too low.

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

Your doctor may give you extra calcium supplements, should your calcium level become too low

While you are having DBL™ Zoledronic Acid IV Infusion

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 all doctors, dentists and pharmacists who are treating you that you are receiving DBL™ Zoledronic Acid IV Infusion.

Tell your doctor if you become pregnant while receiving DBL™ Zoledronic Acid IV Infusion.

Practice good dental hygeine. Be sure to brush and floss your teeth daily, and have regular dental check-ups.

If you develop pain in your mouth, teeth or jaw, or have bleeding gums, or have an unusual feeling in your teeth or gums, tell your doctor and dentist immediately. A dental condition called jaw osteonecrosis has been reported in some patients being treated with zoledronic acid or other drugs in the same class.

Things to be careful of

Be careful driving or operating machinery until you know how DBL™ Zoledronic Acid IV Infusion affects you. The effect of DBL™ Zoledronic Acid IV Infusion on the ability to drive or use machinery has not been studied. Be careful driving or operating machinery until you know how DBL™ Zoledronic Acid IV Infusion affects you.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well after you have been given DBL™ Zoledronic Acid IV Infusion .

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.

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

Tell your doctor or nurse if you notice any of the following 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
  • 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 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

Tell your doctor or dentist 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
  • Any thigh, hip or groin pain
  • signs that the level of calcium in your blood may have fallen too far, such as unusual lightheadedness, 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
  • 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.
  • any ear pain, discharge from the ear and/or an ear infection
  • pain and or ache around the hip and groin area, this may be serious condition of the hip and thigh bone.

Some of the above side effects may be serious. You may need urgent medical attention.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don’t understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After having DBL™ Zoledronic Acid IV Infusion

Storage

If you are keeping a supply of DBL™ Zoledronic Acid IV Infusion at home:

Store the medicine in a cool dry place below 30 degrees C.

Do not store DBL™ Zoledronic Acid IV Infusion 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 DBL™ Zoledronic Acid IV Infusion or the expiry date has passed, return any unused medicine to your pharmacist.

Product description

Availability

DBL™ Zoledronic Acid IV Infusion (4 mg/100 mL) is available in packs of 1, 3, 4, 6 and 10. (not all presentations may be marketed)

What DBL™ Zoledronic Acid IV Infusion looks like

DBL™ Zoledronic Acid IV Infusion is a liquid packaged in plastic infusion bags.

Ingredients

DBL™ Zoledronic Acid IV Infusion

Active ingredient – Zoledronic acid

Inactive ingredients

  • mannitol
  • sodium citrate dihydrate
  • sodium chloride
  • water for injections

DBL™ Zoledronic Acid IV Infusion does not contain sucrose, gluten, tartrazine or any other azo dyes.

Distributor

DBL™ Zoledronic Acid IV Infusion is distributed by:

Pfizer Australia Pty Ltd
ABN 50 008 422 348
Level 17, 151 Clarence Street
Sydney NSW 2000 Australia
Toll Free number: 1800 675 229

Please check with your pharmacist for the latest Consumer Medicine Information

Australian Registration Numbers

  • 4mg/100 mL infusion AUST R - 188261

This leaflet was prepared in January 2019.

Published by MIMS March 2019

BRAND INFORMATION

Brand name

DBL Zoledronic Acid IV Infusion

Active ingredient

Zoledronic acid

Schedule

S4

 

1 Name of Medicine

Zoledronic acid.

6.7 Physicochemical Properties

Chemical Name: 1-hydroxy-2- (1 H-imidazol-l-yl) ethane-1, 1-diphosphonic acid monohydrate.
Empirical Formula: C5H10N2O7P2.H2O.
Molecular Weight: 290.11.

Chemical structure.


CAS number.

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

2 Qualitative and Quantitative Composition

DBL Zoledronic acid IV Infusion is available as a sterile solution of injection administered by infusion. Each bag contains 4 mg zoledronic acid (calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate).
The active ingredient of DBL Zoledronic acid IV Infusion is a bisphosphonate, zoledronic acid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for intravenous infusion.
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.

