Consumer medicine information

BONEFOS®

Sodium clodronate

BRAND INFORMATION

Brand name

Bonefos Capsules

Active ingredient

Sodium clodronate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using BONEFOS®.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Bonefos.

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 taking Bonefos against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

WHAT BONEFOS IS USED FOR

Certain cancers increase bone breakdown and lead to an increased amount of calcium circulating in the bloodstream. This can result in high calcium levels in the blood (hypercalcaemia) or bone destruction (osteolysis) which increases your risk of bone fractures and bone pain.

Bonefos works by stopping calcium from coming out of your bones and keeps your blood calcium at normal levels (normocalcaemia). Bonefos can be used to either bring your blood calcium levels down to a normal level (acute treatment) or to keep it down at a normal level (maintenance treatment).

Bonefos can also be used to treat bone destruction due to breast cancer and bone marrow cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

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

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

BEFORE YOU TAKE BONEFOS

When you must not take it

Do not take Bonefos if you have an allergy to:

  • sodium clodronate, the active ingredient in Bonefos
  • 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

Do not take Bonefos if you have or have had any of the following medical conditions:

  • severe inflammation of the digestive system

Do not take Bonefos if you are taking any other ‘bisphosphonate’ medicine, a class of medicines that prevent the loss of bone mass (used in the treatment of osteoporosis and similar diseases) and is also used in the treatment of high calcium levels in the blood and/or bone destruction due to certain cancers.

Do not take this medicine after the expiry date printed on the carton and blister.

The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering.

If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any medicines, foods, preservatives or dyes.

Tell your doctor if you:

  • have or have had kidney disease
  • are on a low sodium diet
  • are having any invasive dental procedures e.g. tooth extractions
  • any infections in the mouth

Tell your doctor if you need any dental work to be done.

If you develop a rare side-effect affecting the jaw, dental work may make this condition worse.

Talk to your dentist about the need for any dental work to be done before starting Bonefos.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking Bonefos.

Taking other medicines

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

Some medicines and Bonefos may interfere with each other. These include:

  • estamustine phosphate, an anti-cancer drug
  • antacids, medicines used to treat heartburn and indigestion
  • non steroidal anti-inflammatory drugs (NSAIDs), used to treat acute or chronic pain and conditions such as arthritis
  • aminoglycoside antibiotics, given by injection, used to treat serious infections
  • medicines that reduce your blood calcium levels [e.g. corticosteroids, phosphate, calcitonin, mithramycin and diuretics (medicines that increase the excretion of water from your body, and used to treat heart failure, liver cirrhosis, hypertension and certain kidney diseases)]
  • iron supplements

These medicines may be affected by Bonefos or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE BONEFOS

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions printed on the pharmacist label, ask your doctor or pharmacist for help.

How much to take

The following doses are likely to be recommended by your doctor if your kidneys function properly. If your kidneys do not function properly, your doctor may recommend a different dosage regimen.

Follow all directions given to you by your doctor or pharmacist carefully.

Treatment to initially bring blood calcium levels down to normal (acute treatment):
The usual starting dose of Bonefos is 2400-3200 mg in divided doses per day (e.g. three to four 800 mg tablets), depending on how quickly your calcium level drops.

Treatment to maintain blood calcium at normal levels:
The usual dose of Bonefos is 1600 mg in divided doses per day (e.g. four 400 mg capsules or two 800 mg tablets).

Treatment of bone destruction (osteolysis):
The usual dose of Bonefos is 1600 mg in divided doses per day (e.g. four 400 mg capsules or two 800 mg tablets).

How to take it

Swallow the medicine whole with a full glass of water. Do not crush or dissolve the medicine in water.

The Bonefos 800 mg tablet may be broken in half to make swallowing easier but the halves have to be taken at the same time.

Do not chew the medicine.

Do not take the medicine with milk, food or medicines containing calcium.

When to take it

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If possible take your medicine first thing in the morning, on an empty stomach. However, if you cannot take your medicine in the morning, or if your doctor has told you to split your dose, take your medicine at least 2 hours after food or drink (other than plain water).

Certain medicines and food (particularly high calcium food such as milk and cheese) can interfere with the absorption of Bonefos. This may stop your body taking in as much medicine as it should, and then it may not work properly.

Do not eat or drink for an hour after taking Bonefos.

If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of Bonefos.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If you forget to take a dose of Bonefos, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Bonefos. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

WHILE YOU ARE TAKING BONEFOS

Things you must do

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

Tell any doctors, dentists, oral surgeons and pharmacists who treat you that you are taking this medicine.

