Consumer medicine information

ACRIS COMBI

Risedronate sodium; Calcium carbonate

BRAND INFORMATION

Brand name

Acris Combi Combination pack

Active ingredient

Risedronate sodium; Calcium carbonate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ACRIS COMBI.

What is in this leaflet

This leaflet answers some common questions about Acris Combi.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Acris Combi against the benefits expected for you.

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

Keep this leaflet with your medicine.

You may need to read it again.

What ACRIS COMBI is used for

Acris Combi is a combination medicine consisting of 7 tablets for each week of therapy. Each week of therapy includes:

One Acris 35mg Once-a-Week tablet (the small light-orange tablet) and 6 Calcium Carbonate 1250mg tablets (the light lavender tablets).

Acris Combi belongs to a group of medicines called bisphosphonates. It is used to treat:

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

Bone is a living tissue consisting of calcium and other minerals.

Throughout life, old bone is constantly broken down and replaced by new bone.

Acris 35mg Once-a-Week tablets works by helping to:

  • slow down the process of removing old bone. This allows the cells time to rebuild
  • maintaining and increasing bone density.
  • reverse the progression of osteoporosis.

The Calcium Carbonate tablets help to supply the calcium your body needs to build new bone.

Osteoporosis

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

Broken bones may result from injury or falls. Breaks may occur in normal, everyday activity, such as lifting, or from minor injury that would not ordinarily fracture normal bone.

Fractures usually occur at the hip, spine or wrist, although can occur in any bone of the body.

Osteoporosis can also cause back pain, height loss and a curvature of the spine.

Many patients with osteoporosis have no symptoms and may not know that they have osteoporosis.

Osteoporosis can occur in men and women, however it is more common in post menopausal women.

It is also more likely to occur in women who have had an early menopause.

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

This medicine is not addictive.

Acris Combi may be used alone, or in combination with other medicines, to treat your condition.

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.

Before you take ACRIS COMBI

When you must not take it

Do not take Acris Combi if you have an allergy to:

  • any medicine containing risedronate
  • any medicine containing calcium carbonate
  • 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 this medicine if you are unable to stand or sit upright for at least 30 minutes.

Do not take this medicine if you have hypercalciuria.

Hypercalciuria is a condition in which there are high calcium levels present in the blood.

Do not take this medicine if you have kidney stones.

Do not give this medicine to a child under the age of 18 years.

Safety and effectiveness in children younger than 18 years have not been established.

Do not take this medicine if you are pregnant.

Acris Combi is not recommended for use during pregnancy, unless you and your doctor have discussed the risks and benefits involved.

Do not breast-feed if you are taking this medicine.

It is not known whether Acris Combi passes into breast milk.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or 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 other medicines, foods, preservatives or dyes.

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

  • kidney disease
  • problems with your oesophagus (food pipe) such as inflammation or ulcers
  • Sarcoidosis, a disease that results from inflammation of body tissues

Tell your doctor if you have or have had any disturbances of bone and mineral metabolism, for example:

  • vitamin D deficiency
  • parathyroid abnormalities. Parathyroid is a hormone produced by the parathyroid glands in the neck which help control the level of calcium in the body.

Ask your doctor or dentist if you require a dental checkup before starting Acris Combi.

A checkup with your dentist is particularly important if you are being given:

  • any medicines (or having therapy) to treat cancer
  • corticosteroids, medicines which reduce the activity of your immune system, such as prednisone or cortisone.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

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 Acris Combi.

Taking other medicines

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

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

  • antacids, medicines used to treat heartburn and indigestion such as Gaviscon and Mylanta
  • any other products containing calcium
  • iron supplements

These medicines may be affected by Acris Combi or may affect how well it works. You may need to take your medicine at a different time of day to Acris Combi, or you may need to take different medicines.

You can take aspirin while you are being treated with Acris Combi.

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

How to take ACRIS COMBI

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

They may differ from the information contained in this leaflet.

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

How much to take

Take one tablet per day.

