Consumer medicine information

Bondronat

Ibandronate sodium

BRAND INFORMATION

Brand name

Bondronat

Active ingredient

Ibandronate sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bondronat.

What is in this leaflet

This leaflet answers some common questions about BONDRONAT.

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 BONDRONAT 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 BONDRONAT is used for

BONDRONAT contains the active ingredient ibandronic acid. It belongs to a group of medicines called bisphosphonates.

In patients with breast cancer, BONDRONAT is used to slow down the attachment, spread and growth of cancer cells within the bone, known as metastatic bone disease.

BONDRONAT works by stopping the breakdown of bone.

BONDRONAT injection can also be used to lower very high levels of calcium in the blood. High levels of calcium can occur in the presence of a tumour. This is known as hypercalcaemia of malignancy.

Your doctor may have prescribed BONDRONAT for another purpose.

Ask your doctor if you have any questions why BONDRONAT has been prescribed for you.

BONDRONAT is not addictive.

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

Before you take or are given BONDRONAT

Do not take or receive BONDRONAT if:

  1. you have low levels of calcium in your blood (called hypocalcaemia)
  2. you have had an allergic reaction to ibandronic acid, or to any other bisphosphonate medicine or to any of the ingredients listed at the end of this leaflet
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.
  1. the package is torn or shows signs of tampering
  2. 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.
  1. In addition, do not take BONDRONAT tablets if:
  • you have certain disorders of the food-pipe (also called oesophagus) including those that cause difficulty in swallowing
  • you are unable to stand or sit up straight for at least 30 minutes

Do not give BONDRONAT to a child. Safety and effectiveness in children have not been established.

If you are not sure if you should be receiving BONDRONAT, talk to your doctor.

Before you start to take or receive it:

Tell your doctor if:

  1. you have any other health problems, especially the following:
  • poor kidney function
  • disturbances of bone and mineral metabolism
  • poor dental health, such as bleeding gums
  • heartburn
  • swallowing or digestive problems, such as ulcers
  1. you are allergic to any other medicines, foods, dyes or preservatives
  2. you are pregnant or intend to become pregnant
BONDRONAT is not recommended to be used during pregnancy. Your doctor will discuss the risks and benefits of using BONDRONAT if you are pregnant.
  1. you are breast-feeding or planning to breast-feed
It is not known whether BONDRONAT passes into breast milk.

If you have not told your doctor about any of the above, tell them before you start receiving BONDRONAT.

Your doctor may tell you to see a dentist before receiving BONDRONAT to check for problems with your jaw or teeth.

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 BONDRONAT. These medicines include:

  • aminoglycoside medicines, used to treat severe infections, as both agents can lower blood calcium levels
  • non-steroidal anti-inflammatory drugs (also known as NSAIDs), these may cause irritation to the stomach when given with BONDRONAT tablets.
  • calcium supplements, medicines used to treat low calcium levels.
  • antacids, medicines used to treat indigestion and heartburn.

These medicines may be affected by BONDRONAT, 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 BONDRONAT.

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

How to take BONDRONAT tablets

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

Take BONDRONAT tablets exactly as your doctor has prescribed.

The recommended dose of BONDRONAT is one 50 mg tablet once daily. If you have a reduced kidney function, your doctor may decide to lower your dose.

How to take it

Swallow tablets whole with a plain glass of water. Mineral water and other drinks such as juices, coffee and tea will affect how well BONDRONAT tablets work in your body.

Do not chew or suck the tablet. Mouth ulcers may occur if the tablet is chewed or sucked.

Do not lie down for at least 30 minutes after taking BONDRONAT tablets. It is important to remain standing or sitting in an upright position after taking your tablet. This will help make sure the tablet reaches your stomach quickly and avoids irritating your food-pipe (oesophagus).

When to take it

BONDRONAT tablets should be taken at least 30 minutes before the first food, drink (other than plain water) or any other medicine of the day. Food and medicines can interfere with the absorption of BONDRONAT tablets.

How long to use it

Your doctor will decide how long you should take BONDRONAT depending on your response to the medicine and the state of your disease.

If you forget to take it

If you miss a dose do not take more tablets on the same day. Return to taking one tablet per day the following day.

How BONDRONAT injection is given

How is it given

BONDRONAT injection is usually given in a hospital setting.

Your doctor will decide what dose of BONDRONAT injection you will receive, depending on your condition.

BONDRONAT injection is prepared by a healthcare professional. It is added to an infusion bag and given as a 'drip' into a vein, usually over a period of 1-2 hours.