Avoid invasive dental procedures whilst being treated with this medicine if possible.

If you develop a rare side-effect affecting the jaw, dental work may make this condition worse.

Ensure you maintain good oral hygiene whilst taking this medicine.

If you cannot avoid dental work whilst taking this medicine, oral hygiene is important to minimise the risk of developing side-effects.

Tell your doctor if you feel any thigh, hip or groin pain while taking Bonefos.

These symptoms could be an early indication of a possible fracture.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Drink plenty of fluid during treatment, particularly if you have high calcium levels in the blood or kidney disease.

Keep all of your doctor’s appointments so that your progress can be checked and your kidney function can be monitored.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Bonefos to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects such as loss of appetite, nausea, vomiting, constipation and stomach pain (symptoms of hypercalcaemia). If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Do not take half a Bonefos 800 mg tablet as a substitute for one Bonefos 400 mg capsule.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Bonefos.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • nausea, vomiting or diarrhoea
  • stomach pain

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor, dentist or oral surgeon as soon as possible if you notice jaw-bone problems, which may include infection and delayed healing after teeth are pulled out or other work that involves drilling into the jaw.

This may be a serious side effect that requires medical attention. Serious side effects are rare.

Tell your doctor as soon as possible if you notice any of the following:

  • unusual bleeding or bruising under the skin, purple brown spots visible through skin
  • difficulty breathing
  • fever
  • redness of the skin
  • muscle spasm or twitching, numbness or tingling in fingers and toes, depression, irritability, confusion, disorientation (symptoms of low calcium levels in the blood)
  • pain, weakness or discomfort in your thigh, hip or groin (this may be an early sign of a possible fracture of the thigh bone)

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER TAKING BONEFOS

Storage

Keep your medicine in the pack until it is time to take them.

If you take the tablets/capsules out of the pack they may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Bonefos or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car.

Heat and damp can destroy some medicines.

Keep it where 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 this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Bonefos capsules: pale yellow in colour with “BONEFOS” printed in black.

Bonefos tablets: white, oval shaped, scored and embossed with “L134” on one side.

Ingredients

Active ingredients per capsule:

  • Bonefos 400 mg capsule – 400 mg of sodium clodronate.

Inactive ingredients per capsule:

  • lactose
  • purified talc
  • silica colloidal anhydrous
  • calcium stearate
  • gelatin
  • titanium dioxide
  • iron oxide red
  • iron oxide yellow
  • purified water
  • Tekprint SW-9008 black ink.

Active ingredient per tablet:

  • Bonefos 800 mg tablet - 800 mg of sodium clodronate.

Inactive ingredients per tablet:

  • croscarmellose sodium
  • microcrystalline cellulose
  • stearic acid
  • magnesium stearate
  • silica colloidal anhydrous
  • Opadry II complete film coating system 85F18422 white.

Supplier

Made in Finland for:
Bayer Australia Limited
ABN 22 000 138 714
875 Pacific Highway
Pymble, NSW 2073

Australian Registration Numbers

  • 400 mg capsules:
    AUST R 66703 and 66704
  • 800 mg tablets:
    AUST R 181921 and 181922

Date of preparation

August 2013

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered Trademark of Bayer AG, Germany

©Bayer Australia Ltd

All rights reserved.

BRAND INFORMATION

Brand name

Bonefos Capsules

Active ingredient

Sodium clodronate

Schedule

S4

 

Name of the medicine

Sodium clodronate (as tetrahydrate).

Excipients

Capsules.

Purified talc, calcium stearate, anhydrous colloidal silica, lactose, gelatin, purified water, iron oxide red, iron oxide yellow, Tekprint SW-9008 black ink and titanium dioxide. Each capsule contains the equivalent of 64 mg sodium.

Tablets.

Croscarmellose sodium, microcrystalline cellulose, stearic acid, magnesium stearate, anhydrous colloidal silica and Opadry II complete film coating system 85F18422 white. Each tablet contains the equivalent of 128 mg sodium.

Description

Chemical name: disodium (dichloromethylene) bisphosphonate tetrahydrate. CAS: 22560-50-5. Bonefos contains sodium clodronate which is a bone metabolism regulator. Sodium clodronate is a white to off white odourless powder which is freely soluble in water, slightly soluble in methanol, very slightly soluble in dehydrated alcohol and insoluble in toluene, acetone and diethylether.