How to take it

Day 1
Take the Acris 35mg Once-a-Week tablet (light orange coloured tablet) in the morning, at least 30 minutes before your first meal, drink or medication of the day.

Acris is most effective when your stomach is empty.

Take your Acris 35mg Once-a-Week tablet while sitting or standing upright.

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 very important to stay upright until after you have eaten your first food of the day. This will help make sure the tablet reaches your stomach quickly and helps avoid irritation to your oesophagus (food pipe).

Swallow the tablets whole with a glass of plain water.

It is important to take Acris Combi with plain water only (120 mL), not mineral water. Mineral water and other drinks, including fruit juices, coffee and tea, will reduce the effect of Acris Combi.

Do not chew or suck the tablets.

Days 2 to 7
Take one calcium carbonate tablet (light lavender tablet) the day after you start taking the Acris 35mg Once-a-Week.

Continue taking one calcium carbonate tablet each day for the next 6 days.

Always take your calcium carbonate tablet with a meal.

Calcium uptake is improved if taken with food.

Do not take your Acris 35mg Once-a-Week tablet on the same day that you take your calcium carbonate tablet.

The days of the week are printed on the blister foil to help you remember when to take your medicine.

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.

How long to take it

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

If you forget to take it

For the Acris 35mg Once-a-Week tablet (light orange tablet):

Take your Acris 35mg Once-a Week tablet on the following day on an empty stomach (refer 'How to Take it' above).

Do not take two tablets in one day to make up for the tablet you missed.

You should only ever take one tablet per day.

Do not take your Acris 35mg Once-a Week tablet on any day you take your calcium carbonate tablet.

Discard any calcium carbonate tablets (light lavender tablets) left in the blister pack after your weekly cycle. Use a new blister pack every 7th day.

You should be taking one Acris 35mg Once-a-Week tablet (light orange tablet) on Day 1, each week.

For the calcium carbonate tablets (light lavender tablets):

Take the calcium carbonate tablet on the day the missed dose is remembered.

Do not take two tablets in one day to make up for the tablet you missed.

You should only ever take one tablet per day.

Discarding any tablets left in the blister at the end of the weekly cycle.

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 Acris Combi. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking ACRIS COMBI

Things you must do

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

Tell any other doctors and pharmacists who treat you that you are taking this medicine.

If you require a dental procedure, tell your dentist that you are taking Acris Combi.

Invasive dental procedures should be avoided wherever possible.

If you develop a degenerative disease of the jaw (osteonecrosis) while taking Acris Combi, any dental surgery may exacerbate the condition.

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 Acris Combi.

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

Things you must not do

Do not lie down for 30 minutes after taking the Acris 35mg Once-a-Week tablet (light orange tablet).

Do not have any food or drink, except plain water for 30 minutes after taking the Acris 35mg Once-a-Week tablet (light orange tablet).

Do not take Acris Combi 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 change the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Acris Combi affects you.

This medicine may cause dizziness or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

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

This medicine helps most people with osteoporosis, but it may have unwanted side effects in some people.

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 list 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:

  • stomach pain
  • indigestion, an uncomfortable feeling in the stomach or belching after eating
  • diarrhoea
  • constipation
  • aching muscles, muscle tenderness or weakness, not caused by exercise
  • painful, swollen joints
  • painful bones
  • headache
  • nausea
  • runny or blocked nose, sneezing, facial pressure or pain
  • sore throat and discomfort when swallowing
  • dizziness
  • unusual weakness.

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

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

  • blurred vision, difficulty seeing or inflammation of the of the eye
  • delayed healing and/or infection of the jaw or teeth, most commonly following a tooth extraction or invasive dental work.

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

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • signs of allergy such as skin rash, itching or hives, swelling of the face, lips, tongue or other parts of the body; shortness of breath, wheezing or troubled breathing difficulty or pain on swallowing
  • difficulty or pain on swallowing
  • severe skin reaction
  • new or worsening heartburn.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

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 ACRIS COMBI

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 25°C.

Do not store Acris Combi or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness 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.

