Consumer medicine information

Ostira

Zoledronic acid

BRAND INFORMATION

Brand name

Ostira

Active ingredient

Zoledronic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ostira.

What is in this leaflet

This leaflet answers some common questions about Ostira™.

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 Ostira™ 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 Ostira™ is used for

Ostira™ contains the active ingredient zoledronic acid. It belongs to a group of medicines called bisphosphonates.

Ostira™ is used

  • to treat osteoporosis in postmenopausal women to reduce incidence of bone fractures.
  • To strengthen bones in men who have osteoporosis
  • to treat osteoporosis in men and women over 50 years of age, to prevent additional fractures in those who have had a hip fracture,
  • to treat or prevent osteoporosis in men and women caused by treatment with steroid medicines such as prednisone
  • to treat Paget's disease of bone.

Osteoporosis is a disease which causes bones to become less dense, gradually making them weaker, more brittle and likely to break..

Paget's disease is a chronic disorder in which the bone material breaks down more quickly than usual, and new bone material grows more quickly than usual and in a disordered way. The new bone that is formed may be thicker but weaker than normal, which can cause pain and may lead to fractures.

.Your doctor may have prescribed Ostira™ for another purpose.

Ask your doctor if you have any questions regarding why Ostira™ has been prescribed for you.

Ostira™ is not addictive.

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

Before you are given Ostira™

When you must not have it

Do not take or receive Ostira™ 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 have kidney problems
If you are unsure, check with your doctor first

you have uveitis
An inflammatory problem in the eye. If you are unsure, check with 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 Ostira™.

you have low levels of calcium in your blood

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 Ostira™, 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 or parathyroid gland
  • you have a calcium deficiency or a vitamin D deficiency
  • you have or have had uveitis or iritis (inflammatory conditions of the eye).
  • 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 Ostira™. Tell your dentist you may be receiving Ostira™.

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 Ostira™. 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 Ostira™.

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. Also tell your doctor if you are being treated with other medicines which may contain zoledronic acid.

Some medicines may interfere with Ostira™. 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.

These medicines may be affected by Ostira™, 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 Ostira™.

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

How Ostira™ is given

Ostira™ is administered by a healthcare professional in a hospital setting. It is given as a ‘drip’ into a vein, usually over a period of 15 minutes. It is given once per year.

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.

Ostira™ is given as a single infusion over a period of at least 15 minutes. Each dose lasts at least one year. Your doctor will decide if you need additional doses.

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

If you receive too much

As Ostira™ 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 Ostira™

Things you must do

Make sure you follow your doctor's instructions carefully and keep all appointments.

If you get a headache, fever or other flu-like symptoms in the first three days after you are given Ostira™, take paracetamol if your doctor has told you to. Some people get short-lasting flu-like symptoms after having Ostira™. Paracetamol can provide some relief.

Take calcium and vitamin D supplements if your doctor has told you to. Most people with osteoporosis do not get enough calcium and vitamin D in their diet and supplements are needed to help strengthen your bones.

If you are being treated with Ostira™ for Paget's disease, your doctor should advise corrective treatment for a vitamin D deficiency and that you take calcium and vitamin D supplements for at least the first ten days after you have Ostira™ to reduce the risk of low calcium levels in your blood.

Tell all doctors, dentists and pharmacists who are treating you that you are receiving Ostira™.

Tell your doctor if you become pregnant while receiving Ostira™.

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

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well after you have been given Ostira™.

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
  • Muscle weakness
  • 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
  • palpitations or irregular heart beat which may be accompanied by dizziness and breathlessness
  • 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
  • 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 thigh, hip or groin pain, and or ache around the hip and groin area, this may be serious condition of the hip and thigh bone
  • any ear pain, discharge from the ear and/or an ear infection

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 Ostira™

Storage

If you are keeping a supply of Ostira™ at home:

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

Do not store Ostira™ 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 Ostira™ or the expiry date has passed, return any unused medicine to your pharmacist.

Product description

What Ostira™ looks like

Ostira™ is a clear, colourless liquid packaged in plastic infusion bags.

Ingredients

Ostira™

Active ingredient – Zoledronic acid

Inactive ingredients

  • mannitol
  • sodium citrate dihydrate
  • water for injections

Ostira™ does not contain sucrose, gluten, tartrazine or any other azo dyes.

Distributor

Ostira™ 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

  • 5 mg/100 mL infusion AUST R – 188019

This leaflet was prepared in January 2019

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Ostira

Active ingredient

Zoledronic acid

Schedule

S4

 

1 Name of Medicine

Zoledronic acid.

6.7 Physicochemical Properties

Chemical name: 1-hydroxy-2-(1H-imidazol-1-yl)ethane-1, 1-diphosphonic acid. 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

Ostira 5 mg/100 mL contains 5 mg zoledronic acid (anhydrous), corresponding to 5.330 mg zoledronic acid monohydrate. Ostira contains the following excipients: mannitol, sodium citrate dihydrate, water for injections.
The active ingredient of Ostira is a bisphosphonate, zoledronic acid. Although zoledronic acid is marketed as a monohydrate, doses refer to the anhydrous substance.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ostira is a solution for intravenous infusion is administered by 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

Pharmacotherapeutic group.

Bisphosphonate (ATC code: M05B A08).

Mechanism of action.

Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.
The action of bisphosphonates on bone is based on their high affinity for mineralised bone. Intravenously administered zoledronic acid is rapidly distributed to bone. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase, but this does not exclude other mechanisms.

Osteoporosis.

Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated postmenopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilised within the premenopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.
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.

Bone histology.