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 Cmax, synergistic cytostatic effect with other anti-cancer drugs.

Clinical trials.

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

Three randomised, double-blind studies (039, 010, 011) were conducted to assess the efficacy of zoledronic acid in preventing skeletal-related events (SREs) in patients with advanced malignancies involving bone. The primary efficacy variable was the proportion of patients experiencing at least one SRE, defined as radiation therapy to bone, surgery to bone, pathological bone fracture or spinal cord compression.
In Study 039, zoledronic acid 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 2.
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 3.
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 4.
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 preplanned 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 5).
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 6.
Retreatment with zoledronic acid 8 mg was allowed for patients in any of the treatment arms whose serum calcium did not return to normal or remain normal after initial treatment. A minimum of 7 days was allowed to elapse before retreatment to allow for full response to the initial dose. In clinical studies, 69 patients have received a second infusion of 8 mg zoledronic acid for hypercalcaemia. The complete response rate observed in these retreated patients was 52%.
Although these studies used doses of 8 mg and an infusion time of 5 minutes, subsequent safety data have indicated that such dosage regimens are associated with an increased risk of renal impairment. Therefore, doses of zoledronic acid should not exceed 4 mg and should not be administered over less than 15 minutes (see Section 4.4 Special Warnings and Precautions for Use).

5.2 Pharmacokinetic Properties

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

Absorption.

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

Distribution.

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

Metabolism.

Zoledronic acid is not metabolised and is excreted unchanged via the kidney.

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 impairment.

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.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Zoledronic acid IV Infusion 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;
treatment of tumour-induced hypercalcaemia.

4.3 Contraindications

Clinically significant hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of DBL Zoledronic acid IV Infusion.
Pregnancy and breast-feeding.
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).

4.4 Special Warnings and Precautions for Use

Administration of DBL Zoledronic acid IV infusion.

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

Monitoring of metabolic parameters.

Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium and potassium, as well as serum creatinine, should be carefully monitored after initiating zoledronic acid therapy. If hypocalcaemia, hypophosphataemia or hypomagnesaemia occurs, short-term supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
DBL Zoledronic acid IV Infusion 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. Patients being treated with DBL Zoledronic acid IV Infusion for these conditions should not be treated with other strengths of zoledronic acid nor any other bisphosphonate concomitantly.
While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Occasional cases of mild, transient hypocalcaemia, usually asymptomatic, have been reported. Symptomatic hypocalcaemia occurs rarely and can be reversed with calcium gluconate. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcaemia due to relative hypoparathyroidism.

Osteonecrosis of the jaw.

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

Osteonecrosis of other anatomical sites.

Cases of osteonecrosis of other anatomical sites including the hip, femur and external auditory canal have been reported predominantly in adult cancer patients treated with bisphosphonates, including zoledronic acid.

Atypical fractures of the femur.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in zoledronic acid treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of zoledronic acid therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual risk 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 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. However, such reports have been infrequent. This category of drugs includes DBL Zoledronic acid IV Infusion (zoledronic acid). 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 re-challenged with the same drug or another bisphosphonate.

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 renal impairment.

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 patient 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 DBL Zoledronic acid IV Infusion 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 DBL Zoledronic acid IV Infusion is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.3 Contraindications).

Use in patients with severe renal impairment.

Limited clinical data are available in patients with pre-existing renal impairment (see Section 4.3 Contraindications). 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 DBL Zoledronic acid IV Infusion is not recommended in patients with severe renal impairment because there are limited clinical safety and pharmacokinetic data in this population, and there is a risk of renal function deterioration in patients treated with bisphosphonates, including zoledronic acid. In clinical trials, patients with severe renal impairment were defined as those with baseline serum creatinine > 400 micromol/L for patients with TIH and > 265 micromol/L for premenopausal patients with EBC and patients with bone metastases, respectively. In pharmacokinetic studies, patients with severe renal impairment were defined as those with baseline creatinine clearance < 30 mL/min.
In view of the potential impact of bisphosphonates, including zoledronic acid, on renal function, the lack of extensive clinical safety data in patients with severe renal impairment (serum creatinine > 400 micromol/L) and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance < 30 mL/min; see Section 5.2 Pharmacokinetic Properties), the use of DBL Zoledronic acid IV Infusion is not recommended in this patient population.