How long to receive it

For the treatment of hypercalcaemia, only a single dose of BONDRONAT injection is normally required. However, some patients may require a second dose.

For the treatment of metastatic bone disease, BONDRONAT infusion is repeated every 4 weeks.

Your doctor will decide how long you should receive BONDRONAT depending on your response to the medicine and the state of your disease.

If you take or receive too much (overdose)

Immediately telephone your doctor, or Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have taken or been given too much BONDRONAT. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking BONDRONAT

Things you must do

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

Tell your doctor immediately if you experience allergic reactions such as chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips or skin rash during or after receiving BONDRONAT.

Tell your doctor if you become pregnant while receiving BONDRONAT.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor that you are receiving BONDRONAT if you are going to have any laboratory tests.

Be sure to brush and floss your teeth daily, and have regular dental check-ups with your dentist.

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. BONDRONAT may cause jaw-bone problems in some people. Jaw-bone problems may include infection, and delayed healing after teeth are pulled out or other dental work that involves drilling into the jaw.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you must not do

Do not stop taking BONDRONAT or change the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give BONDRONAT to anyone else even if they have the same condition as you.

Do not use BONDRONAT to treat other complaints unless your doctor tells you to.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how BONDRONAT affects you. The effect of BONDRONAT on the ability to drive or use machinery has not been studied. However BONDRONAT is not expected to affect your ability to drive a car or operate machinery.

Side effects

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

BONDRONAT helps most people with high blood calcium levels or people with metastatic bone disease and breast cancer, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical 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:

  • a rise in body temperature or feeling hot
  • fever, chills, headache, sweating, bone or muscle pain, similar to the flu
  • muscle aches
  • diarrhoea
  • indigestion
  • vomiting, abdominal pain
  • dizziness
  • headache
  • nausea

These are the more common side effects of BONDRONAT. Mostly these are mild and last only hours up to a couple of days.

Tell your doctor and dentist immediately if you notice any of the following:

  • tooth, gum or jaw pain
  • bleeding gums
  • sudden loosening of teeth
  • infection in the mouth, poor healing of gums
  • numbness/heaviness in the jaw
  • difficulty swallowing or pain when swallowing
  • irritation in the food-pipe (also called oesophagus)
  • new or worsening heartburn
  • sore mouth, mouth ulcers or cold sores
  • irritated eyes, blurred vision, eye pain, sensitivity to light, runny or itchy eyes
  • new pain, weakness or discomfort in your thigh, hip or groin. You may have early signs of a possible unusual fracture of the thigh bone

Some of these side effects are rare but they may be serious.

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

  • difficulty breathing, chest tightness or wheezing
  • severe lightheadedness
  • severe skin rash, itching, hives
  • swelling of the face, lips, mouth
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals

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 taking BONDRONAT tablets

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the packaging they will not keep well.

Keep the blister pack in a cool dry place where the temperature stays below 30°C.

Do not store BONDRONAT tablets, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills or other places where it may get hot, even for a short period. Heat and dampness can destroy some medicines.

Keep BONDRONAT tablets 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 your doctor tells you to stop taking BONDRONAT tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

Availability

BONDRONAT injection (6 mg/6 mL) is available in packs of one vial.

BONDRONAT tablets are available in blister packs of 28.

What BONDRONAT looks like

BONDRONAT injection is a clear to colourless solution, which is mixed with a sterile infusion solution before being administered as "a drip".

BONDRONAT 50 mg tablets are white to off-white oblong tablet, with "L2" engraved on one side and "IT" engraved on the other side.

Ingredients

BONDRONAT injection solution
Active ingredient

  • ibandronic acid

Inactive ingredients

  • sodium chloride
  • glacial acetic acid
  • sodium acetate
  • water for injections

BONDRONAT tablet
Active ingredient

  • ibandronic acid

Inactive ingredients

  • lactose monohydrate
  • microcrystalline cellulose
  • povidone
  • crospovidone
  • stearic acid
  • colloidal anhydrous silica
  • hypromellose
  • titanium dioxide
  • purified talc
  • macrogol 6000

BONDRONAT injection and tablets do not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Atnahs Pharma Australia Pty Ltd
Level 10 / 10 Shelley Street,
Sydney, NSW, 2000, Australia

BONDRONAT is distributed by:

Clinect Pty Ltd
120 - 132 Atlantic Drive
Keysborough, VIC 3173, Australia

Customer enquiries: 1800 899 005

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Numbers

  • 6 mg/6 mL injection: AUST R 98008
  • 50 mg tablets: AUST R 119673

This leaflet was prepared on 15 October 2018.