In the postmenopausal osteoporosis treatment trial, bone biopsy specimens were obtained between months 33 and 36 from 82 postmenopausal patients with osteoporosis treated with 3 annual doses of zoledronic acid. Of the biopsies obtained, 81 were adequate for qualitative histomorphometry assessment, 59 were adequate for partial quantitative histomorphometry assessment, and 38 were adequate for full quantitative histomorphometry assessment. Micro CT analysis was performed on 76 specimens. Qualitative, quantitative and micro CT assessments showed bone of normal architecture and quality without mineralisation defects.
In the treatment and prevention of glucocorticoid-induced osteoporosis trial, bone biopsy specimens were obtained at month 12 from 23 patients treated with either an annual dose of zoledronic acid or daily oral risedronate (12 in the zoledronic acid treatment group and 11 in the risedronate treatment group). All biopsies were adequate for qualitative histomorphometry assessment. Qualitative assessments showed bone of normal architecture and quality without mineralisation defects. Apparent reductions in activation frequency and remodelling rates were seen when compared with the histomorphometry results seen with zoledronic acid in the postmenopausal osteoporosis population. The long term consequences of this degree of suppression of bone remodelling in glucocorticoid-treated patients is unknown.

Paget's disease of bone.

Paget's disease of bone is a chronic, focal skeletal disorder characterised by greatly increased and disorderly bone remodelling. Excessive osteoclastic bone resorption is followed by irregular osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganised, enlarged and weakened bone structure. Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
In two 6-month randomised comparative, controlled clinical trials in patients with Paget's disease, biochemical markers of bone formation and resorption demonstrated normalisation of bone turnover in more zoledronic acid treated patients compared to risedronate treated patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Bone histology.

In the two trials in patients with Paget's disease, bone histology was evaluated in 7 patients 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralisation defects. These results were consistent with biochemical marker evidence of normalisation of bone turnover.

Clinical trials.

Clinical efficacy for the treatment of postmenopausal osteoporosis.

The efficacy and safety of zoledronic acid were demonstrated in a randomised, double-blind, placebo-controlled, multinational study of 7736 ambulant women aged 65 to 89 years with either: a femoral neck BMD T-score less than or equal to -1.5 and at least two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD T-score less than or equal to -2.5 with or without evidence of an existing vertebral fracture(s). Clinical experience in postmenopausal women without a history of low trauma hip fracture is limited to women aged over 63 years. Patients pretreated with other bisphosphonates were excluded except if they complied with a washout schedule of between two months and two years, determined by the duration of pretreatment; for instance, patients who had used oral bisphosphonates for more than 8 weeks but less than 48 weeks were eligible after a washout period of at least one year; more extensively pretreated patients were eligible after a washout period of at least 2 years.
There are limited 12 month evaluated clinical data on the use of zoledronic acid in patients who had been extensively treated with bisphosphonates but without a washout period. In the pivotal studies, extensively pretreated patients were enrolled after a washout period of two years. This experience should be considered when selecting patients for zoledronic acid treatment.
Zoledronic acid was administered once a year for three consecutive years, as a single 5 mg dose in 100 mL solution infused over at least 15 minutes for a total of three doses. The two primary efficacy variables were the incidence of morphometric vertebral fractures at 3 years, and the incidence of hip fractures over a median duration of 3 years. 7736 women were evaluated for the incidence of hip and all clinical fractures. Of these, 5661 women were evaluated annually for incidence of vertebral fractures. Women who were evaluated for the incidence of vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for women contributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapy included: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded other bisphosphonates. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplements per day.

Primary efficacy variables.

Effect on vertebral fracture.

Zoledronic acid significantly decreased the incidence of one or more new vertebral fractures over three years and as early as the one year time point (see Table 6).
The reductions in vertebral fractures over three years were consistent and significantly greater than placebo regardless of age, geographical region, race, baseline body mass index, number of baseline vertebral fractures, femoral neck BMD T-score or prior bisphosphonate use. Specifically for patients aged 75 years and older, zoledronic acid patients had a 61% reduction in the risk of vertebral fractures compared to placebo patients (p < 0.0001).

Effect on hip fracture.

Zoledronic acid demonstrated a 41% reduction in the risk of hip fractures over 3 years. The hip fracture event rate was 1.4% for zoledronic acid-treated patients compared to 2.5% for placebo-treated patients. The effect over time is displayed in Figure 1.
The reduction in the risk of hip fractures was similar in women who did not take concomitant osteoporosis therapy to women who were allowed to take concomitant therapy. In 6084 women who did not take concomitant osteoporosis therapy, zoledronic acid demonstrated a 41% reduction (95% CI, 13% to 59%) in the risk of hip fractures over this time period. In 1652 women who were allowed to take concomitant osteoporosis therapy, a comparable 42% reduction in the risk of hip fractures was observed (95% CI, -2.7% to 73%). The study was not powered to determine if this difference was statistically significant.
The reductions in hip fractures over three years were greater than placebo regardless of femoral neck BMD T-score.

Secondary efficacy variables.

Effect on vertebral fractures.

Zoledronic acid significantly decreased the risk of one or more new/worsening vertebral fractures at 1 year (58%), 2 years (68%) and 3 years (67%) (all p < 0.0001). Zoledronic significantly decreased the risk of at least one new moderate or severe vertebral fracture at 1 year (60%), 2 years (71%) and 3 years (70%) (all p < 0.0001).

Effect on all clinical fractures.

Zoledronic acid demonstrated superiority to placebo in reducing the incidence of all clinical fractures, clinical vertebral and non-vertebral fractures. All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 7.

Effect on bone mineral density (BMD).

Zoledronic acid significantly increased BMD at the lumbar spine, hip and distal radius relative to treatment with placebo at all time points (6, 12, 24 and 36 months). Treatment with zoledronic acid resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck and 3.2% at the distal radius over 3 years as compared to placebo.

Bone turnover markers.

Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum beta-C-telopeptides (beta-CTx) were evaluated in subsets ranging from 517 to 1246 patients at periodic intervals throughout the study. Treatment with a 5 mg annual dose of zoledronic acid reduces bone turnover markers to the premenopausal range. Repeat dosing does not lead to further reduction of bone turnover markers.

Effect on height.

In the 3-year osteoporosis study, standing height was measured annually using a stadiometer. The zoledronic acid group revealed less height loss compared to placebo (4.2 mm vs. 7.0 mm, respectively (p < 0.001)).

Days of disability.

Zoledronic acid significantly reduced both the days of limited activity and the days of bed rest due to fractures compared to placebo (both p < 0.01). Zoledronic acid also significantly reduced both the days of limited activity and the days of bed rest due to back pain compared to placebo (both p ≤ 0.008).

Effects of prolonged therapy and its discontinuation.

The effects of prolonged zoledronic acid therapy as well as its discontinuation were assessed in a 3 year extension to the treatment of postmenopausal osteoporosis trial. The extension was a randomized, double-blind, multinational study in 2456 ambulatory postmenopausal women who had completed participation in the core study. The same dosing regimen of zoledronic acid was used in the extension study as in the core study (5 mg intravenous infusion once yearly). The trail design did not allow identification of the specific subset of patients likely to benefit.
The extension study demonstrated that the therapeutic benefit of continued annual zoledronic acid therapy on maintaining or increasing BMD in women with postmenopausal osteoporosis is sustained long-term, while the discontinuation of therapy results in a gradual loss of bone mass.
Compared to treatment with zoledronic acid for 3 years followed by 3 years of placebo treatment with zoledronic acid for 6 years significantly reduced the risk of new morphometric vertebral fractures by 52% (p < 0.05) and significantly reduced the risk of new or worsening morphometric fractures by 51% (p < 0.05). No significant differences were observed between the two groups in the risk of clinical, non-vertebral, hip and clinical vertebral fractures. There is no statistically significant difference in clinical fractures between the group who received zoledronic acid for 6 years compared to the group who received zoledronic acid for 3 years followed by 3 years of placebo.
Bone marker levels remained below pre-treatment levels 6 years earlier and mean values remained within the pre-menopausal reference range for all 3 biomarkers. See Figure 2.

Clinical efficacy in the prevention of clinical fractures after hip fracture.

The efficacy and safety of zoledronic acid in the prevention of clinical fractures in patients who suffered a recent low trauma hip fracture were demonstrated in a randomised, double-blind, placebo-controlled, multinational endpoint study of 2127 ambulant men and women aged 50-95 years (mean age of 74.5). The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 2127 men and women with a recent (within 90 days) low trauma hip fracture (pertrochanteric or femoral neck) but not malignant fractures and fractures associated with previously implanted orthopedic devices. The washout periods for patients who had been pretreated with other bisphosphonates were the same as those in the postmenopausal osteoporosis study described above. Patients were followed for an average of 2 years on study drug. The following concomitant osteoporosis therapies were allowed: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone, DHEA(s), ipriflavone, and testosterone, as hormone replacement in the case of hypogonadal men; but excluded other bisphosphonates and parathyroid hormone.
Zoledronic acid was administered once a year as a single 5 mg dose in 100 mL solution, infused over at least 15 minutes, until at least 211 patients had confirmed clinical fractures in the study population. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participants received 1000 to 1500 mg of elemental calcium plus 800 to 1200 IU of vitamin D supplementation per day. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.

Primary efficacy variable.

Effect on all clinical fractures.

In the prevention of clinical fractures after hip fracture trial, treatment with zoledronic acid significantly reduced the incidence of any clinical fracture by 35% (see Table 8).

Secondary efficacy variables.

Other clinical fracture endpoints.

There was also a 46% reduction in the risk of a clinical vertebral fracture; a 27% reduction in the risk for non-vertebral fractures with zoledronic acid. There was a 30% reduced risk for a subsequent hip fracture that was observed for the zoledronic acid group that did not meet statistical significance. See Table 8.

Effect on bone mineral density (BMD).

In the prevention of clinical fractures after hip fracture trial, zoledronic acid treatment significantly increased BMD relative to placebo at the hip and femoral neck at all time points (12, 24 and 36 months). Treatment with zoledronic acid resulted in a 5.4% increase at the total hip and 4.3% at the femoral neck over 24 months as compared to placebo. Similar significant results were observed for femoral neck BMD measures.

Treatment of male osteoporosis.

The efficacy and safety of zoledronic acid in men with osteoporosis were assessed in a randomised, multicentre, double-blind, active-controlled study of 302 men aged 25 to 86 years (mean age of 64 years) with either: a femoral neck BMD T-score less than or equal to -2.0 and a lumbar spine BMD T-score less than or equal to -1.0 or a femoral neck BMD T-score less than or equal to -1.0 and at least one vertebral deformity or a history of an osteoporotic fracture. The duration of the trial was two years. Patients were randomised to either zoledronic acid, which was administered once annually as a single 5 mg dose in 100 mL infused over 15 minutes for a total of two doses, or to oral alendronate 70 mg weekly for two years. All participants received 1000 mg elemental calcium plus 800 to 1000 IU vitamin D supplementation per day. Efficacy was demonstrated if non-inferiority to alendronate was shown with respect to the percentage change in lumbar spine BMD at 24 months relative to baseline.
Zoledronic acid has not been studied in hypogonadal men. Fracture data are not available from the study.

Effect on bone mineral density (BMD).

An annual infusion of zoledronic acid was non-inferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline (zoledronic acid 6.1% compared to alendronate 6.2%). The percentage increases in lumbar spine BMD at month 12 were also similar between treatment groups. The criterion for non-inferiority of zoledronic acid by comparison with alendronate was met as the lower bound of the 95% CI (-1.12 for the ITT population, -1.27 per protocol) exceeded the pre-specified non-inferiority margin of -1.5%.