Product description

What it looks like

Acris 35mg Once-a-Week tablet: light orange film-coated, round, biconvex, tablets marked M on one side of the tablet and 714 on the other side.

Calcium carbonate tablet: light lavender, clear film-coated, modified oval shaped, biconvex, beveled edge tablet debossed with "M CC5" on one side of the tablet and plain on the other side.

Ingredients

Acris 35mg Once-a-Week tablet contains 35 mg of risedronate sodium as the active ingredient.

It also contains the following inactive ingredients:

  • mannitol
  • cellulose - microcrystalline
  • crospovidone
  • silicon dioxide
  • magnesium stearate
  • Opadry II complete film coating system 40L97490 beige (ARTG No. 107225)
  • Opadry complete film coating system YS-1-7006 clear (ARTG No. 12789).

Calcium carbonate tablet contains 1250 mg calcium carbonate (equivalent to elemental calcium 500 mg).

It also contains the following inactive ingredients:

  • hydroxypropylcellulose
  • polysorbate 80
  • water - purified
  • cellulose - microcrystalline
  • croscarmellose sodium
  • Indigo carmine
  • Allura red AC
  • talc - purified
  • magnesium stearate
  • Opadry Aqueous film-coating Y-19-7483 (ARTG No. 3751).

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Acris Combi is supplied in Australia by:
Alphapharm Pty Limited
(ABN 93 002 359 739)
Level 1, 30 The Bond
30 - 34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.alphapharm.com.au

Medical Information
Phone: 1800 028 365

Australian registration numbers:
Acris Combi - Risedronate sodium 35 mg and calcium carbonate 1250 mg tablets: AUST R 166197

This leaflet was prepared on
6 May 2011.

BRAND INFORMATION

Brand name

Acris Combi Combination pack

Active ingredient

Risedronate sodium; Calcium carbonate

Schedule

S4

 

Name of the medicine

Risedronate sodium (as hemipentahydrate) tablet 35 mg, calcium carbonate tablet 1250 mg.

Excipients.

Risedronate tablet.

Mannitol, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate, Opadry II beige 40L97490 (ARTG No. 107225) and Opadry clear YS-1-7006 (ARTG No. 12789).

Calcium carbonate tablet.

Pregelatinised maize starch, hydroxypropylcellulose, polysorbate 80, purified water, microcrystalline cellulose, croscarmellose sodium, Indigo carmine, Allura red AC, purified talc, magnesium stearate, Opadry Aqueous film coating Y-19-7483 (ARTG No. 3751).

Description

Risedronate sodium pentahydrate.

Chemical name: [1-hydroxy-2-(3-pyridinyl) ethylidene]bis(phosphonic acid) monosodium salt hemipentahydrate. Molecular formula: C7H10NO7P2Na.2.5H2O. MW: 350.13. CAS: 329003-65-8. Risedronate sodium (as hemipentahydrate) 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.

Calcium carbonate.

Molecular formula: CaCO3. MW: 100.1. CAS: 471-34-1. Calcium carbonate is a white powder, practically insoluble in water.

Pharmacology

Pharmacodynamics.

Risedronate.

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. Decreases in biochemical markers of bone turnover were similar with risedronate 35 mg once a week (Sanofi-Aventis) and risedronate 5 mg daily. In a study 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.

Comparison of 5 mg daily dose and 35 mg once a week dose (Sanofi-Aventis).

Based on a lumbar spine BMD (bone mineral density), risedronate 35 mg once a week (n = 485) was shown to be therapeutically equivalent to risedronate 5 mg daily (n = 480) in a one year, double blind multicentre study of postmenopausal women with osteoporosis. The two treatment groups were also similar at one year with regard to BMD increases at the total proximal femur, femoral neck and trochanter.

Comparison of 5 mg daily dose and 150 mg once a month dose (Sanofi-Aventis).