Pharmacology

Pharmacodynamics.

Sodium clodronate belongs chemically to the bisphosphonate group, which act primarily on bone tissue. Its major pharmacological action is inhibition of bone resorption.
The mechanism of sodium clodronate's action lies in its protection against the dissolution of hydroxyapatite crystals and direct reduction of osteoclast activity. There is some evidence that sodium clodronate also has indirect effects on osteoclast activity by inhibition of various mediators. The selectivity of the direct effects most likely arises from the strong affinity of sodium clodronate for calcium phosphate and it will, therefore, be distributed mainly to the skeleton.
In concentrations that induce inhibition of bone resorption, sodium clodronate has no effect on the normal mineralisation process in bone tissue.
The therapeutic effect of sodium clodronate is achieved by inhibition of abnormal bone destruction in diseases with increased osteolysis. In hypercalcaemic states, sodium clodronate reduces elevated serum calcium levels and, in normocalcaemic patients, the inhibitory effect on bone resorption manifests as reduced excretion of calcium and hydroxyproline in the urine.
In patients with bone metastases or bone lesions from myeloma, sodium clodronate inhibits the progression of existing skeletal lesions, as well as the formation of new ones. Sodium clodronate also alleviates pain caused by tumour induced bone destruction and reduces the incidence of fractures in these patients.

Pharmacokinetics.

Absorption.

As with other bisphosphonates, the gastrointestinal absorption of oral sodium clodronate is low, at around 2%. Due to the strong affinity of sodium clodronate for calcium and other divalent cations of food, the intestinal absorption of sodium clodronate is negligible when given with meals. The interindividual and intraindividual variation in gastrointestinal absorption is high. Relative to administration two hours before breakfast, the bioavailability of sodium clodronate 2 x 400 mg capsules was reduced by 9, 31, 90 and 67% respectively after administration one hour before breakfast, 30 minutes before breakfast, with breakfast and two hours after breakfast, in healthy volunteers.

Distribution and elimination.

The total systemic clearance is around 110 mL/minute and the renal clearance constitutes about 75% of the plasma clearance. No metabolites of sodium clodronate have been found in the urine, indicating that it is not metabolised, and that the administered drug is the active moiety.
The average volume of distribution is 20 L. This is about 25% of bodyweight, equivalent to the extracellular water volume. The plasma protein binding of clodronate is low.
The elimination of sodium clodronate from serum is characterised by two clearly distinguished phases: the distribution phase with a half-life of about two hours, and a second elimination phase which is very slow because sodium clodronate is strongly bound to bone. The nonrenal clearance of clodronate in the second phase is due to skeletal uptake.
Sodium clodronate which is bound to the bone (approximately 20% of a single dose) will be excreted very slowly, at a rate corresponding to bone turnover.
There is no specific relationship between the plasma/ blood concentrations of sodium clodronate and its therapeutic activity or adverse effects, i.e. the relationship is very varied and could be idiosyncratic at times. However, higher doses, especially intravenous, appear to be more effective in the treatment of hypercalcaemia of malignancy with the increased likelihood of side effects, e.g. hypocalcaemia, extraosseous calcification/ bone formation and renal damage. More studies are needed to elucidate the cause(s) of the variation, which may be multifactorial. There is evidence, however, that renal failure decreases the renal clearance of sodium clodronate and this leads to increased area under the curve (AUCinf). The dose of sodium clodronate (± duration of treatment) would therefore need to be reduced in renal failure patients in order to keep the AUCinf in some control and prevent too much accumulation of sodium clodronate in tissues such as bone.

Clinical Trials

Treatment of hypercalcaemia of malignancy.

Three randomised, double blind, placebo controlled trials were conducted in eligible patients treated with either sodium clodronate (42 patients) or placebo (32 patients). Patients suffered from various malignancies, with or without bone metastases, and hypercalcaemia varied from mild/ moderate (corrected total serum calcium 2.8 to 3.1 mmol/L or serum ionised calcium > 1.6 mmol/L) to severe (corrected total serum calcium > 3.1 mmol/L). Eleven patients received sodium clodronate orally (400 mg x 2 twice daily), 31 patients received intravenous sodium clodronate (300 mg daily), and 32 patients received equivalent placebo treatments. Treatment was continued until normocalcaemia was achieved, or for a maximum of seven days.
Five of the eleven (45%) patients treated with oral sodium clodronate achieved normocalcaemia (corrected total serum calcium < 2.7 mmol/L) compared to none in the placebo exposed patients (p = 0.1). Three of these responders achieved normocalcaemia within seven days.
23 of the 31 (74.2%) patients treated with intravenous sodium clodronate achieved normocalcaemia (corrected total serum calcium < 2.7 mmol/L or serum ionised calcium < 1.4 mmol/L) compared to four (15.4%) in the placebo exposed patients, but some of the responders to sodium clodronate took more than seven days to do so.

