Consumer medicine information

Actonel EC

Risedronate sodium

BRAND INFORMATION

Brand name

Actonel EC, Actonel EC Combi, Actonel EC Combi D

Active ingredient

Risedronate sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Actonel EC.

What is in this leaflet

This leaflet answers some common questions about Actonel EC (enteric-coated tablets).

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 Actonel EC against the benefits this medicine is expected to 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 Actonel EC is used for

Actonel EC is used to treat bone disease and belongs to a group of medicines called bisphosphonates.

Actonel EC works directly on your bones to make them stronger and therefore less likely to break or fracture.

Actonel EC is used to treat:

  • osteoporosis (brittle or fragile bones that may fracture easily)
  • osteoporosis caused by taking steroids

Understanding bone

Bone is a living tissue consisting of calcium and other minerals. Throughout life, old bone is constantly broken down and replaced with new bone. After the age of 35, bone loss may occur faster than your body can replace it. If you lose too much bone then they become weaker and are more likely to break.

Osteoporosis

Osteoporosis (brittle bone disease) is a disease that causes bones to become weaker. Weak bones break (fracture) easily.

Many patients with osteoporosis have no symptoms and may not even know that they have osteoporosis. However osteoporosis makes you more likely to break bones when you have a fall or bump. The spine, hip and wrist are the most likely bones to break, although this can happen to any bone in your body. Osteoporosis can also cause back pain, height loss and a curved back.

Osteoporosis is common in women after the menopause (change of life) and is also more likely to occur in women who have reached the menopause early. Osteoporosis can also occur in women who have not yet reached menopause, and in men.

Long term steroid treatment can also lead to osteoporosis in both men and women.

Actonel EC works by slowing down the process of old bone being removed. This allows the bone-forming cells time to rebuild normal bone.

Actonel EC also helps to rebuild bone mass. This creates stronger bone which is less likely to fracture. Therefore Actonel EC can help reverse the progression of osteoporosis.

Do not give Actonel EC to children or adolescents under 18 years of age.

There have been no studies of its effects in this age group.

There is no evidence that Actonel EC is addictive.

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

Before you take Actonel EC

When you must not take Actonel EC

Do not take Actonel EC if you:

  • have an allergy to Actonel EC or any of the ingredients listed at the end of this leaflet
  • are unable to stand or sit upright for at least 30 minutes
  • have a condition called hypocalcaemia (a low level of calcium in the blood)
  • have severe kidney problems
  • are already taking any products containing risedronate. You should not be taking both Actonel EC and any other products containing risedronate to treat your osteoporosis because they contain the same active ingredient

Do not take Actonel EC if you are pregnant. Actonel EC is not recommended for use during pregnancy, unless you and your doctor have discussed the risks and benefits involved.

Do not take Actonel EC if you are breastfeeding. It is not known whether Actonel EC passes into breast milk.

Do not take Actonel EC after the expiry date printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Actonel EC if the packaging is torn or shows signs of tampering.

Talk to your doctor or pharmacist if you are not sure whether you should start taking Actonel EC.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of using Actonel EC during pregnancy.

Tell your doctor or pharmacist if you are breastfeeding or plan to breastfeed.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • disturbances of bone and mineral metabolism (for example vitamin D deficiency, parathyroid hormone abnormalities)
  • problems with the tube that takes food from your mouth to your stomach (oesophagus) such as ulcers
  • pain, swelling or numbness of the jaw or a "heavy jaw feeling" or loosening of a tooth

Check with your doctor or dentist to see if a dental check-up is required before starting Actonel EC. This is especially important if you are receiving medicines or therapy used to treat cancer or taking corticosteroids, such as prednisone or cortisone.

Tell your doctor about any of the above, before you start taking Actonel EC.

Taking other medicines

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

Some medicines and Actonel EC may interfere with each other if taken at the same time. These include:

  • antacids, medicines used to treat indigestion eg Gaviscon, Mylanta
  • other products containing calcium
  • iron supplements

Check with your doctor or pharmacist if you are not sure whether you are taking any of these products.

You may need to stop taking these products or take them at a different time of day to Actonel EC.

You can take aspirin while you are being treated with Actonel EC.

Your doctor and pharmacist may have more information on medicines to be careful with while taking Actonel EC.

How to take Actonel EC

How much to take

For osteoporosis, the usual dose is one Actonel EC 35mg enteric-coated tablet once a week.

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

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

How to take it

Take your Actonel EC tablet while sitting or standing upright.

Swallow your Actonel EC tablet whole with a glass of plain water (at least 120mL). Do not chew, cut, crush or suck the tablet.

Actonel EC should be taken in the morning either with or without food.

Do not lie down immediately after swallowing it. It is important to stay upright, for example, sitting, standing or walking around, for at least 30 minutes after swallowing your tablet. It is also important to take Actonel EC with plain water only (at least 120mL), not mineral water. This will help make sure the tablet reaches your stomach quickly and helps avoid irritation to your oesophagus.

When to take it

Actonel EC Should be taken in the morning either with or without food. Take your Actonel EC 35mg Once-a-Week enteric-coated tablet on the same day each week.

This tablet should be taken each week. Choose a day of the week that suits you the best.

If you forget to take your tablet

If you have forgotten to take your 35mg enteric-coated tablet, just take your tablet on the day you remember (as per the instructions described under 'How to Take it' above).

Do not take two tablets in one day to make up for the tablet you missed. Return to taking one tablet once a week, as originally scheduled on your chosen day.

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.

How long to take it

Continue taking Actonel EC for as long as your doctor recommends it.

Do not stop taking Actonel EC without checking with your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (13 11 26) or go to accident and emergency at your nearest hospital.

If you or somebody else has accidentally taken a large number of tablets, drink a full glass of milk or antacids. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using Actonel EC

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking Actonel EC.

If you require a dental procedure, tell your dentist that you are taking Actonel EC. Invasive dental procedures should be avoided where possible.

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

If you develop a toothache, jaw pain, painful exposed bone or swelling, especially following dental work, tell your doctor or dentist immediately.

Speak to your doctor and dentist about good oral hygiene and regular dental check-ups while you are using Actonel EC.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Actonel EC.