Published by MIMS January 2019

BRAND INFORMATION

Brand name

Bondronat

Active ingredient

Ibandronate sodium

Schedule

S4

 

1 Name of Medicine

Ibandronic acid (as the monosodium salt monohydrate).

6.7 Physicochemical Properties

Ibandronate sodium has the full chemical name of [1-hydroxy-3-(methylpentylamino)propylidene]bis-phosphonic acid, monosodium salt, monohydrate.
Its molecular weight is 359.

Chemical structure.


CAS number.

CAS registry number: 138926-19-9.

2 Qualitative and Quantitative Composition

Bondronat is available as a concentrated injection for intravenous (IV) infusion containing 6 mg ibandronic acid (as the monosodium salt monohydrate 6.75 mg).
Bondronat is also available as film-coated tablets containing 50 mg ibandronic acid (as the monosodium salt monohydrate 56.25 mg). The tablets also contain lactose.
Ibandronate sodium is a white to off-white powder and is freely soluble in water.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Bondronat is a sterile, clear and colourless concentrated injection for intravenous (IV) infusion.
Bondronat 50 mg tablets are white to off-white, oblong, film-coated tablets, engraved with "IT" on one side and "L2" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ibandronic acid is a nitrogen-containing bisphosphonate with affinity for bone that inhibits osteoclast-mediated bone resorption. In animals, ibandronic acid inhibits experimentally induced bone resorption caused by ovariectomy, retinoids, tumours or parathyroid hormone-related protein but does not interfere with osteoclast recruitment. The inhibition of endogenous bone resorption has been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.
There was no evidence of impaired mineralisation after short-term subcutaneous treatment of growing rats with 5 mg/kg/day of ibandronic acid. This dose is greater than 300 times the dose shown to inhibit tumour related osteolysis in rats, and 5000 times the optimal antiresorptive dose in aged ovariectomised rats. In animal models of metastatic bone disease, ibandronic acid not only prevented the development of osteolytic bone lesions but also suppressed the progression of already established lesions, which were induced by human breast cancer cells. Several mechanisms may be involved in the inhibition of tumour osteolytic lesion development by ibandronic acid, including direct effects on bone, osteoclasts and tumour cells.
Clinical studies in patients with tumour-induced hypercalcaemia demonstrated that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.
Clinical studies in patients with metastatic bone disease have shown that there is a dose dependent inhibitory effect of bone osteolysis, expressed by markers of bone resorption, and a dose-dependent effect on skeletal events.
Bone resorption due to malignant disease is characterised by excessive bone resorption not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical trials.

Treatment of metastatic bone disease.

Three similarly designed phase III multi-centre, randomised, double-blind, placebo-controlled trials were conducted to investigate the efficacy and safety of Bondronat in the treatment of metastatic bone disease (MBD) due to breast cancer. The primary efficacy endpoint was the Skeletal Morbidity Period Rate (SMPR), defined as the number of 12 week Periods with New Bone Complications (PNBC) of Metastatic Bone Disease over Total Observation Time. A new bone complication was defined as a composite endpoint comprising the following skeletal related events (SREs) as sub-components: vertebral fractures; non-vertebral pathological fractures; bone complications requiring radiotherapy; bone complications requiring surgery.
The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were, therefore, counted only once in any given 12 week period for the purposes of the analysis. Supportive analyses for the primary efficacy endpoint included mean number of bone events, proportion of patients with new events and time to first new bone event. Secondary efficacy endpoints included quality of life (sum of scores of five functional parameters), bone pain score, analgesic requirement, WHO performance status, patient survival and markers of bone turnover.

Intravenous.

In the IV study 466 patients were randomised to receive 4 weekly treatment for up to 60 weeks. 154 patients received Bondronat 2 mg IV injection, 154 received 6 mg Bondronat by infusion (over 1 - 2 hours) and 158 patients received placebo approximately half by bolus injection and half by infusion.
A statistically significant reduction (20%) in the SMPR was shown for the 6 mg treatment group compared to placebo. The beneficial effects of the 6 mg dose were most apparent in the reduced need for radiotherapy and the number of vertebral fractures. A statistically significant reduction was also observed in the mean number of new bone events for the 6 mg treatment group compared placebo and time to first event (Table 4).
For secondary efficacy endpoints, a statistically significant improvement in bone pain score was shown for Bondronat 6 mg treatment group compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesic. The bone pain and analgesic consumption assessments were performed using a scoring system, with a score of 0 - 4 for bone pain and a score of 0 - 6 for analgesic consumption. The quality of life was assessed as the sum of scores of five functional parameters (physical, role, cognitive, emotional and social function) and demonstrated that the overall quality of life scores decreased significantly less for patients treated with Bondronat compared with placebo (Table 4). There was a marked depression of urinary markers of bone resorption (pyridinoline and deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to placebo.