Treatment and prevention of glucocorticoid-induced osteoporosis.

The efficacy and safety of zoledronic acid in the treatment and prevention of glucocorticoid-induced osteoporosis were assessed in a randomised, multi-centre, double-blind, stratified, active-controlled study of 833 men and women aged 18 to 85 years (mean age of 54.4 years) treated with ≥ 7.5 mg/day oral prednisone (or equivalent). Patients in the prevention subpopulation were treated with glucocorticoids ≤ 3 months prior to randomisation, and the treatment subpopulation was treated with glucocorticoids ≥ 3 months prior to randomisation. The duration of the trial was one year. Patients were randomised to either zoledronic acid, which was administered once as a single 5 mg dose in 100 mL infused over 15 minutes, or to oral risedronate 5 mg daily for one year. All participants received 1000 mg elemental calcium plus 400 to 1000 IU vitamin D supplementation per day.
The study was designed to show non-inferiority of a single infusion of zoledronic acid relative to risedronate in these two subpopulations. Efficacy was demonstrated if non-inferiority to risedronate was shown sequentially with respect to the percentage change in lumbar spine BMD at 12 months relative to baseline in the treatment and prevention subpopulations, respectively.
This was not a fracture study and limited data only are available: over the 12 months of the study, new vertebral fractures detected by X-ray morphometry occurred in 5/379 (1.3%) of zoledronic acid-treated patients and assessed, compared to 3/381 (0.8%) in the risedronate treated group. An analysis of the time to first clinical fracture during the study period showed no difference between the treatment groups. During the 12 month study, 8 zoledronic acid-treated patients and 7 risedronate treated patients had at least one clinical fracture.

Effect on bone mineral density (BMD).

Non-inferiority to risedronate was shown. There was a trend to greater increase in BMD in the zoledronic acid-treated group in both the treatment and prevention sub-populations at all sites, which included the lumbar spine, femoral neck, total hip, trochanter and distal radius at 12 months compared to risedronate. A summary of the key results appears in Table 9.

Clinical efficacy for the treatment of Paget's disease of bone.

Zoledronic acid was studied in male and female patients aged above 30 years with mild to moderate Paget's disease of the bone (median serum alkaline phosphatase level 2.6-3.0 times the upper limit of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.
The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months was demonstrated in two 6-month controlled comparative trials. The primary objective of these trials was to show non-inferiority of zoledronic acid compared to risedronate with respect to the proportion of patients who achieved a therapeutic response at 6 months. Non- inferiority was defined as: zoledronic acid is non-inferior to risedronate if the lower bound of a two-sided 95% confidence interval for the difference between zoledronic acid and risedronate in the proportion of therapeutic responders exceeded -0.16. If non-inferiority was shown and the predefined non-inferiority margin was exceeded, testing for superiority would be performed.
The primary outcome variable was the proportion of patients achieving a therapeutic response defined as either normalisation of serum alkaline phosphatase (SAP) or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. SAP excess was defined as the difference between the measured level and midpoint of the normal range.
At 6 months, combined data from both trials showed that 96.0% (169/176) zoledronic acid treated patients achieved a therapeutic response as compared with 74.3% (127 of 171) of patients treated with risedronate (p < 0.001). In addition, at 6 months, 88.6% (156/176) of zoledronic acid-treated patients achieved remission (normalisation of SAP levels) compared to 57.9% (99/171) of patients treated with risedronate (p < 0.0001). Non-inferiority was found (the difference between combined groups was 0.22 (0.14, 0.30)).
In combined data from both trials, after 2 months, the therapeutic response rate was 90% (158/176) and the SAP normalisation rate was 63% (111/176) compared to 47% (81/171) and 26% (45/171) respectively for risedronate (all p < 0.001).
In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were observed over 6 months for zoledronic acid and risedronate.
The adverse reaction profile reflects a very common incidence of acute phase reactions in the zoledronic acid group (influenza-like illness, pyrexia, myalgia, arthralgia and bone pain).

Extended observation period.

Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period. Of the 152 zoledronic acid-treated patients and 115 risedronate-treated patients who entered an extended observation study, after a median duration of follow-up of 32 months from time of dosing, 142 zoledronic acid-treated patients maintained their therapeutic response compared to 50 risedronate-treated patients (p < 0.0001).

5.2 Pharmacokinetic Properties

Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients yielded the following pharmacokinetic data, which were found to be dose independent.
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak levels.

Absorption.

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

Distribution.

There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (alpha and beta, with t1/2, values below) presumably represent rapid uptake into bone and excretion via the kidneys.
Zoledronic acid is not highly bound to plasma proteins (approximately 30-60% bound) and binding is concentration and divalent cation ion dependent. Interactions resulting from displacement of highly protein-bound drugs are unlikely.

Metabolism.

Zoledronic acid is not metabolised in humans. The substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, therefore zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems.

Excretion.

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t1/2alpha 0.24 and t1/2beta 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t1/2gamma 146 hours.
Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 L/h, independent of dose, and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. 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.
No specific drug-drug interaction studies have been conducted with zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems.

Pharmacokinetics in special patient groups.

The renal clearance of zoledronic acid was 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 patients studied. Small observed increases in AUC(0-24 hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50-80 mL/min) and moderate (Clcr = 35-50 mL/min) renal impairment are not necessary. The use of zoledronic acid in patients with creatinine clearance < 35 mL/min is not recommended due to limited clinical safety data in such patients (see Section 4.3 Contraindications). No dose adjustment is necessary in patients with creatinine clearance ≥ 35 mL/min.