If you become pregnant while taking Actonel EC tell your doctor or pharmacist.

If you develop new or unusual pain in your hip or thigh, tell your doctor.

Rarely, patients have experienced fracture in a specific part of the thigh bone.

Things you must not do

Do not lie down for 30 minutes after taking Actonel EC.

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

Do not take Actonel EC to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking Actonel EC without checking with your doctor or pharmacist.

Side Effects

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

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 pharmacist if you notice any of the following and they worry you:

  • stomach pain
  • diarrhoea
  • aching muscles, joints or bones
  • headache
  • nausea
  • runny nose
  • sore throat
  • dizziness

These side effects are usually mild.

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

  • skin rash or redness of the skin, sometimes made worse by sunlight, itchiness
  • blurred vision, pain or redness in the eyes
  • problems with your jaw or teeth, associated with delayed healing and/or infection often following a tooth extraction or invasive dental work

These side-effects are rare.

If any of the following happen, stop taking Actonel EC and tell your doctor immediately:

  • difficulty or pain on swallowing
  • chest pain
  • new or worsening heartburn

These side effects may be due to irritation or ulceration of the food pipe. They may worsen if you continue taking the tablets. These side effects are rare.

If any of the following happen, stop taking Actonel EC and tell your doctor immediately or go to accident and emergency at your nearest hospital:

  • swelling of the face, lips, mouth, throat or tongue
  • severe skin reactions

These may be serious side effects. You may need urgent medical attention.

Other side effects not listed above may occur in some patients.

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

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

After using Actonel EC

Storage

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

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store Actonel EC or any other medicine in the bathroom or near a sink.

Do not leave medicines in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

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

Product description

What Actonel EC looks like

Actonel EC 35mg Once-a-Week - oval yellow enteric-coated tablet, with EC 35 marked on one side

Ingredients

Active ingredient:

Each Actonel EC 35mg Once-a-Week tablet contains 35 mg risedronate sodium per tablet

Other inactive ingredients include:

  • edetate disodium
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • sodium starch glycollate
  • stearic acid
  • magnesium stearate
  • methacrylic acid ethyl acrylate copolymer
  • triethyl citrate
  • talc- purified
  • iron oxide yellow CI77492
  • simethicone
  • polysorbate 80

Actonel EC does not contain sucrose, gluten, tartrazine or any other azo dyes.

The 35mg tablets are supplied in pack sizes of 1, 2#, 4, 10#, 12# and 16# tablets.

# non-marketed presentations

Australian Registration Numbers:

AUST R 166838

Supplier

Actonel EC is supplied in Australia by:

Theramex Australia Pty Ltd
Level 34, 60 Margaret Street,
Sydney NSW 2000
1800 THERAMEX or 1800 843 726

Date of Preparation: December 2018

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Actonel EC, Actonel EC Combi, Actonel EC Combi D

Active ingredient

Risedronate sodium

Schedule

S4

 

1 Name of Medicine

Risedronate sodium.

2 Qualitative and Quantitative Composition

Each Actonel EC enteric-coated tablet contains the equivalent of 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. Actonel EC tablets have a pH-sensitive enteric coating and contain a chelating agent disodium edetate (EDTA). The formulation is designed to allow dosing with food, reducing the impact of food on risedronate absorption.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Enteric-coated-tablet.
Actonel EC tablets are oval, yellow enteric-coated tablets engraved with EC 35 on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of osteoporosis.
Treatment of glucocorticoid induced osteoporosis.
Preservation of bone mineral density in patients on long-term corticosteroid therapy.

4.2 Dose and Method of Administration

Actonel EC should be taken in the morning, either with or without food. To facilitate delivery to the stomach, and thus reduce the potential for oesophageal irritation, enteric coated Actonel 35 mg Once-a-Week should be swallowed whole while the patient is in an upright position with plain water. Patients should not chew, cut or crush the tablet because of a potential for oropharyngeal irritation, and because the tablet coating is an important part of the formulation. Patients should avoid lying down for 30 minutes after taking the medication.
The recommended dose is 35 mg once a week taken on the same day each week.

Use in the elderly.

No dose adjustment is necessary.

Renal insufficiency.

No dose adjustment is necessary in patients with mild to moderate renal insufficiency (creatinine clearance 30 to 60 mL/minute). Enteric coated Actonel 35 mg Once-a-Week is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/minute) due to limited clinical data.

Hepatic insufficiency.

Dose adjustments are unlikely to be needed in patients with hepatic impairment.

Paediatrics.

Safety and efficacy of enteric coated Actonel 35 mg Once-a-Week has not been established in patients under 18 years of age.

Compatibility with other drugs.

Calcium supplements and antacids will interfere with the absorption of risedronate and therefore should be taken at a different time of the day.

4.3 Contraindications

Known hypersensitivity to the drug or any of the ingredients.
Hypocalcaemia (see Section 4.4 Special Warnings and Precautions for Use).
Inability to stand or sit upright for at least 30 minutes.

4.4 Special Warnings and Precautions for Use

General.

Calcium supplements and antacids can interfere with the absorption of risedronate and should not be taken at the same time as Actonel EC.
Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Thus caution should be used:
in patients who have a history of oesophageal disorders which delay oesophageal transit or emptying, e.g. stricture or achalasia;
in patients who are unable to stay in the upright position for at least 30 minutes after taking the tablet;
if Actonel EC is given to patients with active or recent oesophageal or upper gastrointestinal problems (including known Barrett's oesophagus).
For patients to gain maximum benefit from Actonel EC, doctors must stress the importance of taking Actonel EC as per the dosage instructions (see Section 4.2 Dose and Method of Administration). This is especially important in the case of patients with a history of oesophageal disorders.
Hypocalcaemia must be corrected before starting Actonel EC therapy. Bone and mineral metabolism dysfunction (e.g. vitamin D deficiency and parathyroid abnormalities) should be effectively treated before starting enteric coated Actonel therapy. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

Gastrointestinal.