Oral.

The treatment of metastatic bone disease of breast cancer with Bondronat 50 mg tablets was assessed in two randomised placebo controlled phase III trials with duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (n = 277) or Bondronat 50 mg (n = 287) once daily.
In order to minimise the effect of early selective dropout and pre-scheduled radiotherapy in some patients which was completed during the first treatment period, all data from the first 12 weeks has been excluded from the efficacy analysis.
Pooled data demonstrated a significant reduction in SMPR for the treatment group compared to placebo, with a reduced need for radiotherapy being the most apparent difference. There was also a significant reduction in the mean number of events per patient for the treatment group compared to placebo (Table 5).
For the secondary endpoints, a statistically significant improvement in bone pain score was shown for Bondronat 50 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics compared to placebo. The deterioration in Quality of Life and WHO performance status was significantly less in Bondronat treated patients compared with placebo. There was a marked depression of urinary CTx, a marker of bone resorption, which was statistically significant compared to placebo (Table 6).
A Poisson regression multivariate analysis was conducted to determine the number of new bone events while adjusting for the differences in the baseline characteristics of the patients treated. The 6 mg IV dose demonstrated a significant treatment effect over placebo with a mean risk reduction of approximately 40% (p = 0.0033), while the 50 mg oral dose demonstrated a mean risk reduction of 38% (p = 0.0001) (Table 7).

Treatment for tumour-induced hypercalcaemia.

Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic acid on tumour induced osteolysis, and specifically on tumour induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.
A single infusion of 2 - 6 mg Bondronat was effective in reducing elevated serum calcium levels in patients with hypercalcaemia of malignancy with and without metastases. Lower initial calcium levels were associated with a greater likelihood of treatment response, as were higher doses (up to 4 mg). The drug was also more likely to be effective in patients with hypercalcaemia due to local osteolytic lesions than in those with humoral hypercalcaemia. The time to response was 2 - 4 days in 75% of responding patients with the remaining 25% of responses occurring on days 5 - 7. The median time to relapse (re-increase of albumin-corrected serum calcium to above 3 mmol/L) was 18 - 19 days.

Study P3.

Study P3 was an open, randomised, multicentre, phase II dose-finding study in which the efficacy and safety of Bondronat was evaluated in 174 patients with hypercalcaemia of malignancy. One patient died prior to treatment with the study drug. Of the 173 patients eligible for evaluation, 56, 56 and 60 patients were treated with a single IV infusion of 0.6, 1.1 and 2 mg Bondronat, respectively.
Response to this single infusion was defined as attainment of the normal range of albumin-corrected serum calcium (≤ 2.7 mmol/L) for at least one visit and a reduction of the albumin-corrected serum calcium ≥ 0.3 mmol/L, compared with baseline.
The response was dose related. 44%, 52.2% and 67.3% of the patients achieved a normal range of serum calcium with a single dose of 0.6 mg, 1.1 mg and 2 mg Bondronat, respectively.
Forty nine patients (28.3%) then received a second infusion of Bondronat between days 2 and 49 after the first infusion because of insufficient efficacy or hypercalcaemia relapse. 46, 2 and 1 patient(s) received 2, 1.6 and 1.1 mg Bondronat, respectively. Response was measured using the same criteria as above. Twenty one patients were withdrawn prior to response and were censored from the study and 9 patients reached the normal range.

Study P6.

Study P6 was a double blind, randomised, multicentre, dose finding study in which the efficacy and safety were assessed in 147 patients with malignant hypercalcaemia (baseline albumin-corrected serum calcium ≥ 3.0 mmol/L after adequate hydration). Of the 131 randomised patients eligible for final evaluation, 45, 44 and 42 patients were treated with 2, 4 and 6 mg, respectively.
Response was defined as achieving the normal range of serum calcium (≤ 2.7 mmol/L) on at least one visit and a reduction of the albumin-corrected serum calcium of ≥ 0.3 mmol/L, compared with baseline. Pooled response rates for the studies are presented in Table 8.

5.2 Pharmacokinetic Properties

The pharmacological effects of ibandronic acid are not directly related to actual plasma concentrations. This was demonstrated by various studies in animals and humans, in which equivalent efficacy of ibandronic acid was demonstrated following either daily or intermittent regimens, consisting of a drug-free interval of several weeks (at least 6 weeks in rats, at least 11 weeks in dogs, at least 30 days in monkeys, and at least 9.5 weeks in humans) provided the same total dose was administered over this period.