Based on effects on mean percent change in lumbar spine BMD, risedronate sodium 150 mg (n = 561) once a month was shown to be equivalent to risedronate sodium 5 mg (n = 561) daily in a one year, double blind, multicentre study of postmenopausal women with osteoporosis. Both groups had statistically significant mean percent increases in lumbar spine BMD from baseline to month 6, 12 and endpoint. The two treatment groups were also similar with regard to BMD increases at the total proximal femur and trochanter.

Calcium carbonate.

In case of calcium deficiency, oral intake of calcium supplementation supports the remineralisation of the skeleton. Administration of calcium counteracts the calcium deficiency induced increase in parathyroid hormone (PTH) and bone resorption. A meta-analysis of randomised controlled trials has suggested that oral vitamin D supplementation between 700-800 IU per day reduces the risk of hip and nonvertebral fractures in elderly patients. These results were complemented by a subsequent meta-analysis suggesting that oral vitamin D reduces the risk of hip fractures only when calcium supplementation is added.

Pharmacokinetics.

Risedronate.

Absorption.

Risedronate is relatively rapidly absorbed (tmax ≈ 1 hour) throughout the upper gastrointestinal (GI) tract. Absorption is independent of dose over the range studied (single dose study, 2.5 to 30 mg; multiple dose studies, 2.5 to 5 mg daily and up to 150 mg monthly). In a 13 week pharmacokinetic study with 5 mg daily and 35 mg weekly and 50 mg weekly dosing (N ~ 19/group), a comparison of the average serum concentration (Cavg) for 35 mg/week and 5 mg/day was not statistically significantly different. The 95% confidence interval for Cavg was 57.1-101.2, with a point estimate of 76.0% for the 35 mg dose compared to the 5 mg dose. Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate is administered with food. Bioavailability was similar in men and women. Although administration of risedronate either 30 minutes prior to breakfast or 2 hours after dinner reduces absorption of risedronate by 55% compared to administration in the fasting state (i.e. no food or beverages for 10 hours prior to, or 4 hours after, dosing), and administration one hour prior to breakfast reduces absorption by 30%, risedronate has been shown to be effective in clinical trials when administered 30 minutes (or longer) before the first meal or beverage of the day (e.g. breakfast) and also when administered 2 hours (or longer) prior to and following food or beverages at other times of the day.
A bioavailability study was conducted comparing the generic risedronate sodium 35 mg tablet against the originator risedronate sodium 35 mg tablet. The generic and originator mean Cmax for risedronate was 14.00 nanogram/mL and 15.09 nanogram/mL respectively. The Cmax point estimate for risedronate was 0.98 with the 90% confidence interval between 0.91 and 1.06. The mean AUC point estimate for risedronate was 0.96 with the 90% confidence interval between 0.89 and 1.04. The Tmax for the generic tablet was 0.959 hours and for the originator tablet was 1.182 hours.

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. 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 in the Absorption section, the percent of dose excreted in urine was measured. The point estimate for the 35 mg versus 5 mg doses was 66.8% (95% CI, 48.0-95.8). Although this was statistically significantly different, the clinical relevance is unknown.
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 risedronate from the surface of the bone.

Calcium carbonate.

Calcium is eliminated through faeces, urine and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption.

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.

Geriatric.

Risedronate pharmacokinetics are similar in older subjects (age 45 to 76 years) with normal renal function (creatinine clearance 80 to 120 mL/min) to that observed in young subjects (age 18 to 45 years). No dosage adjustment is necessary (see Dosage and Administration).

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 risedronate 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 risedronate 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.

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.

35 mg once a week dose.

Risedronate 35 mg once a week (n = 485) was shown to be therapeutically equivalent to risedronate 5 mg daily (n = 480) in a 1 year double blind multicentre study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4.0% (3.7, 4.3; 95% CI) in the 5 mg group (n = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35 mg group (n = 387) and the mean difference between 5 mg daily and 35 mg once a week was 0.1% (-0.42, 0.55; 95% CI) (see Table 1). While once a week doses of risedronate resulted in slightly smaller increases in lumbar spine BMD compared to daily doses of 5 mg after 6 months, the two regimens are equivalent after 12 months. The clinical relevance of these 6 month BMD differences is unknown. The results of the intent to treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. This study is of 2 years' duration, the results of which will be included as soon as they are available.
Very few patients in any treatment group had new fractured vertebrae at month 12 (5 mg daily: 1.5%; 35 mg once a week: 1.3%). No patient had more than one new fractured vertebra. There were no statistically significant differences in the percentage of patients with new vertebral fractures among the 2 treatment groups.