Actonel EC like other bisphosphonates may cause local irritation of the upper GI mucosa. Since some bisphosphonates have been associated with oesophagitis and oesophageal ulcerations, and gastroduodenal ulceration doctors should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction, especially in patients with a history of upper GI disease or who are using NSAIDs or aspirin concomitantly. Doctors should be particularly careful to emphasise the importance of taking Actonel EC as per the dosage instructions to patients who have a history of oesophageal disorders.
There is very little experience with risedronate in patients with inflammatory bowel disease.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/ risk assessment.
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. 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.

Atypical stress fractures.

A small number of patients on long-term bisphosphonate therapy (usually longer than three years), mostly in connection with the use of alendronate have developed stress fractures of the proximal femoral shaft (also known as insufficiency or atypical fractures), some of which occurred in the absence of apparent trauma. Some of these patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred.
Approximately one-third of these fractures were bilateral; therefore the contralateral femur should be examined in patients who have sustained a femoral shaft stress fracture.
It is not known to what extent other agents of the aminobisphosphonate class, including Actonel, may be associated with this adverse event. Prior treatment with alendronate should be a cause for added vigilance. Patients with suspected stress fractures should be evaluated, including evaluation for known causes and risk factors (e.g. vitamin D deficiency, malabsorption, glucocorticoid use, previous stress fracture, lower extremity arthritis or fracture, extreme or increased exercise, diabetes mellitus, chronic alcohol abuse), and receive appropriate orthopaedic care.
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.
Discontinuation of bisphosphonate therapy in patients with stress fractures is advisable pending evaluation of the patient, based on individual benefit/ risk assessment. Causality has not been excluded in regard to bisphosphonate use and stress fractures.

Osteomalacia.

The potential for risedronate to induce osteomalacia was investigated in the Schenk rat assay. This assay is based on histologic examination of the epiphyses of the growing rats after drug treatment. Risedronate did not interfere with bone mineralisation even at the highest dose tested (5 mg/kg/day, subcutaneously) which was > 3000 times the lowest antiresorptive dose (1.5 microgram/kg/day). These data indicate that risedronate administered at therapeutic doses is unlikely to induce osteomalacia.

Use in hepatic impairment.

No studies have been performed to assess the safety or efficacy of Actonel in patients with hepatic impairment.

Use in renal impairment.

Enteric-coated Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Use in the elderly.

Of the patients receiving Actonel EC in postmenopausal osteoporosis studies, 59% were 65 and over, while 13% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

Safety and efficacy of risedronate have not been established in patients under 18 years of age.

Effect on laboratory tests.

Bisphosphonates are known to interfere with the use of bone-imaging agents. However specific studies with risedronate have not been performed.
Small asymptomatic decreases in serum calcium and phosphorus levels have been observed in some patients.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Risedronate is not systemically metabolised, does not induce or inhibit hepatic microsomal drug metabolising enzymes (cytochrome P450) and has low protein binding.
The results of in vitro studies indicated that the chelating agent (EDTA) in enteric coated Actonel 35 mg once weekly is not likely to result in changes in absorption of concomitant medications, including those with a narrow therapeutic index or antivirals.
A phase 1 single dose, crossover study in 101 postmenopausal women evaluated the relative bioavailability of enteric coated Actonel 35 mg Once-a-Week tablets taken after breakfast and following a 600 mg elemental calcium/ 400 IU vitamin D supplement, compared to enteric coated Actonel 35 mg taken after breakfast alone. The addition of the calcium/ vitamin D supplement following the meal resulted in an approximate 38% reduction in the amount of risedronate absorbed.
Although not specifically studied, if considered appropriate, enteric coated Actonel 35 mg may be considered for concomitant use with hormone replacement therapy.
A phase 1, single dose, crossover study in 87 postmenopausal women evaluated the absorption of enteric coated Actonel 35 mg following 5 days of esomeprazole 40 mg therapy compared to enteric coated Actonel 35 mg alone. During concomitant use of esomeprazole, bioavailability of enteric coated Actonel 35 mg is reduced by 32% to 48% depending on the time of esomeprazole administration (prior to the evening meal or prior to breakfast, respectively).
In the phase 3 study evaluating enteric coated Actonel 35 mg, efficacy as measured by mean percent change in BMD from baseline was not diminished in patients reporting concomitant use of H2-blockers or proton pump inhibitors (PPIs).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A fertility study in male and female rats showed no adverse effects at oral doses up to 16 mg/kg/day, corresponding to systemic exposure (serum AUC0-24h) about 30 times higher than that in humans dosed at 30 mg/day. At higher dose levels, systemic toxicity, testicular atrophy and reduced fertility were seen in male rats, but these effects are unlikely to have clinical relevance.
(Category B3)
Risedronate has not been studied in pregnant women. Risedronate should only be used during pregnancy if the potential benefit justifies the potential risk to mother and foetus. If administration during pregnancy is contemplated, serum calcium levels should be monitored and calcium supplementation provided in late gestation. Animal studies suggest that periparturient maternal hypocalcaemia and foetal ossification effects may occur.
Animal studies have shown that risedronate sodium crosses the placenta to a minimal extent in rats. The drug had no teratogenic activity in rats or rabbits at oral doses up to 80 and 10 mg/kg/day respectively. However, suppression of foetal growth and retardation of ossification were observed at the highest dose level in rats. When administered to rats during late gestation, maternal deaths and parturition failure were observed at oral dose levels greater than 2 mg/kg/day. These effects were probably secondary to maternal hypocalcaemia. Systemic exposure (AUC0-24 h) at the no-effect level in rats was similar to that in patients with Paget's disease, and about 6 times higher than that in patients with corticosteroid induced osteoporosis. Systemic exposure in rabbits was not measured.
Risedronate was detected in feeding pups exposed to lactating rats for a 24 hour period postdosing, indicating a small degree of lacteal transfer. It is not known whether risedronate is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
As with other bisphosphonates in preclinical models, foetuses from risedronate treated dams showed ossification changes in sternebrae and/or skull at doses as low as 3.2 mg/kg/day. This is equivalent to the human 30 mg dose and 6 times the human 5 mg dose based on surface area, mg/m2. Treatment with risedronate during mating and gestation with doses of 3.2 mg/kg/day has resulted in periparturient hypocalcaemia and mortality in rats allowed to deliver.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Osteoporosis - Actonel 5 mg daily dosing (immediate release tablets).