Absorption.

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration. Maximum observed plasma concentrations were reached within 0.5 - 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or drink (other than plain water).

Bioavailability.

Bioavailability is reduced by about 90% when oral ibandronic acid is administered with food in comparison with bioavailability seen in fasted subjects. When taken 30 minutes before a meal, the reduction in bioavailability is approximately 50%. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.
Plasma concentrations of ibandronic acid increase in a dose-proportional manner after oral administration up to 100 mg and after IV administration up to 6 mg.
Bioavailability was reduced by approximately 75% when Bondronat tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets be taken after an overnight fast, and fasting should continue for at least 30 minutes after the dose.

Distribution.

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the volume of distribution is at least 90 L and the amount reaching the bone is estimated to be 40 - 50% of the dose. Protein binding in human plasma is low (approximately 87% bound at therapeutic concentrations).

Metabolism.

There is no evidence that ibandronic acid is metabolised in humans.

Elimination.

Ibandronic acid is removed from the circulation via bone absorption (40 - 50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10 - 60 hours. However, early plasma levels fall quickly reaching 10% of peak values within 3 - 8 hours after IV or oral administration, respectively. No systemic accumulation was observed when ibandronic acid was administered intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease.
Total clearance of ibandronic acid is low with average values in the range 84 - 160 mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50 - 60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

Pharmacokinetics in special populations.

Gender.

Bioavailability and pharmacokinetics of ibandronic acid is similar in both men and women.

Race.

Studies involving Asian and Caucasian healthy volunteers showed no clinically relevant differences in the pharmacokinetics of ibandronic acid.

Patients with renal impairment.

Intravenous.

Exposure to ibandronic acid in patients with various degree of renal impairment is related to creatinine clearance (CLcr). In clinical pharmacology trial WP18551, after a single dose IV administration of 6 mg (infusion time of 15 minutes), mean AUC0-24 increased by 14% and 86% respectively, in subjects with mild (mean estimated CLcr = 68.1 mL/min) and moderate (mean estimated CLcr = 41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr = 120 mL/min). In subjects with severe renal impairment (mean estimated CLcr = 21.2 mL/min), who received a single dose of 2 mg (infusion time of 15 minutes), mean AUC0-24h was increased by 110% compared to healthy volunteers. Mean Cmax was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. There is no evidence of a reduction in tolerability associated with an increase in exposure. However, an adjustment in the dose is recommended in patients with moderate renal impairment (CLcr ≥ 30 and ≤ 50 mL/min) or severe renal impairment (CLcr ≤ 30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease (see Section 4.2 Dose and Method of Administration, Special patient groups).

Oral.

Patients with severe renal impairment (CLcr ≤ 30 mL/min) receiving oral administration of 10 mg ibandronic acid daily for 21 days had 2 - 3 fold higher plasma concentrations than patients with normal renal function (CLcr > 90 mL/min). Total clearance of ibandronic acid was reduced to 44 mL/min in patients with severe renal impairment compared with 129 mL/min in patients with normal renal function. There was no reduction in tolerability associated with the increase in exposure. However, reduction of the oral dose to one 50 mg tablet once weekly is recommended in patients with severe renal impairment (CLcr ≤ 30 mL/min). No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥ 50 and < 80 mL/min). A reduction in the oral dose to one 50 mg tablet every second day is recommended in patients with moderate renal impairment (CLcr ≥ 30 and < 50 mL/min) (see Section 4.2 Dose and Method of Administration, Special patient groups).
Approximately 37% of ibandronic acid was cleared from the body during a standard 4 hour haemodialysis procedure.

Patients with hepatic impairment.

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolised but cleared by renal excretion and by uptake into bone. No dosage adjustment is necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is low at therapeutic concentrations (85%), hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

Elderly.

There were no clinically significant differences in the pharmacokinetics of ibandronic acid in elderly patients. No dosage adjustment is necessary.

Children.

The pharmacokinetics of ibandronic acid in patients less than 18 years of age has not been studied.

5.3 Preclinical Safety Data

Genotoxicity.

The mutagenic and clastogenic potential of ibandronic acid was assessed in a standard range of tests. In vitro tests included the Salmonella typhimurium, Escherichia coli and Chinese hamster V79 mammalian cell line assays for gene mutation and a human peripheral lymphocyte assay for chromosomal aberrations, each with and without metabolic-activation. In vivo mouse micronucleus tests for chromosomal damage were conducted by both the oral and IV routes of administration. There was no evidence for any mutagenic or clastogenic activity with ibandronic acid.