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of DBL Zoledronic acid IV Infusion in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In clinical studies, zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, 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.
Caution is indicated when zoledronic acid is used in combination with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when intravenous bisphosphonates are used in combination with thalidomide.
Caution is advised when bisphosphonates are administered with aminoglycosides and loop diuretics since both agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.

4.6 Fertility, Pregnancy and Lactation

The fertility was decreased in rats dosed with SC 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 testicularatrophy and/or mineralization 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)
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
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 embryo-fetal 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, DBL Zoledronic acid IV Infusion 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, breast-feeding should be discontinued before DBL Zoledronic acid IV Infusion administration.

4.8 Adverse Effects (Undesirable Effects)

Overview of clinical trial data.

Frequencies of adverse reactions to zoledronic acid 4 mg are mainly based on data collected from chronic treatment. 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. Intravenous administration has been most commonly associated with a flu-like syndrome in approximately 9% of patients, consisting of bone pain, fever, fatigue and rigors. 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.
There have been some reports of impaired renal function (2.3%) with chronic administration of zoledronic acid 4 mg. However, other risk factors in this severely ill patient population may have contributed as well.
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.
While not observed with zoledronic acid, administration of other bisphosphonates has been associated with bronchoconstriction in acetylsalicylic acid-sensitive asthmatic patients.

The following adverse drug reactions have been accumulated from clinical studies following predominantly chronic treatment with zoledronic acid.

Adverse reactions are ranked under headings of frequency, using the following convention:
Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Blood and lymphatic system disorders.

Common: anaemia.
Uncommon: thrombocytopenia, leukopenia.
Rare: pancytopenia.

Cardiovascular disorders.

Common: hypertension, hypotension.
Rare: bradycardia.

Eye disorders.

Common: conjunctivitis.
Uncommon: blurred vision.
Very rare: uveitis, episcleritis.

Gastrointestinal disorders.

Common: nausea, vomiting, anorexia, constipation.
Uncommon: diarrhoea, abdominal pain, dyspepsia, stomatitis, dry mouth.

General disorders and administration site conditions.

Common: fever, flu-like syndrome (including fatigue, rigors, malaise and flushing), asthenia, peripheral oedema.
Uncommon: injection site reactions (including pain, irritation, swelling, induration, redness), chest pain, weight increase.

Immune system disorders.

Uncommon: hypersensitivity reaction.
Rare: angioneurotic oedema.

Laboratory abnormalities.

Very common: hypophosphataemia.
Common: blood creatinine and blood urea increased, hypocalcaemia.
Uncommon: hypomagnesaemia, hypokalaemia.
Rare: hyperkalaemia, hypernatraemia.

Musculoskeletal, connective tissue and bone disorders.

Common: bone pain, joint stiffness, myalgia, arthralgia, generalised pain.
Uncommon: muscle cramps.

Nervous system disorders.

Common: headache, paraesthesia.
Uncommon: dizziness, taste disturbance, hypoaesthesia, hyperaesthesia, tremor.

Psychiatric disorders.

Common: sleep disturbance.
Uncommon: anxiety.
Rare: confusion.

Renal and urinary disorders.

Common: renal impairment.
Uncommon: acute renal failure, haematuria, proteinuria.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea, cough.

Skin and subcutaneous tissue disorders.

Common: hyperhidrosis.
Uncommon: pruritus, rash (including erythematous and macular rash).

Postmarketing experience.