The phase IIIA clinical trials were designed to include patients with a history of upper GI disorder. Patients were permitted concomitant use of NSAIDs and aspirin. In these patients the incidence of upper GI adverse reactions in the Actonel group was similar to that in the placebo control group.
Abdominal and musculoskeletal pain were commonly reported (1% to 10%). Glossitis, iritis, and duodenitis were reported uncommonly (0.1% to 1%). There were rare reports (< 0.1%) of abnormal liver function tests.

Laboratory test findings.

Asymptomatic, small decreases in serum calcium and phosphorus levels have been observed in some patients.
Actonel has been studied for up to 3 years in over 5000 women enrolled in phase 3 clinical trials for treatment or prevention of postmenopausal osteoporosis. Most adverse events reported in these trials were either mild or moderate in severity, and did not lead to discontinuation from the study. The incidence of serious adverse events in the placebo group was 24.9% and in the Actonel group was 26.3%. The percentage of patients who withdrew from the study due to adverse events was 14.4% and 13.5% for the placebo and Actonel groups respectively. Table 1 lists adverse events reported in ≥ 5% of Actonel treated patients and at an incidence higher than in the placebo group in phase 3 postmenopausal osteoporosis trials. Adverse events are shown without attribution of causality.

Endoscopic findings.

Actonel clinical studies enrolled over 5000 postmenopausal women and included patients with pre-existing gastrointestinal disease and concomitant use of NSAIDs or aspirin. Investigators were encouraged to perform endoscopies in any patients with moderate to severe gastrointestinal complaints while maintaining the blind. These endoscopies were ultimately performed on equal numbers of patients between the treated and placebo groups [75 (11.9%) Actonel; 75 (14.5%) placebo]. Across treatment groups, the percentage of patients with normal oesophageal, gastric, and duodenal mucosa on endoscopy was similar [20% placebo and 21% Actonel]. Positive findings on endoscopy were also generally comparable across treatment groups [58 (82.9%) placebo and 57 (81.4%) Actonel].

Gastrointestinal adverse events.

There was a higher number of reports of mild duodenitis [11 (15.7%)] in the Actonel group [7 (10%) placebo], however there were more duodenal ulcers [33 (47.1%)] in the placebo group [26 (37.1%) Actonel]. The number of patients who had positive findings and withdrew from the studies was similar across treatment groups [26 (37.1%) placebo and 27 (38.6%) Actonel] and there was no evidence of treatment related oesophageal, gastric, or duodenal ulcers/ erosions.
Actonel has been studied in phase 3 corticosteroid induced osteoporosis trials enrolling more than 500 patients. The adverse event profile in this population was similar to that seen in postmenopausal osteoporosis trials, except for musculoskeletal events, which were reported by > 10% of patients and occurred at a greater frequency in the Actonel 5 mg treatment group [75 (43.1%)] compared to the placebo group [57 (33.5%)]. The adverse experiences reported [165 placebo and 167 Actonel] have usually been mild or moderate and generally have not required discontinuation of treatment. The occurrence of adverse events does not appear to be related to patient age, gender, or race.

Osteoporosis - Actonel EC Once-a-Week dosing.

The safety of Actonel EC for the treatment of postmenopausal osteoporosis was assessed in a double blind, multicentre study comparing Actonel 5 mg immediate release daily (N = 307) and enteric coated Actonel 35 mg once weekly administered either at least 30 minutes before (N = 308) or immediately following (N = 307) breakfast in postmenopausal women 50 years of age or older. The duration of the trial was 2 years, with 307 patients exposed to Actonel 5 mg immediate release daily and 615 exposed to enteric coated Actonel 35 mg Once-a-Week. Patients with pre-existing gastrointestinal disease (with the exception of those with a positive occult faecal blood test or history of inflammatory bowel disease, malabsorption or sprue) and concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and H2-antagonists were included in this clinical trial. All women received daily supplementation with 1000 mg of elemental calcium plus 800-1000 IU vitamin D.
The overall safety and tolerability profiles were similar across the immediate-release and enteric-coated treatment groups. The incidence of all-cause mortality was 0.3% in the Actonel 5 mg immediate-release daily group and 0.2% in the combined enteric-coated Actonel 35 mg once-a-week group. The incidence of serious adverse events was 10.1% in the Actonel 5 mg daily group and 10.4% in the combined enteric-coated Actonel 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 9.1% in the Actonel 5 mg immediate-release daily group and 10.1% in the combined enteric-coated Actonel 35 mg once-a-week group. Table 2 lists adverse events reported in ≥ 2% of patients, combining before and after breakfast dosing of enteric-coated Actonel 35 mg once-a-week. Adverse events are shown without attribution of causality.

Acute phase reactions.

Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of symptoms consistent with acute phase reaction was 1.3% in the Actonel 5 mg immediate release daily group, and 1.8% in the combined enteric coated Actonel 35 mg Once-a-Week group. These incidence rates are based on reporting of one or more prespecified acute phase reaction like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.0% of patients on Actonel 5 mg immediate release daily and 0.0% of patients on enteric coated Actonel 35 mg Once-a-Week.

Gastrointestinal adverse events.

The incidence of gastrointestinal adverse events in the Actonel 5 mg immediate release daily group compared with the combined enteric coated Actonel 35 mg once weekly group were: dyspepsia (5.2% vs. 4.9%), diarrhoea (6.2% vs. 8.3%), constipation (3.6% vs. 5.5%), abdominal pain (3.3% vs. 6.3%), abdominal pain upper (2.6% vs. 6.0%), gastroesophageal reflux disease (2.9% vs. 2.3%).

Musculoskeletal adverse events.

The incidence of musculoskeletal adverse events in the Actonel 5 mg immediate release daily group compared with the combined enteric coated Actonel 35 mg once weekly group were: arthralgia (10.7% vs. 9.1%), back pain (8.8% vs. 9.4%), musculoskeletal pain (4.2% vs. 3.9%).

Treatment discontinuations.