Treatment of osteolysis.

Multiple myeloma.

Two clinical trials were conducted in patients with recently diagnosed multiple myeloma and osteolytic lesions or a paraprotein in the blood or urine.
In one trial, 536 recently diagnosed patients were randomised to receive either 1,600 mg (4 x 400 mg capsules daily) of sodium clodronate (n = 264) or placebo (n = 272) indefinitely, with a follow-up of one to three years. There were significant reductions in the incidence of vertebral and nonvertebral fractures in the clodronate group (see Table 1).
A log-rank comparison of the proportion of patients remaining event free of nonvertebral fracture or hypercalcaemia over four years favoured the clodronate group (p = 0.021).
In the second trial, 336 recently diagnosed multiple myeloma patients (intent to treat) were randomised to receive either 2400 mg (2 x 400 mg capsules tds) of sodium clodronate (n = 168) or placebo (n = 168) for two years. There was a significant reduction in the incidence of osteolytic lesions in the clodronate group, but no significant reduction in the incidence of vertebral or nonvertebral fractures (see Table 2).

Breast cancer.

Two clinical trials were conducted in breast cancer patients with bone metastases.
In one trial, 173 women were randomised to receive either 1600 mg (4 x 400 mg capsules daily) of sodium clodronate (n = 85) or placebo (n = 88) for 18 months to 3 years. Even though this study was designed to evaluate the cumulative number of events and was not powered to evaluate the number of patients having an event (or being event free) at one or two years, the proportion of patients remaining event free of each endpoint at two years favoured the sodium clodronate group. However there were no significant differences between treatments on the log-rank comparisons of total experience (see Table 3).
In the second trial, 144 women received either 1600 mg (2 x 400 mg capsules twice daily) of sodium clodronate (n = 73) or placebo (n = 71). Patients were followed for a period of one year. The log-rank comparison of the time patients remained free of a new bone event was marginally significant in favour of the clodronate group. Bone pain was significantly reduced in the clodronate group (see Table 4).
In the multiple myeloma and breast cancer trials, there were substantial numbers of patients lost to follow-up, however this did not appear to advantage any particular treatment group.

Indications

Treatment of hypercalcaemia of malignancy.
Treatment of osteolytic bone metastases due to carcinoma of the breast and treatment of osteolytic lesions of multiple myeloma.

Contraindications

Hypersensitivity to sodium clodronate or to any of the excipients contained in Bonefos. Severe inflammation of the gastrointestinal tract. Concomitant use of other bisphosphonates.

Precautions

Prior to treatment with sodium clodronate, renal excretion of excess plasma calcium should be promoted by restoration and maintenance of adequate fluid balance and urine output. Adequate fluid intake must be maintained during sodium clodronate treatment. This is particularly important when administering sodium clodronate to patients with hypercalcaemia or renal failure.
Bonefos tablets and capsules contain sodium which should be taken into account for patients on a low sodium diet or with renal disease (see Excipients for the sodium content of each presentation).
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer. Many of these patients were also receiving chemotherapy and corticosteroids.
Preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor dental hygiene) and invasive dental procedures should be avoided while patients are being treated with bisphosphonates.
For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
Clinical judgment of the treating doctor should guide the management plan of each patient based on individual benefit/ risk assessment.
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. So far, these fractures have not been reported with Bonefos. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in 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.
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Effects on fertility.

Treatment of male rats with an oral sodium clodronate dose of 600 mg/kg/day (1.5 times the 3200 mg human dose based on surface area mg/m2) depressed mating behaviour and reduced fertility. No adverse effects on male rat reproductive performance or female fertility were seen with an oral dose of 200 mg/kg/day.

Use in pregnancy.