Carcinogenicity.

A two year carcinogenicity study was conducted with ibandronic acid administrated to rats at oral doses of 0 (control), 3, 7 or 15 mg/kg/day. There were no neoplastic findings considered to be related to treatment with ibandronic acid. In an 18 month carcinogenicity study ibandronic acid was administered to mice at oral doses of 0 (control), 5, 20, or 40 mg/kg/day. There were no neoplastic findings as a result of treatment with ibandronic acid. In a 90 week carcinogenicity study ibandronic acid was administered to mice at oral (drinking water) doses of 0 (control), 5, 20, and 80 mg/kg/day. There were no neoplastic findings as a result of treatment with ibandronic acid.

4 Clinical Particulars

4.1 Therapeutic Indications

Bondronat Injection and Tablets are indicated for the treatment of metastatic bone disease in patients with breast cancer.
Bondronat Injection is indicated for the treatment of tumour-induced hypercalcaemia with or without metastases.

4.3 Contraindications

Bondronat Injection and Tablets must not be used in patients with: hypocalcaemia (see Section 4.4); a known hypersensitivity to ibandronic acid, other bisphosphonates or any of the excipients.
Bondronat tablets must not be used in patients: with abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia (see Section 4.4); who are unable to stand or sit upright for at least 30 minutes (see Section 4.4; Section 4.2).

4.4 Special Warnings and Precautions for Use

General.

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat infusion solution is administered IV.
Clinical placebo-controlled, randomised studies in patients with metastatic bone disease due to breast cancer have not shown any evidence of deterioration in renal function with long-term Bondronat therapy. Nevertheless, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.
In patients treated for hypercalcaemia, the onset of action of Bondronat is not immediate, so all patients should be adequately hydrated with normal saline and their urine output should be maintained. Over-hydration should be avoided in patients at risk of cardiac failure.
Since non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant medication with Bondronat.
Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with the absorption of Bondronat tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration.

Anaphylactic reaction/shock.

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with IV ibandronic acid.
Appropriate medical support and monitoring measures should be readily available when Bondronat is administered intravenously. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the infusion and initiate appropriate treatment.

Gastrointestinal irritation.

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).
Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention to the dosing instructions and be able to comply with these instructions (see Section 4.2).
Physicians should be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue Bondronat and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Hypocalcaemia.

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy. Adequate intake of calcium and vitamin D is important in all patients.
Infusion of Bondronat may present a risk of hypocalcaemia. In most cases, plasma calcium concentrations remain within the normal range during the administration of recommended doses of Bondronat. Hypocalcaemia was reported in about 2% of patients treated with doses up to 4 mg. If plasma calcium falls into the hypocalcaemic range, the patients usually remain asymptomatic. In severe or symptomatic cases of hypocalcaemia, oral or parenteral calcium supplementation may be required.

Osteonecrosis.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis), has been reported in patients treated with bisphosphonates. Most cases have been reported in patients being treated with IV bisphosphonates. Some cases of osteonecrosis of the jaw have occurred after treatment with oral bisphosphonates for osteoporosis.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with Bondronat, particularly in patients with concomitant risk factors (e.g. cancer, chemotherapy including angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene). While on treatment, patients should avoid invasive dental procedures if possible.
For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, treatment should be discontinued. Dental surgery for these patients may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether the discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Cases of osteonecrosis of other oro-facial sites including the external auditory canal have also been reported in patients treated with bisphosphonates including Bondronat. Risk factors are similar as for osteonecrosis of the jaw. Other risk factors may include repetitive minor trauma (e.g. habitual cotton bud use). The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Paediatric use.

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

Use in the elderly.

No overall differences in efficacy or safety were observed between the elderly patients and younger patients.

Effects on laboratory tests.

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Bondronat have not been performed.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interactions of clinical significance are likely since Bondronat does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats. Bondronat is eliminated by renal secretion only and does not undergo any biotransformation. In rats, there was no evidence for renal secretion of ibandronic acid by known acidic and basic transport systems involved in the excretion of other drugs.

General.

In clinical studies, Bondronat has been administered concomitantly with commonly used anti-cancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

Aminoglycosides.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

Calcium supplements/antacids.

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of Bondronat tablets, which is consistent with findings in animal studies. Therefore, with such products, including food, intake must be delayed for 30 minutes following oral administration of Bondronat.

H2 blockers.

In healthy male volunteers and postmenopausal women, IV ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal range of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when Bondronat is administered with H2-antagonists or other drugs that increase gastric pH.