The overall incidence of patients discontinuing treatment due to a treatment emergent adverse event was similar across all groups (9.1% vs. 10.1% for the immediate release and combined enteric coated groups, respectively). Study discontinuations in the Actonel 5 mg immediate release daily group compared with the combined enteric coated Actonel 35 mg Once-a-Week group included: diarrhoea (0.7% vs. 0.7%), abdominal pain (0.7% vs. 1.3%), abdominal pain upper (0.0% vs. 1.1%), abdominal pain lower (1% vs. 0.0%), gastroesophageal reflux disease (0.7% vs. 0.2%), myalgia (0.3% vs. 0.3%), arthralgia (0.0% vs. 0.5%).

Laboratory test findings.

The mean values for serum calcium, phosphorus, and magnesium were within the normal range at all time points and similar across treatment groups. The mean changes from baseline at each postbaseline time point were small for each parameter, with no clinically important differences across treatment groups.
The mean values for serum iPTH 1-84 were within the normal range at all time points and similar across treatment groups. Mean changes from baseline at each postbaseline time point were small and most prominent at day 14.
In all treatment groups, small mean decreases in serum calcium and the expected reciprocal small mean increases in iPTH 1-84 were seen at day 14; these changes were as would be expected upon initiation of antiresorptive therapy, and were not symptomatic or clinically meaningful. At week 104, the number of patients shifting from normal to high iPTH 1-84 was similar across the 3 groups.

Actonel postmarketing data.

The following additional adverse reactions have been very rarely reported during postmarketing use.

Eye disorders.

Iritis, uveitis.

Musculoskeletal and connective tissues disorders.

Osteonecrosis of the jaw.

Skin and subcutaneous tissue disorders.

Hypersensitivity and skin reactions, including angioedema, generalised rash, and bulbous skin reactions, some severe.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific information is available on the treatment of overdose with risedronate. Decreases in serum calcium following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcaemia may also occur in some of these patients. Administration of milk or antacids (containing magnesium, calcium or aluminium) to chelate risedronate may be helpful for Actonel immediate release tablets and reduce absorption of the drug. The impact of this intervention for Actonel EC tablets has not been evaluated. The enteric coated Actonel formulation is less sensitive to the binding effects of divalent cations. Standard procedures that are effective for treating hypocalcaemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionised calcium and to relieve signs and symptoms of hypocalcaemia.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Risedronate is a potent pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast mediated bone resorption. Risedronate is a third generation bisphosphonate. In preclinical studies risedronate demonstrated potent antiosteoclast and antiresorptive activity, increasing bone mass and biomechanical strength dose dependently. The activity of risedronate was confirmed by bone marker measurements during pharmacodynamic and clinical studies.
With risedronate 5 mg daily, decreases in biochemical markers of bone turnover were observed within 1 month of treatment and reached a maximum decrease in 3-6 months, remaining stable during the course of therapy. This data demonstrates that risedronate causes a moderate reduction in bone resorption and bone turnover. The new steady state approximates the rate of bone turnover seen in premenopausal women. In a 2 year study comparing Actonel 5 mg daily immediate release versus enteric coated Actonel 35 mg Once-a-Week oral dosing regimens (i.e. taken either before or after breakfast) in postmenopausal women, there was no significant differences in mean percent change from baseline in urinary collagen crosslinked N-telopeptide (NTX/Cr) between the enteric coated and the immediate release groups. At 2 years, the mean reductions from baseline in urine NTX/Cr were 46% in the Actonel 5 mg daily group, 51% in the enteric coated Actonel 35 mg Once-a-Week before breakfast group and 49% in the enteric coated Actonel 35 mg Once-a-Week following breakfast group. In addition, serum bone specific alkaline phosphatase at 2 years was reduced by 33% in the Actonel 5 mg daily group, 35% in the enteric coated Actonel 35 mg Once-a-Week before breakfast group and 35% in the enteric coated Actonel 35 mg Once-a-Week following breakfast group.
In a study with immediate release Actonel 35 mg Once-a-Week in men with osteoporosis, decreases in biochemical markers of bone turnover were observed at the earliest time point of 3 months and continued to be observed at 24 months.

Clinical trials.

Treatment of osteoporosis.

The clinical program involved a wide range of early and late postmenopausal women with and without fracture, including those with a history of GI disease and those using aspirin, NSAIDs, proton pump inhibitors and H2-blockers. The fracture efficacy of Actonel 5 mg daily (risedronate immediate release formulation) in the treatment of postmenopausal osteoporosis was demonstrated in two large, randomised, placebo controlled, double blind studies which enrolled a total of almost 4000 women under similar protocols. The multinational study (RVE) was conducted primarily in Europe and Australia; a second study was conducted in North America (RVN). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in the multinational study, and 2.5 in the North American study, with a broad range of baseline BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low vitamin D levels also received supplemental vitamin D 500 IU/day. The number of evaluable patients treated were:
RVN: 5 mg risedronate n = 696; placebo n = 678. RVE: 5 mg risedronate n = 344; placebo n = 346. RVN and RVE: n = 1040; placebo n = 1024.

Effect on vertebral fracture.

The pivotal studies of Actonel in the treatment of postmenopausal osteoporosis clearly demonstrate that Actonel 5 mg daily reduces vertebral fracture incidence in patients with low bone mass and vertebral fractures, regardless of age, years since menopause, or disease severity at baseline. Actonel 5 mg daily significantly reduced the risk of new vertebral fractures in each of the two large treatment studies. In the multinational study, treatment with Actonel 5 mg daily for 3 years significantly reduced the risk of new vertebral fractures by 49% compared to treatment with placebo (p < 0.001) (Figure 1). A similar, significant reduction of 41% was seen in the North American study (p = 0.003). The effect of Actonel 5 mg daily on vertebral fracture incidence was seen as early as the end of the first year of treatment in each study. In the multinational study, the incidence of new vertebral fractures after 1 year was reduced from 13.3 to 5.6%, an absolute risk reduction of 8% and a relative risk reduction of 61% (p < 0.001). In the North American study, the incidence of new vertebral fractures after 1 year was reduced from 6.4 to 2.4%, an absolute risk reduction of 4% and a relative risk reduction of 65% (p < 0.001). At both 1 and 3 years, the reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population. Treatment with Actonel 5 mg daily also significantly reduced the proportion of patients experiencing new and worsening vertebral fractures in each of the studies.

Effect on nonvertebral fractures.