(Category B3)
Sodium clodronate may, through its pharmacological effects on calcium homoeostasis, be hazardous to the foetus and/ or newborn child. Reproduction studies in rats using the oral route of administration showed decreased postimplantation survival at 1000 mg/kg/day (2.5 times the 3200 mg human dose based on surface area, mg/m2) and decreased bodyweight in normal pups at birth (200 mg/kg/day). Sites of incomplete ossification were increased and dry weights of fetal tibiae reduced at 600 mg/kg/day (1.5 times the 3200 mg human dose based on surface area, mg/m2). Protracted parturition due to maternal hypocalcaemia occurred in rats at doses of 600 mg/kg/day. Postimplantation survival was reduced also when pregnant rabbits were treated at doses up to 700 mg/kg/day (3.2 times the 3200 mg human dose based on surface area, mg/m2). There are, however, no adequate or well controlled trials of sodium clodronate in pregnant women. Sodium clodronate should not be used for pregnant women, unless the therapeutic advantages clearly outweigh the risks.

Use in lactation.

There is no clinical experience with clodronate in lactating women and it is not known whether it passes into breast milk. There have been no animal studies investigating the passage of sodium clodronate into the milk. Because many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in breastfeeding infants from clodronate, breastfeeding under the treatment with clodronate is not recommended.

Paediatric use.

The safety and efficacy of the use of sodium clodronate in children has not been established. Hence, it should not be used in children unless the expected benefits outweigh any potential risks.

Carcinogenicity, mutagenicity and impairment of fertility.

Oral sodium clodronate did not show any oncogenic activity in long-term animal studies, and was inactive in tests for gene mutations (Salmonella typhimurium and mouse lymphoma cells), clastogenicity (Chinese hamster ovary cells in vitro and mouse micronucleus assay) and DNA damage (unscheduled DNA synthesis).

Use in elderly.

There are no special dosage recommendations for the elderly.

Interactions

Sodium clodronate forms poorly soluble complexes with divalent cations. Therefore, it should not be taken with food or drugs containing divalent cations (e.g. antacids or iron preparations).
Concomitant use with other bisphosphonates is contraindicated.
Bisphosphonates are known not to affect the antineoplastic activity, in experimental tumours, of various anticancer agents including carmustine, cyclophosphamide, doxorubicin and fluorouracil. Sodium clodronate may enhance serum levels of estamustine phosphate by up to 80%. There are no other known interactions between sodium clodronate and anticancer agents.
The use of sodium clodronate with other agents indicated for reduction of calcium, e.g. corticosteroids, phosphate, calcitonin, mithramycin and loop diuretics, may potentiate their hypocalcaemic effect depending on tumour type and pathophysiological situation.
Sodium clodronate has been reported to be associated with renal dysfunction when used simultaneously with nonsteroidal anti-inflammatory drugs (NSAIDs), most often diclofenac.
Due to increased risk of hypocalcaemia, caution should be taken when using clodronate together with aminoglycosides. There is no evidence from clinical experience that sodium clodronate interacts with other medication such as steroids, diuretics, analgesics or chemotherapeutic agents (as discussed above).

Adverse Effects

Clinical trials experience.

The following adverse reactions may occur in although the frequency of reactions may differ. The following frequencies are used. Common (≥ 1/100 to < 1/10); rare (≥ 1/10,000 to < 1/1,000).

Metabolism and nutrition disorders.

Common: hypocalcaemia (asymptomatic), elevated lactic acid dehydrogenase, increased serum parathyroid hormone associated with serum calcium decreased, serum alkaline phosphatase increased*. Rare: hypocalcaemia (symptomatic).

Gastrointestinal disorders.

Common: diarrhoea, nausea, vomiting, epigastric pain.

Hepatobiliary disorders.

Common: transaminases increased.

Skin and subcutaneous tissue disorders.

Rare: hypersensitivity reaction manifesting as skin reaction.
*In patients with metastatic disease, may also be due to hepatic and bone disease.
Bisphosphonates are rarely reported to cause bronchoconstriction in patients with aspirin sensitive asthma.

Postmarketing experience.

Body as a whole.

Rare: cases of headache, transient fever, generalised erythema, purpura.

Haematological.

Rare: thrombocytopenia, marrow depression.

Respiratory, thoracic and mediastinal disorders.

Impairment of respiratory function in patients with aspirin sensitive asthma. Hypersensitivity reactions manifesting as respiratory disorder.

Renal and urinary disorders.

Single cases of renal failure, in rare cases with fatal outcome, have been reported especially with concomitant use of NSAIDs, most often diclofenac.

Musculoskeletal and connective tissue disorders.