Hormone replacement therapy.

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

Melphalan/prednisolone.

When co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Rat fertility was unaffected by an oral ibandronic acid dose of 16 mg/kg/day. Females were treated from 14 days prior to mating to the end of gestation, and pre-implantation losses were increased at oral doses of 1 - 16 mg/kg/day. Fertility and sperm concentrations in rats were reduced following IV doses of 0.3 and 1 mg/kg/day given to males for 28 days prior to and during mating. Females were treated from 14 days prior to mating to gestation day 7, and decreased corpora lutea and increased post-implantation loss were observed with a dose of 1.2 mg/kg/day. Animal:human exposure comparisons are not valid because of differences in frequency of dosing.
(Category B3)
Bondronat should not be used during pregnancy.
There was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in orally treated rats (30 mg/kg/day) and rabbits (20 mg/kg/day). No teratogenicity was observed in rats treated with IV doses of 0.1 - 1.5 mg/kg/day or in rabbits treated with IV doses of 0.03 - 0.20 mg/kg/day. Animal:human exposure comparisons are not valid because of differences in frequency of dosing.
Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. There was an increase in foetal visceral variations (renal pelvis ureter syndrome) and ibandronic acid interfered with natural delivery (dystocia). Dystocia could be partially reversed by calcium supplementation.
There is no clinical experience with Bondronat in pregnant women.
Bondronat should not be used during lactation.
It is not known whether Bondronat is excreted in human milk. After IV administration ibandronic acid was excreted in the milk of lactating rats.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical trials.

Treatment of metastatic bone disease.

Adverse reactions from the phase III trial, reported as remotely, possibly, or probably related to study medication at a frequency ≥ 2% in patients treated intravenously, at 4 week intervals, with Bondronat 6 mg are listed in Table 2. Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo treated patients are excluded.
Adverse reactions from pooled oral phase III trials, reported as remotely, possibly, or probably related to study medication, at a frequency ≥ 2% in patients treated with Bondronat 50 mg once daily are listed in Table 3. Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo treated patients are excluded.
The following adverse reactions occurred < 1% in patients receiving Bondronat 50 mg once daily.

Blood and lymphatic system disorders.

Anaemia.

Nervous system disorders.

Dysgeusia, paraesthesia.

Gastrointestinal disorders.

Abdominal pain, dry mouth, duodenal ulcer, haemorrhage, dysphagia, gastritis.

Skin and subcutaneous tissue disorders.

Pruritus.

Renal and urinary disorders.

Uraemia.

General disorders.

Chest pain, influenza-like illness, malaise, pain NOS.

Investigations.

Increased blood parathyroid hormone.

Treatment of tumour-induced hypercalcaemia.

The most common adverse reaction associated with IV infusion of Bondronat is a rise in body temperature, which occurred in up to 9% of patients. Occasionally, this was combined with one or more of the following symptoms: fever, chills, headache, heat sensation, sweating, bone and/or muscle ache-like pain (2 - 3% of all patients). In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.
Serum calcium may fall to hypocalcaemic values in about 2% of patients treated with doses up to 4 mg (see Section 4.4).
Frequently, the decreased renal calcium excretion is accompanied by a fall in serum phosphate levels not requiring therapeutic measures. Clinically relevant hypophosphataemia and hypomagnesaemia were reported in less than 1% of patients.
Gastrointestinal intolerability has been reported in isolated cases.
Administration of other bisphosphonates has been associated with broncho-constriction in aspirin-sensitive asthmatic patients.

Postmarketing experience.

Musculoskeletal and connective tissue disorders.

Osteonecrosis of the jaw and of other oro-facial sites, including the external auditory canal, has been reported very rarely in patients treated by ibandronic acid.
In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Eye disorders.

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with bisphosphonates, including ibandronic acid. In some cases, these events did not resolve until the bisphosphonate was discontinued.

Gastrointestinal disorders.

Stomatitis has been reported in patients receiving bisphosphonates.

Immune system disorders.

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with ibandronic acid (see Section 4.4).
Allergic reactions including asthma exacerbation have been reported.
Severe cutaneous adverse reactions including Stevens-Johnson Syndrome, Erythema Multiforme and Bullous Dermatitis have been reported.

Injury, poisoning and procedural complications.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including ibandronate, however causality has not been established.

Reporting suspected adverse reactions.

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 https://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Treatment of metastatic bone disease.

Bondronat is intended for long-term administration unless clinically inappropriate.

Intravenous.