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 0.4, 0.3 and 1.0 mg/kg respectively, for at least 104 weeks without evidence of carcinogenic potential. Pharmacological bone changes typically observed following long-term bisphosphonate administration to young animals with growing skeletons were observed in these studies, suggesting systemic exposure to zoledronic acid in both species.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of osteoporosis in postmenopausal women to reduce the incidence of hip, vertebral and non-vertebral fractures. Treatment of osteoporosis in patients over 50 years of age with a history of at least one low trauma hip fracture, to reduce the incidence of further fractures.
To increase bone mineral density in men with osteoporosis.
To increase bone mineral density in patients with osteoporosis associated with long term glucocorticoid use.
To prevent glucocorticoid-induced bone mineral density loss.
Treatment of Paget's disease of bone.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients or to any bisphosphonates; hypocalcaemia; renal impairment (creatinine clearance < 35 mL/min); current or recent uveitis, or a history of bisphosphonate-associated uveitis; pregnancy and lactation.
Not recommended in patients with severe renal impairment (calculated creatinine clearance by Cockcroft-Gault formula of ≤ 30 mL/min).

4.4 Special Warnings and Precautions for Use

General.

The dose of 5 mg zoledronic acid must be administered intravenously over at least 15 minutes.
Zoledronic acid is also marketed in different strengths and is used for oncology indications. Patients being treated with zoledronic acid for oncology should not be treated with other strengths of zoledronic acid nor any other bisphosphonate concomitantly.
Consider carefully before using zoledronic acid in patients who have been extensively pre-treated with other bisphosphonates. Consider discontinuing zoledronic acid on the occurrence of atypical fractures such as subtrochanteric fractures or atypical stress fractures. The optimum duration of bisphosphonate treatment is currently unknown. The risk:benefit ratio of prolonged therapy should be estimated in each patient. No data are available on recommencing therapy after cessation of treatment.

Acute phase reaction.

Post-dose symptoms commonly occur within the first three days following Ostira administration and may include fever, flu-like symptoms, myalgia, arthralgia and headache (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration). The incidence of these symptoms can be reduced by approximately 50% with the administration of paracetamol shortly following Ostira administration. Non-steroidal anti-inflammatory agents are not recommended first line to manage the acute phase reaction.

Hydration.

Patients must be appropriately hydrated prior to administration of Ostira. This is especially important in the elderly and for patients receiving diuretic therapy. Adequate hydration can be achieved by the patient drinking two glasses of fluid (such as water) before and two glasses of fluid after the infusion.

Pre-existing hypocalcaemia or vitamin D deficiency.

If there are clinical reasons to suspect hypocalcaemia, vitamin D deficiency or other disturbances of mineral metabolism (e.g. thyroid surgery, parathyroid surgery, calcium malabsorption), the appropriate tests should be performed and, if abnormalities are discovered, these should be corrected before initiating therapy with Ostira (see Section 4.3 Contraindications). Physicians should consider monitoring after treatment in patients with pre-existing disturbances of mineral metabolism.

Calcium and vitamin D supplementation.

Treatment of osteoporosis.

Adequate supplemental calcium and vitamin D intake is important in men and women with osteoporosis if dietary intake is inadequate.

Prevention of clinical fractures after a hip fracture.

Supplemental calcium and vitamin D intake is recommended for patients treated to prevent fractures after a hip fracture.

Treatment of Paget's disease of bone.

Elevated bone turnover is a characteristic of Paget's disease of bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic may develop and is usually maximal within the first 10 days after infusion of zoledronic acid (see Section 4.8 Adverse Effects (Undesirable Effects)). Adequate vitamin D intake is recommended in association with zoledronic acid administration (see Section 4.4 Special Warnings and Precautions for Use, Pre-existing hypocalcaemia or vitamin D deficiency). In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following zoledronic acid administration. Patients should be informed about symptoms of hypocalcaemia. Physicians should consider clinical monitoring for patients at risk.

Musculoskeletal pain.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates including zoledronic acid.

Osteonecrosis of the jaw (ONJ).

Osteonecrosis of the jaw has been reported predominately in cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Symptoms include persistent pain and/or non-healing sores of the mouth or jaw. Many had signs of local infection including osteomyelitis.
Discuss with the patient the need to have dental work completed before commencing zoledronic acid treatment. A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). 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 reduces the risk of osteonecrosis of the jaw. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
In the treatment of postmenopausal osteoporosis trial in 7714 patients who received zoledronic acid or placebo, ONJ has been reported in one patient with zoledronic acid and one patient treated with placebo. Both cases resolved. In the prevention of clinical fractures after hip fracture trial in 2111 patients who received zoledronic acid or placebo there were no reports of ONJ (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Osteonecrosis of other anatomical sites.

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

Atypical fractures of the femur.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in association with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse of short oblique 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 weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate 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. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
During bisphosphonate treatment, including zoledronic acid, patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for possible femur fracture.

Use in renal impairment.

Renal impairment has been observed following the administration of zoledronic acid (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience), especially in patients with pre-existing renal compromise or other risk factors including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), or dehydration occurring after zoledronic acid administration. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.
The following precautions should be taken into account to minimize the risk of renal adverse effects:
Ostira should not be used in patients with severe renal impairment (creatinine clearance < 35 mL/min) due to limited clinical safety data in such patients (see Section 4.3 Contraindications).
Ostira should be used with caution when concomitantly used with other medicinal products that could impact renal function (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Creatinine clearance should be calculated (e.g. Cockcroft-Gault formula) before each Ostira dose (see Section 4.3 Contraindications). Transient increase in serum creatinine may be greater in patients with underlying impaired renal function; interim monitoring of serum creatinine should be considered in at-risk patients.
Patients, especially elderly patients and those receiving diuretic therapy should be appropriately hydrated prior to administration of Ostira (see Section 4.4 Special Warnings and Precautions for Use, Hydration).
A single dose of Ostira should not exceed 5 mg and the duration of infusion should not be less than 15 minutes (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

The postmenopausal osteoporosis trial included 3868 zoledronic acid-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 zoledronic-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.