5 mg Daily dose and 150 mg once a month dose.

Information pertaining to the clinical trials of these tablet strengths can be found in the Actonel Combi PI.

Treatment of osteoporosis in men.

Risedronate 35 mg once a week 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%). Risedronate 35 mg once a week 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.

Corticosteroid induced osteoporosis.

Histology/ histomorphometry.

Histologic evaluation of 70 bone biopsy samples from 48 women on corticosteroid therapy who received either placebo or risedronate once daily for 1 year (including 22 pairs of biopsies, 16 from risedronate treated patients) showed that bone formed during treatment with risedronate was of normal lamellar structure and normal mineralisation, with no bone or marrow abnormalities observed. Histomorphometric evaluation indicated that risedronate 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 risedronate treated patients; cortical porosity increased, however, in the placebo group. These findings indicate that bone formed during risedronate treatment is of normal quality.

Indications

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

Contraindications

Risedronate.

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

Calcium carbonate.

Known hypersensitivity to the drug or any of the ingredients.
Hypercalcaemia.
Hypercalciuria.
Nephrolithiasis.

Precautions

Risedronate.

General.

Food, certain medication containing polyvalent cations (such as calcium, magnesium, iron and aluminium) and beverages (except plain water) can interfere with the absorption of bisphosphonates and should not be taken at the same time as risedronate tablets.
Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Thus caution should be used with the following.
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 risedronate 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 risedronate, doctors must stress the importance of taking risedronate as per the dosage instructions (see Dosage and Administration). This is especially important in the case of patients with a history of oesophageal disorders.
Hypocalcaemia must be corrected before starting risedronate therapy.
Bone and mineral metabolism dysfunction (e.g. vitamin D deficiency and parathyroid abnormalities) should be effectively treated before starting risedronate therapy. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.
Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Gastrointestinal.

Risedronate like other bisphosphonates may cause local irritation of the upper GI mucosa. Since some bisphosphonates have been associated with oesophagitis and oesophageal ulcerations, 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 risedronate 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.
In patients with mild to moderate renal impairment or a history of absorptive or renal hypercalciuria, nephrocalcinosis, kidney stone formation, or hypophosphataemia, renal function, serum and urinary calcium and phosphate should be monitored regularly.

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. The number of reported cases of this condition is very low (some 40 reported cases worldwide in connection with alendronate as of 2009).
It is not known to what extent other agents of the aminobisphosphonate class, including risedronate, 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.

Calcium carbonate.

During long-term treatment, serum and urinary calcium levels should be followed and renal function should be monitored through measurement of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics (see Interactions with Other Medicines) and in patients with a high tendency to calculus formation. Treatment must be reduced or suspended if urinary calcium exceeds 7.5 mmol/24 hours (300 mg/24 hours). In case of hypercalcaemia or signs of impaired renal function, treatment with calcium should be discontinued.
Calcium should be used with caution in patients suffering from sarcoidosis because of the increased risk of metabolism of vitamin D to its active metabolite. In these patients, serum calcium levels and urinary calcium excretion must be monitored.
Calcium should be used with caution in immobilised patients with osteoporosis due to the increased risk of hypercalcaemia. The calcium treatment might be discontinued in prolonged immobilisation and should only be resumed once the patient becomes mobile again.

Renal impairment.

Risedronate.

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

Calcium carbonate.

Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics and in patients with high tendency to calculus formation. In the case of hypercalcemia or signs of impaired renal function, treatment with calcium should be discontinued.

Effects on fertility.

Risedronate.

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.

Use in pregnancy.

(Category B3)

Risedronate.

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 (AUC0-24h) 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.

Calcium carbonate.