The recommended dose is 6 mg IV given every 4 weeks. The dose should be infused over 1 - 2 hours. For infusion, the contents of the vial should be added to 500 mL isotonic sodium chloride solution (or 500 mL 5% glucose solution).

Oral.

The recommended oral dose is one 50 mg film-coated tablet once daily.
Bondronat should be taken 30 minutes before the first food or drink of the day (other than plain water) or any other oral medication or supplement (including calcium).
Tablets should be swallowed whole with a full glass of plain water (180 - 240 mL) while the patient is standing or sitting in an upright position.
Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration.
Plain water is the only drink that should be taken with Bondronat. Please note that some mineral waters may have a higher concentration of calcium and therefore, should not be used.
Patients should not lie down for 30 minutes after taking Bondronat tablets.

Treatment of tumour-induced hypercalcaemia.

Prior to treatment with Bondronat the patient should be adequately rehydrated with 0.9% sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general, patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ≥ 3 mmol/L or ≥ 12 mg/dL) 4 mg will be an adequate single dosage. In patients with moderate hypercalcaemia (albumin corrected serum calcium < 3 mmol/L or < 2 mg/dL) 2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms of efficacy.

*Note.

Albumin-corrected serum calcium (mmol/L)
= serum calcium (mmol/L) - [0.02 x albumin (g/L)] + 0.8; or
Albumin-corrected serum calcium (mg/dL)
= serum calcium (mg/dL) + 0.8 x [4 - albumin (g/dL)].
To convert the albumin-corrected serum calcium in mmol/L value to mg/dL, multiply by 4.
In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The median time to relapse (re-increase of albumin corrected serum calcium above 3 mmol/L) was 18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.
A limited number of patients (n = 50) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.
Bondronat concentrate for infusion should be administered as an IV infusion. For this purpose, the contents of the vial should be added to 500 mL isotonic sodium chloride solution (or 500 mL 5% glucose solution) and infused over 1 - 2 hours. Bondronat concentrate should not be mixed with calcium containing solutions.
To avoid potential incompatibilities, Bondronat concentrated solution for infusion should only be diluted with isotonic sodium chloride solution or 5% dextrose solution.
As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for infusion is administered intravenously.

Special patient groups (see Section 5.2, Pharmacokinetics in special populations).

Patients with renal impairment.

IV infusion for metastatic bone disease.

For patients with mild renal impairment (CLcr ≥ 50 and < 80 mL/min) no dosage adjustment is necessary. For breast cancer patients with moderate renal impairment (CLcr ≥ 30 and < 50 mL/min) or severe renal impairment (CLcr < 30 mL/min) being treated for metastatic bone disease the following dosing recommendations in Table 1 should be followed (see Section 5.2, Pharmacokinetics in special populations, Patients with renal impairment).

Film-coated tablets.

For patients with mild renal impairment (CLcr ≥ 50 and < 80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥ 30 and < 50 mL/min) a dosage adjustment to one 50 mg film-coated tablet every second day is recommended. For patients with severe renal impairment (CLcr < 30 mL/min) the recommended dose is 50 mg once weekly (see Section 5.2, Pharmacokinetics in special populations, Patients with renal impairment).

Patients with hepatic impairment.

No dosage adjustment is necessary.

Elderly.

No dosage adjustment is necessary.

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

No specific information is available on the treatment of overdosage with Bondronat. However, oral overdosage may result in upper gastrointestinal adverse reactions, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind Bondronat. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.
Standard haemodialysis procedures result in significant clearance of ibandronic acid.
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

Concentrated injection for IV infusion.

The concentrated injection also contains sodium chloride, glacial acetic acid, sodium acetate and water for injections.

Film-coated tablets.

The tablets also contain lactose monohydrate, microcrystalline cellulose, povidone, crospovidone, stearic acid and colloidal anhydrous silica. The tablet film-coating contains hypromellose, titanium dioxide, purified talc and macrogol 6000.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Concentrated injection for IV infusion.

Store below 30°C. After reconstitution, store at 2 - 8°C (Refrigerate. Do not freeze).
Bondronat is for single use in one patient only. Discard any residue.
From a microbiological point of view, Bondronat infusion solution should be used immediately. If necessary, storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours, stored at 2 - 8°C (Refrigerate. Do not freeze). The product is not intended to be stored after dilution unless the dilution has taken place under controlled and validated aseptic conditions.

Film-coated tablets.

Store below 30°C.

6.5 Nature and Contents of Container

Concentrated injection for IV infusion.

Bondronat 6 mg/6 mL vial is available in packs of one.

Film-coated tablets.

The tablets are available in blister packs of 28.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

Summary Table of Changes