Paediatric use.

Ostira is not recommended for use in children and adolescents below 18 years of age due to lack of data on safety and efficacy.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Specific drug-drug interaction studies have not been conducted with zoledronic acid. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see Section 5.2 Pharmacokinetic Properties). Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound drugs are therefore unlikely. Zoledronic acid is eliminated by renal excretion.

Drugs that could impact renal function.

Caution is indicated when Ostira is administered in conjunction with drugs that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration).

Drugs primarily excreted by the kidney.

In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidneys may increase.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was decreased in rats dosed subcutaneously (SC) with zoledronic acid 0.1 mg/kg/day for 71 days (males) or 15 days (females), with animal/human exposure margins 2-89 based on cumulative AUC for unbound drug), 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 (exposure margin 1). In dogs, testicular and prostatic atrophy and oligospermia were observed at 0.2 mg/kg/day intravenously (IV) for 3 months (exposure margin 160). Testicular atrophy and/or mineralization were additionally observed in the dog at 0.03 mg/kg IV dosed every 2 to 3 days for 6 months (exposure margin 56), although no such changes were seen at 0.1 mg/kg for 12 months (exposure margin 269). 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 IV daily for 3 months (exposure margin 14). There were no effects on reproductive organs in dogs dosed with up to 1 mg/kg zoledronic acid by IV infusion once every 3 weeks for 26 weeks (exposure margin 60).
(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.
There were no data on the use of zoledronic acid in pregnant women. Teratology studies were performed in rats and rabbits, both via subcutaneous administration. Teratogenicity was observed in rats at doses ≥ 0.2 mg/kg (0.2 times clinical exposure based on unbound AUC) and was manifested by external, visceral and skeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological effects were observed in rabbits, but maternal toxicity and increased embryo/foetal resorption occurred at ≥ 0.03 mg/kg (0.14 times clinical exposure based on dose adjusted for body surface area). In the absence of adequate data in pregnant women, Ostira is contraindicated during pregnancy. Women who might become pregnant at some time in the future should be warned about the long half-life of bisphosphonates.
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 Ostira administration.

4.8 Adverse Effects (Undesirable Effects)

Adverse events in clinical trials.

Postmenopausal osteoporosis.

In the Phase III randomised, double blind, placebo controlled, multinational study of 7736 postmenopausal women aged 65-89 years (see Section 5.1 Pharmacodynamic Properties, Clinical trials), there were no significant differences in the overall incidence of serious adverse events compared to placebo and most adverse events were mild to moderate. The incidence of all-cause mortality was similar between groups: 3.4% in the zoledronic acid group and 2.9% in the placebo group. Zoledronic acid was administered once yearly for three consecutive years for a total of three doses.
Consistent with the intravenous administration of bisphosphonates, zoledronic acid has been most commonly associated with the following post-dose symptoms: fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occur within the first 3 days following zoledronic acid administration. The majority of these symptoms were mild to moderate in nature and resolved within 3 days of the event onset. The incidence of these symptoms decreased markedly with subsequent annual doses of zoledronic acid.
The incidence of post-dose symptoms occurring within the first 3 days after administration of zoledronic acid can be reduced by approximately 50% with the administration of paracetamol shortly following zoledronic acid administration.
Adverse events occurring in ≥ 2.0% of postmenopausal women with osteoporosis are shown in Table 1.
The safety results in the three year extension to the treatment of postmenopausal osteoporosis trial suggest that the overall safety profile for zoledronic acid 5 mg yearly is similar in patients who continued therapy for 6 years to patients who stopped treatment after 3 years.

Prevention of clinical fractures after hip fracture.

In a randomised, double-blind, placebo-controlled, multinational endpoint study of 2127 men and women aged 50-95 years with a recent (within 90 days) low trauma hip fracture, 1065 patients were exposed to zoledronic acid and 1062 patients exposed to placebo. Zoledronic acid was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of 2 years on study drug. All participants received 1000 to 1500 mg of elemental calcium plus 800 to 1200 IU of vitamin D supplementation per day.
Most adverse events were of mild to moderate severity and did not lead to discontinuation. The incidence of serious adverse events was 38% in the zoledronic acid group and 41% in the placebo group. All cause mortality was 9.6% in the zoledronic acid treated group compared to 13.3% in the placebo group. This corresponds to a 28% reduction in the risk of all cause mortality (p = 0.01).
Zoledronic acid was associated with the following post-dose symptoms: fever (7%) and arthralgia (3%), which occur within the first 3 days following zoledronic acid administration. The majority of these symptoms were mild to moderate in nature and resolved within 3 days of the event onset. The incidence of these symptoms decreased with subsequent doses of zoledronic acid. The main reason for the lower rate of post-dose symptoms in this trial compared to the rate of post-dose symptoms in the treatment of postmenopausal osteoporosis trial was that, in this prevention of clinical fractures after hip fracture trial, paracetamol was provided to patients and its use encouraged to manage post-dose symptoms.
Adverse events occurring in ≥ 2.0% of men and women following hip fracture (prevention of clinical fractures after hip fracture) are shown in Table 1.

Treatment of male osteoporosis.

The safety of zoledronic acid in men with osteoporosis or significant osteoporosis secondary to hypogonadism was assessed in a two-year randomised, multicentre, double-blind, active-controlled group study of 302 men aged 25-86 years. One hundred and fifty three patients were exposed to zoledronic acid administered once annually as a single 5 mg dose in 100 mL infused over 15 minutes for a total of two doses and 148 patients were exposed to oral alendronate 70 mg weekly for two years. All participants received 1000 mg elemental calcium plus 800 to 1000 IU vitamin D supplementation per day.
The incidence of serious adverse events was similar between the zoledronic acid and alendronate treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the zoledronic acid and alendronate treatment groups, with the exception of a higher incidence of post-dose symptoms in the zoledronic acid group that occurred within 3 days after infusion. The overall safety and tolerability profile of zoledronic acid in male osteoporosis was similar to that reported in the zoledronic acid postmenopausal osteoporosis trial.
Adverse events reported in at least 2% of men with osteoporosis and more frequently in the zoledronic acid treatment group than the alendronate group and either not reported in the postmenopausal osteoporosis trial or reported more frequently in the osteoporosis trial in men are presented in Table 2.