During pregnancy the daily intake should not exceed 1500 mg calcium. In pregnant women, overdoses of calcium should be avoided as permanent hypercalcemia has been related to adverse effect on the developing foetus.

Use in lactation.

Risedronate.

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.

Calcium carbonate.

Calcium passes into breast milk.

Paediatric use.

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

Genotoxicity.

Risedronate.

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.

Risedronate.

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.

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.

Interactions

Risedronate.

No specific drug interactions studies have been performed. However risedronate is not systemically metabolised, does not induce or inhibit hepatic microsomal drug metabolising enzymes (cytochrome P450) and has low protein binding.
Concomitant intake of medications containing polyvalent cations (e.g. calcium, magnesium, iron, aluminium, antacids) will interfere with the absorption of risedronate and should be taken at a different time of the day.
Risedronate may be used concomitantly with hormone replacement therapy or the contraceptive pill.
During clinical trials, patients were exposed to a wide variety of commonly used concomitant medication while taking risedronate. No clinically relevant interactions were noted. The medications included NSAIDs, aspirin, H2-blockers, proton pump inhibitors, antacids, calcium channel blockers, beta-blockers, thiazides, glucocorticoids, anticoagulants, anticonvulsants and cardiac glycosides. There are no clinical data concerning the concomitant medication with 2 or more bisphosphonates and such concomitant medication is not recommended.
In the phase III postmenopausal trials with 5 mg daily dosing, 29% and 37% of patients used aspirin and NSAIDs respectively. The incidence of upper GI adverse events in risedronate patients (aspirin/ NSAIDs taken ≥ 3 days/week) was similar to that in placebo treated patients. In the phase III once a week study, 57% and 40% of patients used aspirin and NSAIDs respectively. In the phase III study comparing 75 mg on 2 consecutive days a month and 5 mg daily in postmenopausal women, acetyl salicylic acid/ NSAID use was reported by 54.8% of patients. Similar percentages of patients experienced upper gastrointestinal adverse events regardless of NSAIDs and aspirin use.

Calcium carbonate.

Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcemia serum calcium should be regularly monitored during concomitant use of thiazide diuretics.
Systemic corticosteroids reduce calcium absorption. During concomitant use, it may be necessary to increase the dose of calcium carbonate.
Calcium carbonate may interfere with the absorption of concomitant administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before or four to six hours after oral intake of calcium.
Hypercalcaemia may increase the toxicity of cardiac glycosides during treatment with calcium. Such patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.
If a bisphosphonate or sodium fluoride is used concomitantly, this preparation should be administered at least three hours before intake of calcium carbonate since gastrointestinal absorption may be reduced.
Oxalic acid (found in spinach and rhubarb) and phytic acid (found in whole cereals) may inhibit calcium absorption through formation of insoluble compounds with calcium ions. The patient should not take calcium products within two hours of eating foods high in oxalic acid and phytic acid.
Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.
Concurrent administration of antacids containing aluminium hydroxide and cholecalciferol is not recommended in patients on haemodialysis as absorption of aluminium may be increased. Concurrent use should be avoided.

Adverse Effects

Osteoporosis, risedronate 5 mg daily dosing.

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.
Risedronate 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 risedronate 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 risedronate groups respectively.
Table 2 lists adverse events reported in ≥ 5% of risedronate 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.
There was a higher number of reports of mild duodenitis [11 (15.7%)] in the risedronate group [7 (10%) placebo], however there were more duodenal ulcers [33 (47.1%)] in the placebo group [26 (37.1%) risedronate]. 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%) risedronate] and there was no evidence of treatment related oesophageal, gastric, or duodenal ulcers/ erosions.
Risedronate 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 risedronate 5 mg treatment group [75 (43.1%)] compared to the placebo group [57 (33.5%)]. The adverse experiences reported [165 placebo and 167 risedronate] 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, risedronate 35 mg once a week dosing.