Cases of osteonecrosis of the jaw have been reported (see Precautions).
Severe bone, joint and/or muscle pain has been reported in patients taking Bonefos. However, such reports have been infrequent and in randomised placebo controlled studies no differences are apparent between placebo and Bonefos treated patients. The onset of symptoms varied from days to several months after starting Bonefos.
During postmarketing experience the following reactions have been reported with other bisphosphonates. Atypical subtrochanteric and diaphyseal femoral fractures. So far, these reactions have not been reported with Bonefos (bisphosphonate class adverse reaction) (see Precautions).

Eye disorders.

Uveitis has been reported with Bonefos during postmarketing experience. The following reactions have been reported with other bisphosphonates: Conjunctivitis, episcleritis and scleritis. Conjunctivitis was only reported with Bonefos in one patient concomitantly treated with another bisphosphonate. So far, episcleritis and scleritis have not been reported with Bonefos (bisphosphonate class adverse reaction).

Dosage and Administration

Bonefos 400 mg capsules should be swallowed whole. A Bonefos 800 mg tablet is scored and may be divided into two to ease swallowing, but the halves have to be taken at the same time of administration. The halved Bonefos 800 mg tablets are not intended to be used in therapy as a substitute for the 400 mg capsule. Bonefos tablets should not be crushed or dissolved before intake. A daily dose of 1,600 mg can be taken either as a single dose or divided into two doses. When higher daily doses are used, the part of the dose exceeding 1600 mg should be taken separately (as a second dose) as recommended below.
When taken as a single dose, Bonefos should preferably be taken in the morning on an empty stomach together with a glass of plain water. If it is not possible to take the dose in the morning, Bonefos should be taken more than two hours after eating or drinking (with the exception of plain water). If the daily dose is divided into two intakes, the first dose should be taken as recommended for single dosing and the second dose should be taken more than two hours after eating or drinking or taking any other oral medications.
After Bonefos intake, it is recommended that the patient refrains from eating and drinking for an hour.
Bonefos must not be taken with milk, food or drugs containing calcium and other divalent cations because they impair the absorption of sodium clodronate (see Interactions with Other Medicines).

Adult patients with normal renal function.

Treatment of hypercalcaemia due to malignancy.

For the treatment of hypercalcaemia of malignancy, a starting dose of 2400 or 3200 mg daily should be used in divided doses and, depending on the individual response, this can be reduced gradually to 1600 mg daily in order to maintain normocalcaemia.

Treatment of osteolytic bone metastases due to carcinoma of the breast and treatment of osteolytic lesions of multiple myeloma.

When oral therapy is used to treat increased bone resorption without hypercalcaemia, the dosage is individual. The recommended starting dose is 1,600 mg daily. The majority of patients will be satisfactorily treated at this dosage. If clinically necessary, the dose may be increased, but is not recommended to exceed 3,200 mg daily. A daily dose of 1,600 mg can be taken either as a single dose or divided into two doses.

Patients with renal failure.

Sodium clodronate is eliminated mainly via the kidneys. Therefore, it should be used with caution in patients with renal failure. Daily doses exceeding 1600 mg should not be used. It is recommended that the clodronate dosage be reduced as follows. For mild renal failure (creatinine clearance 50 to 80 mL/minute), use 1600 mg daily (no dose reduction recommended); for moderate renal failure (creatinine clearance 30 to 50 mL/minute) use 1,200 mg daily; for severe renal failure (creatinine clearance 10-30 mL/minute) use 800 mg daily.
There are no data on the use of oral sodium clodronate in patients with creatinine clearance less than 10 mL/minute or in patients on dialysis.

Duration of treatment.

The duration of treatment is recommended to be lifelong.

Overdosage

Treatment of overdose should be symptomatic. Adequate hydration should be ensured and renal function and serum calcium should be monitored. In cases of overdose, it is advisable to contact the Poisons Information Centre (131 126) for recommendations on the management and treatment of overdose.

Presentation

Capsules, 400 mg (≡ sodium clodronate tetrahydrate 500 mg, pale yellow, marked BONEFOS): 30's*, 100's (blister); 30's*, 100's* (bottle).
Tablets, 800 mg (≡ sodium clodronate tetrahydrate 1,000 mg, white, oval shaped, scored, marked L134): 10's* (sample pack), 60's (blister); 10's*, 60's* (bottle).
*Not currently marketed in Australia.

Storage

Bonefos tablets should be stored below 25°C.
Bonefos capsules should be stored below 30°C.

Poison Schedule

S4.