In a prospectively planned analysis of pooled data from the multinational and North American studies, Actonel 5 mg daily significantly reduced the cumulative incidence of patients experiencing osteoporosis related nonvertebral fractures (wrist, humerus, clavicle, pelvis, hip, and leg) over 3 years by 36% (p = 0.005). See Figure 2.
The incidence of nonvertebral fractures in the pooled analysis (RVN and RVE) was lower in the 5 mg risedronate group than in the placebo group for all fractures at these sites combined, as well as for the wrist, humerus, pelvis, and leg separately. This difference was significant for all nonvertebral osteoporosis related fractures (p = 0.005), as well as for the humerus (p = 0.024) and pelvis (p = 0.044), while a trend was seen at the wrist (p = 0.075) (Table 3).
These findings demonstrate a beneficial effect of risedronate in preventing nonvertebral, osteoporosis related fractures.

Effect on height.

In the two 3 year osteoporosis treatment studies, standing height was measured yearly by stadiometer. As shown in Figure 3, treatment with Actonel 5 mg daily was associated with a significant reduction of about 50% in the annual rate of height loss compared to treatment with placebo.

Effect on bone mineral density.

The results of four, large, randomised, placebo controlled trials in women with postmenopausal osteoporosis demonstrate that Actonel 5 mg daily reverses the progression of disease, increasing BMD at the spine, hip, and wrist compared to the effects seen with placebo. In the large multinational vertebral fracture treatment study previously described, Actonel 5 mg daily produced increases in lumbar spine BMD which were progressive over at least 2 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points. The mean increase in BMD at the lumbar spine was 5.9%, compared to placebo at the end of 3 years. In the North American fracture trial, similarly progressive and significant increases were seen; the mean increase was 4.3%, compared to placebo. Actonel 5 mg also produced significant mean increases in BMD at the hip (femoral neck and trochanter) in each trial, compared to losses in BMD in the placebo group. The increases compared to placebo were 3.1% at the femoral neck and 6.4% at the trochanter in the multinational study, and 2.8% and 3.9%, respectively, in the North American study. Significant mean increases in the BMD of the midshaft radius, a skeletal site high in cortical bone, were also observed in each study in patients receiving Actonel treatment. These findings indicate that Actonel treatment produces positive effects at all measured skeletal sites of clinical importance for osteoporotic fractures.
Positive effects of Actonel treatment on BMD were also demonstrated in each of two large, randomised, placebo controlled trials in which almost 1200 postmenopausal women were recruited on the basis of low lumbar spine bone mass (more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture. After 1.5 to 2 years, Actonel produced significant mean increases in BMD of the lumbar spine compared to placebo (5% and 4.1% in the two studies), femoral neck (2.8% and 2.3%), and trochanter (3.3% and 3.3%) in these women with low bone mass.

Histology/ histomorphometry.

Histological evaluation of 278 bone biopsy samples from 204 postmenopausal women who received Actonel or placebo once daily for 2 to 3 years (including 74 pairs of biopsies, 43 from Actonel treated patients) showed a moderate decrease in bone turnover in Actonel treated women. Histological assessment showed no osteomalacia, impaired bone mineralisation, or other adverse effects on bone in Actonel treated women. These findings demonstrate that the bone formed during Actonel administration is of normal quality.

Bone markers.

In clinical studies, dose dependent decreases in biochemical markers of bone turnover were observed with Actonel 5 mg treatment. These effects were seen within 1 month of treatment and reached a plateau, with levels about 40% below baseline values, by the sixth month of treatment which remained stable during continuous treatment for up to 3 years. These data demonstrate that 5 mg Actonel causes a moderate reduction in bone resorption without oversuppression of bone formation. This new steady state approximates the rate of bone turnover seen in premenopausal women.

Combined administration with hormone replacement therapy.

The effects of combining Actonel 5 mg daily with conjugated oestrogen treatment (0.625 mg daily) were compared to the effects of conjugated oestrogen alone in a 1 year, randomised, double blind study in more than 500 postmenopausal women (mean lumbar spine BMD 1.3 SD below the premenopausal mean). Actonel 5 mg daily in postmenopausal women taking oestrogen produced significant mean increases from baseline in BMD of the femoral neck (2.7%) and the midshaft radius (0.7%) at 12 months. These increases were greater than the increases observed in the oestrogen alone group, and reached statistical significance in favour of the combined treatment at the femoral neck and midshaft radius.
Consistent with the changes in BMD, the reduction in bone turnover was significantly greater in the combined Actonel plus oestrogen group compared to the oestrogen alone group (40% to 47% versus 35% to 40%) and remained within the premenopausal range. Histologic evaluation of 93 bone biopsy samples from 61 women on oestrogen therapy who received either placebo or Actonel once daily for 1 year (including 32 pairs of biopsies, 16 from Actonel treated patients) found decreases in bone turnover in the Actonel treated patients that were consistent with the changes in bone turnover markers. Bone histology demonstrated that the bone of patients treated with Actonel plus oestrogen was of normal lamellar structure and normal mineralisation.

Endoscopic findings.

Actonel endoscopic findings from patients with moderate to severe GI complaints in both Actonel and control patients showed no evidence of treatment related gastric, duodenal or oesophageal ulcers. Duodenitis was rarely observed in the Actonel group. Four out of five patients with endoscopically diagnosed oesophageal strictures had been taking risedronate 5 mg for more than 6 months.

Treatment of osteoporosis in men.

Actonel 35 mg Once-a-Week (immediate release) demonstrated efficacy in men with osteoporosis (age range 36 to 84 years) in a 2 year, double blind, placebo controlled study in 284 patients (risedronate sodium 35 mg n = 191). All patients received supplemental calcium and vitamin D. The primary efficacy endpoint was assessed by the percentage change from baseline in lumbar spine BMD at endpoint (month 24 or last postbaseline observation). Secondary efficacy measures included lumbar spine and proximal femur BMD at 6, 12 and 24 months; BMD responders (defined as patients who had a positive lumbar spine BMD change at month 24); bone turnover markers at 6, 12 and 24 months; body height; incidence of new vertebral fractures and incidence of clinical fractures. Increases in BMD were observed as early as 6 months following initiation of risedronate sodium treatment. The primary analysis showed a statistically significant difference between risedronate and placebo in least squares mean percent change from baseline to endpoint (p < 0.0001). The estimated difference at endpoint between risedronate and placebo in the ITT population was 4.53% (95% CI: 3.46%, 5.60%). Actonel 35 mg Once-a-Week (immediate release) produced mean increases in BMD at the lumbar spine, femoral neck, trochanter and total hip compared to placebo after 2 years of treatment. The bone effect (BMD increase and BTM decrease) of risedronate sodium is similar in males and females.