The following adverse reactions have been reported during post-approval use of zoledronic acid. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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 of these patients 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, 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 (advanced breast cancer, multiple myeloma).
The following events have also been reported: hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors, atrial fibrillation, somnolence, bronchoconstriction, anaphylactic reaction/shock, urticaria, uveitis, episcleritis, scleritis and orbital inflammation, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction, including zoledronic acid).

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.

4.2 Dose and Method of Administration

Dosage.

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 DBL Zoledronic acid, IV infusion 4 mg/100 mL given as an intravenous infusion lasting no less than 15-minutes, every 3 to 4 weeks. Patients should also be administered an oral calcium supplement of 500 mg and 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 DBL Zoledronic acid IV Infusion 4 mg/100 mL given as a single intravenous infusion of no less than 15 minutes (see Instructions for use and handling). The hydration status of patients must be assessed prior to administration of DBL Zoledronic acid IV Infusion to assure that patients are adequately hydrated prior to and following administration of DBL Zoledronic acid IV infusion. Following an initial dose of 4 mg, the median time to relapse is 30 days.

Method of administration.

DBL Zoledronic acid IV Infusion is administered by intravenous infusion. DBL Zoledronic acid IV Infusion must only be used by clinicians experienced in the administration of intravenous bisphosphonates.

Instructions for use and handling.

DBL Zoledronic acid IV infusion contains no antimicrobial agent and is for single use in one patient only. Discard any remaining residue.
DBL Zoledronic acid IV Infusion is available as a 4 mg/100 mL sterile solution for infusion). If refrigerated, the solution must be allowed to reach room temperature before administration.
DBL Zoledronic acid IV Infusion must not be mixed or given intravenously with any other medication and must be given through a separate vented infusion line at a constant infusion rate. If refrigerated, allow the refrigerated solution to reach room temperature before administration. Aseptic techniques must be followed during the preparation of the infusion.
Only clear solution free from particles and discolouration should be used.
After opening, the solution is chemically and physically stable for at least 24 hours at 2°C to 8°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.

Dosage adjustment.

Renal impairment.

The use of DBL Zoledronic acid IV Infusion 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 DBL Zoledronic acid IV Infusion 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 DBL Zoledronic acid IV Infusion dose is recommended (see Section 4.4 Special Warnings and Precautions for Use) (see Table 1).
Following initiation of therapy, patients who receive DBL Zoledronic acid 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 DBL Zoledronic acid IV Infusion outweighs the possible risk. Patients being treated for bone metastases should have the dose of zoledronic acid 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. DBL Zoledronic acid IV Infusion should be resumed at the same dose administered prior to treatment interruption.

Instructions on preparing reduced doses of zoledronic acid.

In patients with mild to moderate renal impairment, which is defined as CLcr 30 to 60 mL/min, reduced zoledronic acid dosages are recommended, except in patients with TIH.

Hepatic impairment.

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

Dialysis.

This is insufficient data on the use of zoledronic acid in dialysis patients, no specific recommendation can be given for this patient population.

Concomitant disease.

Insufficient data available on the use of zoledronic acid in patients with concomitant disease. No specific recommendations can be given.
The maximum dose is not specified.

Monitoring advice.

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 DBL Zoledronic acid IV Infusion therapy.

Other relevant information such as relationship to meals and compatibility with other medicines and fluids.

Insufficient data available.

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.

4.9 Overdose

Clinical experience with acute over-dosage 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

DBL Zoledronic acid IV Infusion 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 Celsius. Medicines should be kept out of the reach of children.

6.5 Nature and Contents of Container

DBL Zoledronic acid IV Infusion contains 4 mg zoledronic acid (calculated as the anhydrous form, corresponding to 4.264 mg zoledronic acid monohydrate) as a solution for infusion in polypropylene (PP) plastic bags.

Pack sizes.

Packs of 1, 3, 4, 6 and 10 bags (not all presentations may be marketed).

6.6 Special Precautions for Disposal

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

Summary Table of Changes