Treatment and prevention of glucocorticoid-induced osteoporosis.

The safety of zoledronic acid in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomised, multicentre, double-blind, active-controlled, stratified study of 833 men and women aged 18-85 years treated with ≥ 7.5 mg/day oral prednisone (or equivalent). Patients in the prevention subpopulation were treated with glucocorticoids ≤ 3 months prior to randomisation, and the treatment subpopulation was treated with glucocorticoids > 3 months prior to randomisation.
The duration of the trial was one year, with 416 patients exposed to zoledronic acid administered once as a single 5 mg dose in 100 mL infused over 15 minutes and 417 patients exposed to oral risedronate 5 mg daily for one year. All participants received 1000 mg elemental calcium plus 400 to 1000 IU vitamin D supplementation per day.
The incidence of serious adverse events was similar between the zoledronic acid and risedronate treatment groups. Overall safety and tolerability were similar between the zoledronic acid and risedronate groups, with the exception of a higher incidence of post-dose symptoms in the zoledronic acid group that occurred within 3 days after infusion. The overall safety and tolerability profile of zoledronic acid in glucocorticoid-induced osteoporosis was similar to that reported in the zoledronic acid postmenopausal osteoporosis clinical trial.
Adverse events reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or reported more frequently in the treatment and prevention of glucocorticoid induced osteoporosis trial are presented in Table 3.

Paget's disease of bone.

In the Paget's disease trials, two 6-month, double blind, comparative, multinational studies of 349 men and women aged > 30 years with moderate to severe disease and with confirmed Paget's disease of bone, 177 patients were exposed to zoledronic acid and 172 patients exposed to risedronate. Zoledronic acid was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months.
The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia and bone pain) were reported in 25% of patients in the zoledronic acid treated group compared to 8% in the risedronate treated group. Symptoms usually occur within the first 3 days following zoledronic acid administration. The majority of these symptoms resolved within 4 days of onset.
Adverse events occurring in at least 2% of the Paget's patients receiving zoledronic acid (single 5 mg IV infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4.

Adverse effects with suspected relationship to product.

Table 5 lists the adverse effects suspected (investigator assessment) to be associated with zoledronic acid in the pooled studies supporting the indications: treatment of osteoporosis in men and postmenopausal women, prevention of clinical fractures after low trauma hip fracture, treatment and prevention of glucocorticoid induced osteoporosis and Paget's disease of the bone by system organ class and by 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) adverse drug effects.
Additional adverse effects which were reported in the individual studies but are not included in the Table 5 (due to a lower frequency in the zoledronic acid group compared with that of the placebo group when the data were pooled) include: ocular hyperaemia, C-reactive protein increased, hypocalcaemia, dysgeusia, toothache, gastritis, palpitation, infusion site reaction.

Atrial fibrillation.

In one clinical trial, the overall incidence of atrial fibrillation was 2.5% (96 out of 3862) and 1.9% (75 out of 3852) in patients receiving zoledronic acid and placebo, respectively. The rate of atrial fibrillation serious adverse effects was increased in patients receiving zoledronic acid (1.3%) (51 out of 3862) compared with patients receiving placebo (0.6%) (22 out of 3852). The mechanism behind the increased incidence of atrial fibrillation is unknown. These imbalances were not observed in other trials; the overall pooled atrial fibrillation incidences were 2.6% for zoledronic acid and 2.1% for placebo and for serious adverse effects, the pooled incidences were 1.3% for zoledronic acid and 0.8% for placebo.

Local reactions.

In the treatment of postmenopausal osteoporosis trial, local reactions at the infusion site such as redness, swelling and/or pain were reported (0.7%) following the administration of zoledronic acid. In the prevention of clinical fractures after hip fracture trial, the event rate was comparable for both zoledronic acid and placebo treatment groups.

Laboratory test abnormalities.

In the treatment of postmenopausal osteoporosis trial, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/L) following zoledronic acid administration. No symptomatic cases of hypocalcaemia were observed.
In the prevention of clinical fractures after hip fracture trial, there were no patients who had treatment emergent serum calcium levels below 1.87 mmol/L.
In the Paget's disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, all of which resolved.
In 2010, the atypical femoral fractures task force report identified that subtrochanteric and diaphyseal fractures, with or without atypical features have been estimated as 1 to 3 reports per 1,000,000 patient years of exposure to bisphosphonates.

Class effects.

Renal impairment.

Treatment with intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise or additional risk factors (e.g. advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medications, concomitant diuretic therapy, severe dehydration), the majority of whom received a 4 mg dose every 3-4 weeks, but it has been observed in patients after a single administration.
In the treatment of postmenopausal osteoporosis trial, the change in creatinine clearance (measured annually prior to dosing), and the incidence of renal failure and impairment were comparable for both the zoledronic acid and placebo treatment groups over 3 years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of zoledronic acid-treated patients versus 0.8% of placebo-treated patients.
In the prevention of clinical fractures after hip fracture trial, the change in creatinine clearance (measured annually prior to dosing), and the incidence of renal failure and impairment were comparable for both the zoledronic acid and placebo treatment groups over 3 years.
In clinical trials in Paget's disease, there were no cases of renal deterioration following a single 5 mg 15-minute infusion.

Osteonecrosis of the jaw (ONJ).