Actonel EC.

Enteric coated Actonel 35 mg Once-a-Week administered either before or after breakfast was shown to be therapeutically equivalent to Actonel 5 mg daily (immediate release formulation) in a 2 year, double blind, multicentre study of postmenopausal women with osteoporosis. The primary efficacy endpoint of percent change from baseline in lumbar spine BMD at week 52 was met. Secondary efficacy endpoints included percent change from baseline in lumbar spine BMD at week 104; nonvertebral fractures at week 104 which were consistent with the primary outcome measure; and change in bone turnover markers. Table 4 presents the primary efficacy analysis of intent-to-treat patients with last observation carried forward (LOCF) at 1 year, as well as the 2 year results.
The mean percent change from baseline in lumbar spine BMD at week 104 endpoint was 4.1% for the 5 mg immediate release before breakfast group, 5.2% for the 35 mg enteric coated following breakfast group and 5.1% for the 35 mg enteric coated before breakfast group. The 35 mg enteric coated weekly regimen either before or following breakfast was determined to be noninferior to the 5 mg immediate release before breakfast regimen with respect to percent change in lumbar spine BMD at week 52 and week 104 endpoints. No clinically relevant differences in mean percent increases from baseline to week 104 for total proximal femur, femoral neck and trochanter BMD were seen in each of the 35 mg enteric coated weekly groups compared to the 5 mg immediate release daily group.
There were no clinically relevant differences in any of the bone turnover markers at any time point compared to 5 mg IR daily dose.
There were no statistically significant differences in either of the 35 mg enteric coated groups compared to the 5 mg immediate release group in incidence of new morphometric vertebral fractures at week 52, or at week 104 endpoint.

Corticosteroid induced osteoporosis.

Bone mineral density.

Two 1 year, double blind, placebo controlled trials demonstrated that Actonel 5 mg once daily was effective in maintaining or increasing BMD in men and women initiating or continuing corticosteroid therapy. The first study enrolled 228 patients, each of whom had initiated corticosteroid therapy (> 7.5 mg/day of prednisone or equivalent) within the previous 3 months for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline. All patients in this study received supplemental calcium 500 mg/day. After 1 year of treatment, the placebo group lost BMD at the lumbar spine, femoral neck, and trochanter, as shown in Figure 4. Actonel 5 mg once daily prevented this bone loss with a statistically significant difference from placebo of 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter. The results at these three sites were also statistically significant when the subgroups of men or postmenopausal women were analysed separately. Actonel prevented bone loss regardless of underlying disease, age, race, gender, corticosteroid dose, or baseline BMD.
The effect of risedronate discontinuation on bone mineral density was studied in a double blind, placebo controlled study in postmenopausal women with glucocorticoid dependent rheumatoid arthritis. Women were treated for 2 years with risedronate 2.5 mg daily, cyclic risedronate (averaged 2.5 mg of risedronate per day over the 96 week active period), or placebo and then followed without treatment for one more year. Patients continued glucocorticoid treatment during the third year of the study. Risedronate discontinuation resulted in bone loss at all skeletal sites (proximal femur and lumbar spine) during the third year. The rate of bone loss, however, was similar to the placebo group indicating that bone loss was not accelerated after risedronate was discontinued. The study supports the use of continuous treatment with risedronate to prevent bone loss.
A second study of similar design enrolled 290 patients with continuing, long-term use (> 6 months) of corticosteroids for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1.64 SD below the young healthy population mean), with 28% of the patients more than 2.5 SD below the mean. All patients in this study received supplemental calcium 1000 mg/day. Patients also received supplemental vitamin D 400 IU/day. After 1 year of treatment, the BMD of the placebo group remained near baseline levels at the lumbar spine, femoral neck, and trochanter. Actonel 5 mg once daily improved bone mass with a statistically significant mean increase compared to placebo of 2.7% at the lumbar spine and 1.9% at the femoral neck as shown in Figure 5. At the trochanter, a statistically significant increase from baseline was demonstrated (2.4%). Actonel was effective regardless of age, race, gender, underlying disease, corticosteroid dose, or baseline BMD.

Vertebral fractures.

Vertebral fractures were monitored for safety in the two placebo controlled studies. The incidence of vertebral fractures in each study was 15% to 17% in the placebo patients. The risk of vertebral fractures was reduced approximately 70% in the patients treated with Actonel 5 mg compared to patients treated with placebo. This decrease reached statistical significance when the studies were pooled, but not when analysed individually.

Bone marker data.

Actonel 5 mg daily produced significant reductions in biochemical markers of bone turnover relative to placebo. Deoxypyridinoline/ creatinine and bone specific alkaline phosphatase (SAP) were significantly reduced by approximately 20% relative to placebo after 1 and 3 months of treatment, respectively, and remained reduced (maximum 35% and 26%, respectively) for the duration of the treatment period.

Histology/ histomorphometry.

Histologic evaluation of 70 bone biopsy samples from 48 women on corticosteroid therapy who received either placebo or Actonel once daily for 1 year (including 22 pairs of biopsies, 16 from Actonel treated patients) showed that bone formed during treatment with Actonel was of normal lamellar structure and normal mineralisation, with no bone or marrow abnormalities observed. Histomorphometric evaluation indicated that Actonel reduces bone resorption and produces a mild to moderate decrease in the rate of bone turnover. The rate of bone formation was preserved or increased and there was no evidence of impaired mineralisation. The structure of the cortical bone (cortical thickness and porosity) was maintained in the Actonel treated patients; cortical porosity increased, however, in the placebo group. These findings indicate that bone formed during Actonel treatment is of normal quality.