In a one year, double blind, multicentre study comparing risedronate 5 mg daily and risedronate once a week 35 mg in postmenopausal women with osteoporosis, the overall safety and tolerability profiles were similar. Table 3 lists the adverse events in > 5% of patients from this trial. Events are shown without attribution of causality.
In a 2 year study in men with osteoporosis, the overall safety and tolerability were similar between the treatment and the placebo groups. Adverse experiences were consistent with those previously observed in women.

Postmarketing data.

Risedronate.

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.

Calcium carbonate.

The following additional adverse reactions have been described.

Uncommon.

Hypercalcaemia and hypercalciuria.

Rare.

Constipation, flatulence, nausea, abdominal pain, diarrhoea, pruritis, rash and urticaria.

Dosage and Administration

Risedronate must only be taken with plain water.
Plain water is the only drink that should be taken with risedronate tablets. Please note that some mineral waters or water from regional areas may have a higher concentration of calcium and therefore should not be used.
Risedronate must be taken 30 minutes before the first food or drink other than water. To facilitate delivery to the stomach, risedronate should be taken in an upright position and the patient should avoid lying down for 30 minutes. Patients should not chew or suck on the tablet because of the potential for oropharyngeal irritation.

Osteoporosis.

The recommended dose is 35 mg once a week taken on the same day each week.

Acris Combi.

Acris Combi is a two component therapy consisting of 7 tablets in a blister, 1 risedronate 35 mg film coated tablet (light orange tablet) and 6 calcium carbonate 1250 mg (equivalent to elemental calcium 500 mg) film coated tablets (light lavender tablets). Acris Combi is intended for patients for whom the amount of calcium included is considered to provide adequate supplementation, based on individual assessment. Supplemental vitamin D should be considered if the dietary intake is inadequate.
The recommended dose in adults is 1 Acris 35 mg tablet on the first day, followed, beginning on the next day, by 1 calcium carbonate 1250 mg (equivalent to elemental calcium 500 mg) tablet daily for 6 days. This 7 day sequence is then repeated each week.
The Acris 35 mg tablet should always be taken on the same day each week, in accordance with the directions described above.
The calcium component should commence on the day after the Acris 35 mg tablet is taken, one calcium tablet should be taken each day for the next 6 days. The tablet should be swallowed whole. Calcium absorption is improved if taken with food. Therefore, patients should take the calcium tablet with a meal.
Patients should be instructed that if the Acris dose is missed, the Acris tablet should be taken on the next day in the morning according to the dosing instructions. On the following day they should take their next calcium tablet (light lavender tablet). Patients should not take more than 1 tablet from the blister strip per day.
If the calcium dose (light lavender tablet) is missed, the patient should be instructed to continue taking one tablet of calcium each day beginning on the day the missed dose is remembered. Any remaining calcium tablets in the blister at the end of the weekly cycle should be discarded.
Patients should be instructed to start a new blister strip every 7 days. They should begin the new strip by taking the Acris 35 mg tablet (light orange tablet) on their originally chosen day of the week.

Use in the elderly.

No dose adjustment is necessary.

Renal Impairment.

No dose adjustment is necessary in patients with mild to moderate renal insufficiency (creatinine clearance 30 to 60 mL/minute). Risedronate is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/minute) due to limited clinical data.

Paediatrics.

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

Compatibility with other drugs.

Calcium, antacids, aluminium and some oral medications will interfere with the absorption of risedronate and therefore should be taken at a different time of the day.

Overdosage

Risedronate.

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. 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.

Calcium carbonate.

Because of its limited intestinal absorption, overdosage with calcium carbonate is not likely. However, overdose can lead to hypercalcaemia.
For information on the management of oversdosage, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Each blister contains risedronate tablets, 35 mg (light orange, round, biconvex, bevelled edge, film coated, marked M on one side, 714 on reverse): 1's; calcium carbonate tablets, 1250 mg (≡ 500 mg elemental Ca) (light lavender, modified oval shaped, biconvex, bevelled edge, clear, film coated, marked M CC5 on one side, plain on reverse): 6's: 7's*, 14's*, 28's, 84's*, 112's* (PVC/Al blister pack).
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.