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 jaw has multiple 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 dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged.
In the treatment of postmenopausal osteoporosis trial in 7736 patients, ONJ has been reported in one patient treated with zoledronic acid and one patient treated with placebo. Both cases resolved.
In the prevention of clinical fractures after hip fracture trial, there were no reports of osteonecrosis of the jaw.

Eye disorders.

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates. In the treatment of postmenopausal osteoporosis trial, 9 (0.2%) patients treated with zoledronic acid and 1 (< 0.1%) patient treated with placebo developed iritis/uveitis/episcleritis. Patients who develop ocular symptoms after a zoledronic acid infusion should seek medical help.

Post-marketing experience.

The following adverse effects 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.
Hypersensitivity reactions including rare cases of bronchoconstriction, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported.
Rare cases of renal impairment including renal failure requiring dialysis or with a fatal outcome, especially in patients with pre-existing renal compromise or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period have been reported.
In very rare cases, the following events have been reported: dehydration secondary to post-dose symptoms such as fever, vomiting and diarrhoea; hypotension in patients with underlying risk factors; osteonecrosis of the jaw; scleritis and orbital inflammation.

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.

Treatment of postmenopausal osteoporosis.

For the treatment of postmenopausal osteoporosis the recommended dose is a single intravenous infusion of 5 mg of Ostira administered once a year. Adequate supplemental calcium and vitamin D intake is important in women with osteoporosis if dietary intake is inadequate. In the treatment of postmenopausal osteoporosis trial, all women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplements per day (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Prevention of clinical fractures after a hip fracture.

For the prevention of clinical fractures after a low trauma hip fracture, the recommended dose is a single intravenous infusion of 5 mg Ostira administered once a year.
In patients with a recent low-trauma hip fracture, a loading dose of 50,000 to 125,000 IU of vitamin D given orally or via the intramuscular route is recommended prior to the first infusion with Ostira (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Supplemental calcium and vitamin D intake is recommended for patients treated to prevent clinical fractures after a low trauma hip fracture (see Section 4.4 Special Warnings and Precautions for Use, Calcium and vitamin D supplementation).

Treatment of osteoporosis in men.

For the treatment of osteoporosis in men, the recommended dose is a single intravenous infusion of 5 mg Ostira administered once a year.
Adequate supplemental calcium and vitamin D intake is important in men with osteoporosis if dietary intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use).

Treatment and prevention of glucocorticoid-induced osteoporosis.

For the treatment and prevention of glucocorticoid-induced osteoporosis, the recommended dose is a single intravenous infusion of 5 mg Ostira administered once a year.
Adequate supplemental calcium and vitamin D intake is important in patients with osteoporosis if dietary intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use).

Treatment of Paget's disease of bone.

For the treatment of Paget's disease, Ostira should be prescribed only by physicians with experience in treatment of Paget's disease of the bone. The recommended dose is a single intravenous infusion of 5 mg Ostira.

Method of administration.

Ostira (5 mg in 100 mL ready to infuse solution) is administered intravenously via a vented infusion line, given at a constant infusion rate. The infusion time must not be less than 15 minutes (see Instructions for use and handling).
Ostira must only be used by clinicians experienced in the administration of intravenous bisphosphonates.

General.

The incidence of post-dose symptoms occurring within the first three days after administration of Ostira can be reduced with the administration of paracetamol shortly following Ostira administration.
Patients must be appropriately hydrated prior to administration of Ostira. This is especially important in the elderly and for patients receiving diuretic therapy (see Section 4.4 Special Warnings and Precautions for Use). Adequate hydration can be achieved by the patient drinking two glasses of fluid (such as water) before and after the infusion.
The inclusion and exclusion criteria of the clinical trials should be used as a basis for patient selection (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Instructions for use and handling.

Ostira 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.
Use in one patient on one occasion only. Any unused solution should be discarded.
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 Ostira in patients with creatinine clearance < 35 mL/min is not recommended due to limited clinical safety data in such patients (see Section 4.3 Contraindications).
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 mL/min.

Hepatic impairment.

No dose adjustment is required for patients with hepatic impairment.

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.

Elderly patients.

No dose adjustment is necessary (see Section 4.4 Special Warnings and Precautions for Use). However, because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

Monitoring advice.

Re-treatment of Paget's disease.

Specific re-treatment data are not available. After a single treatment with zoledronic acid in Paget's disease, an extended remission period is observed in responding patients. Of the 152 zoledronic acid-treated patients who entered the extended observation study of the pivotal studies, after a median duration of follow-up of 32 months from time of dosing, 142 zoledronic acid-treated patients maintained their therapeutic response (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
However, re-treatment with Ostira may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, in patients who failed to achieve normalisation of serum alkaline phosphatase, or in patients with symptoms, as dictated by medical practice 12 months after the initial dose.
In patients with Paget's disease, adequate vitamin D intake is recommended in association with Ostira administration (see Section 4.4 Special Warnings and Precautions for Use, Pre-existing hypocalcaemia or vitamin D deficiency). In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following Ostira administration (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

There are no data to suggest that zoledronic acid affects the ability to drive or use machines. However, patients should be warned about post-infusion hypocalcaemia which is usually asymptomatic but occasionally causes tetany.

4.9 Overdose

Clinical experience with acute overdosage is limited. Patients who have received doses higher than those recommended should be carefully monitored. In the event of overdose leading to clinically significant hypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an infusion of calcium gluconate.
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

Ostira solution for infusion must not be allowed to come into contact with any calcium- or other divalent cation containing solutions.

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. Ostira must be kept out of the reach of children.

6.5 Nature and Contents of Container

Ostira 5 mg/100 mL solution for infusion is sterile, clear and colourless. It is supplied in a 100 mL transparent polypropylene (PP) plastic bag.

Pack sizes.

Ostira is supplied as packs containing one bag and multipacks comprising three, four, six or ten packs. Not all pack sizes 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