5.2 Pharmacokinetic Properties

Absorption.

The mean absolute oral bioavailability of the 30 mg risedronate immediate release tablet is 0.63% (90% confidence interval [CI]: 0.54% to 0.75%) and is similar to an oral solution. The peak concentration (Tmax) for the immediate release tablet is achieved at ~ 1 hour. The enteric coated Actonel 35 mg tablet achieves Tmax at ~ 3 hours when administered 4 hours prior to a meal. Using urinary excretion data, the fraction of the dose absorbed from enteric coated Actonel 35 mg Once-a-Week is independent of risedronate dose over the range studied (single dose, from 20 mg to 100 mg).

Food effect.

A crossover pharmacokinetic study that evaluated the food effect in relation to the bioavailability of Actonel 35 mg enteric coated (EC) and Actonel 35 mg immediate release (IR) tablet was performed. An assessment of mean risedronate urinary excretion is summarised by treatment regimen in Table 5.
The bioavailability of the Actonel EC tablets decreased by ~ 30% when administered immediately after a high fat breakfast compared to administration 4 hours before a meal. The bioavailability of the Actonel EC tablets administered after a high fat breakfast was similar to Actonel IR tablets dosed 4 hours before a meal and was approximately 2-fold greater than the Actonel IR tablet administered 30 minutes prior to a high fat breakfast. The bioavailability of the Actonel EC tablets administered 4 hours before a meal was approximately 3-fold greater than Actonel IR tablets administered 30 minutes prior to a high fat breakfast.

Distribution.

The mean steady-state volume of distribution is 6.3 L/kg in humans. Human plasma protein binding of risedronate is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that 40-45% of the dose was distributed in the bone after 72 hours. At the same time, risedronate levels in soft tissues of rats and dogs were at least 40 and 16 times lower than those in bone respectively. The remainder of the dose was mainly excreted in the urine. This is likely to be considerably lower in humans who excrete 65% of an intravenously administered dose in the urine in 24 hours. After multiple oral dosing in rats, accumulation of risedronate was observed in bone but not in soft tissues.

Metabolism.

There is no evidence of systemic metabolism of risedronate.

Excretion.

Approximately half the absorbed dose is excreted in the urine within 24 hours. 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min and mean total clearance is 122 mL/min for the immediate release tablets. The difference primarily reflects nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent and there is a linear relationship between renal clearance and creatinine clearance. In the same pharmacokinetic study mentioned (see Absorption), the percent of dose excreted in urine was measured. Unabsorbed risedronate is eliminated unchanged in the faeces. Following absorption, the serum concentration time profile is multiphasic with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. Although the elimination rate from human bone is unknown, the 480 hour half-life is hypothesised to represent the dissociation of Actonel from the surface of the bone.

Special groups.

Paediatric.

Safety and efficacy of risedronate have not been established in patients under 18 years of age.

Gender.

Bioavailability and pharmacokinetics following oral administration are similar in men and women.

Use in the elderly.

Of the patients receiving Actonel EC in postmenopausal osteoporosis studies, 59% were 65 and over, while 13% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Ethnicity.

Pharmacokinetic differences due to ethnicity have not been studied.

Renal insufficiency.

Risedronate is excreted intact primarily via the kidney. There is limited clinical data in patients with severe renal impairment (creatinine clearance < 30 mL/min) and therefore Actonel is not recommended for this patient group.
No dosage adjustment is necessary in patients with a creatinine clearance ≥ 30 mL/min.

Hepatic insufficiency.

No studies have been performed to assess the safety or efficacy of Actonel in patients with hepatic impairment. Risedronate is not metabolised in rat, dog, and human liver preparations. Insignificant amounts (< 0.1% of intravenous dose) of risedronate are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Risedronate did not cause gene mutations in bacterial or mammalian cells in vitro, nor did it cause DNA damage in rat hepatocytes in vitro. In clastogenicity assays, risedronate was positive in an in vitro assay using Chinese hamster ovary cells at cytotoxic concentrations (7-18% cell survival), but there was no evidence of chromosomal damage when the assay was repeated at concentrations leading to 48-74% cell survival. Risedronate was negative at oral doses up to 1336 mg/kg in an in vivo assay (chromosomal aberrations in rat bone marrow).

Carcinogenicity.

No evidence of carcinogenicity was observed in either rats (treated for 104 weeks with up to 24 mg/kg/day) or mice (treated for 80 weeks with up to 32 mg/kg/day). Systemic exposure (serum AUC0-24h) at the high dose in rats was 160 times greater than that in humans dosed at 30 mg/day. Systemic exposure was not assessed in mice, but the highest dose in the carcinogenicity study was at least 30 times higher than the dose required for pharmacological effects on bone. Thus, risedronate sodium appears to have no carcinogenic potential at therapeutic dose levels.

6 Pharmaceutical Particulars

6.1 List of Excipients

Actonel EC tablets have a pH-sensitive enteric-coating and contain a chelating agent disodium edetate (EDTA). Each Actonel EC tablet also contains, microcrystalline cellulose, colloidal anhydrous silica, sodium starch glycollate type A, stearic acid, magnesium stearate, methacrylic acid - ethyl acrylate copolymer (1:1), triethyl citrate, - purified talc, iron oxide yellow, simethicone and polysorbate 80.

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

Actonel EC - Store below 30°C.

6.5 Nature and Contents of Container

Actonel EC Once-a-Week tablets are packaged in a clear PVC/aluminium foil blister strip contained in a carton. Pack sizes are 1, 2, 4, 10, 12 or 16 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Risedronate sodium is a fine, white to off-white, odourless, crystalline powder. It is soluble in water and in aqueous solutions and essentially insoluble in common organic solvents.

Chemical structure.

The chemical structure of risedronate sodium is the following:
Chemical Name: [1-hydroxy-2-(3-pyridinyl) ethylidene]bis(phosphonic acid) monosodium salt.
Molecular Formula: C7H10NO7P2Na.
Molecular Weight: Anhydrous: 305.10.
Hemi-pentahydrate: 350.13.

CAS number.

115436-72-1 (risedronate sodium).

7 Medicine Schedule (Poisons Standard)

S4-Prescription Only Medicine.

Summary Table of Changes