Actonel Combi film-coated tablets.

Light-orange tablets:

Each film-coated tablet contains 35 mg risedronate sodium, which is equivalent to 32.5 mg risedronic acid.

Blue tablets:

Each film-coated tablet contains 1250 mg calcium carbonate, which is equivalent to 500 mg elemental calcium.

Excipients: Each light-orange film-coated tablet contains lactose.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Risedronate sodium tablet:

Oval, light-orange, film-coated tablet with RSN on one side and 35 mg on the other.

Calcium carbonate tablet:

Capsule-shaped, blue, film-coated tablet with NE 2 on both sides.

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures.

Actonel Combi is a two component therapy consisting of 7 tablets in a blister, 1 Actonel 35 mg film-coated tablet (light-orange tablet) and 6 calcium 500 mg film-coated tablets (blue tablets). Actonel 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 Actonel 35 mg tablet on the first day followed beginning on the next day by 1 calcium 500 mg tablet daily for 6 days. This 7 day sequence is then repeated each week.

Actonel 35 mg (light-orange tablet):

The Actonel 35 mg tablet should always be taken on the same day each week.

The absorption of risedronate sodium is affected by food, thus to ensure adequate absorption patients should take the Actonel 35mg tablet:

• Before breakfast: at least 30 minutes before the first food, other medicinal product or drink (other than plain water) of the day.

The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach the Actonel 35 mg tablet is to be taken while in an upright position with a glass of plain water (120 ml). Patients should not lie down for 30 minutes after taking the tablet (see section 4.4).

Calcium carbonate (blue tablet):

Beginning on the day after the Actonel 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 Actonel (light-orange tablet) dose is missed, the Actonel 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 (blue tablet). Patients should not take more than 1 tablet from the blister strip per day.

If the calcium dose (blue 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 Actonel 35 mg tablet (light-orange tablet) on their originally chosen day of the week.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-eva luated periodically based on the benefits and potential risks of risedronate on an individual patient basis, particularly after 5 or more years of use.

Elderly: Since the target population is postmenopausal women, a specific dosage instruction for the elderly is not warranted. This has also been shown in the very elderly, 75 years old and above.

Renal Impairment: No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of risedronate sodium is contraindicated in patients with severe renal impairment (creatinine clearance lower than 30ml/min) (see sections 4.3 and 5.2).

Paediatric population: Risedronate sodium is not recommended for use in children below age 18 due to insufficient data on safety and efficacy (also see section 5.1).

Hypersensitivity of risedronate sodium, calcium carbonate or to any of the excipients.

Hypocalcaemia (see section 4.4)

Hypercalcaemia

Hypercalciuria

Nephrolithiasis

Pregnancy and lactation.

Severe renal impairment (creatinine clearance <30ml/min)

Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) may interfere with the absorption of risedronate sodium and should not be taken at the same time (see section 4.5). Therefore the risedronate sodium tablet (light-orange tablet) should be taken at least 30 minutes before the first food, other medicinal product or drink of the day (see section 4.2).

Efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis is related to the presence of low bone mineral density (BMD) [T-score at hip or lumbar spine -2.5 standard deviations SD)] and/or preva lent fracture.

High age or clinical risk factors for fracture alone are not sufficient reasons to initiate treatment of osteoporosis with a bisphosphonate.

The evidence to support efficacy of bisphosphonates including risedronate sodium in very elderly women (>80 years) is limited (see section 5.1).

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 risedronate is given to patients with active or recent oesophageal or upper gastrointestinal problems.

Prescribers should emphasise to patients the importance of paying attention to the dosing instructions and be alert to any signs or symptoms of possible oesophageal reaction. The patients should be instructed to seek timely medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or new/worsened heartburn.

Hypocalcaemia should be treated before starting Actonel Combi therapy. Other disturbances of bone and mineral metabolism (i.e. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Actonel Combi therapy.

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 bisphophonates. 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.

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 fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending eva luation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be eva luated for an incomplete femur fracture.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Risedronate sodium:

No formal interaction studies have been performed with risedronate sodium, however no clinically relevant interactions with other medicinal products were found during clinical trials. In the risedronate sodium Phase III osteoporosis studies with daily dosing, acetyl salicylic acid or non-steroidal anti-inflammatory drug (NSAID) use was reported by 33% and 45% of patients respectively. In the Phase III once a week study, acetyl salicylic acid or NSAID use was reported by 57% and 40% of patients respectively. Among regular acetyl salicylic acid or NSAID users (3 or more days per week) the incidence of upper gastrointestinal adverse events in risedronate sodium treated patients was similar to that in control patients.

If considered appropriate risedronate sodium may be used concomitantly with oestrogen supplementation.

Concomitant ingestion of medications containing polyvalent cations (e.g. calcium, magnesium, iron and aluminium) will interfere with the absorption of risedronate sodium (see section 4.4).

Risedronate sodium is not systemically metabolised, does not induce cytochrome P450 enzymes, and has low protein binding.

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 digitalis and other cardiac glycosides (risk of dysrhythmia) 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.

This medicinal product is contraindicated during pregnancy and lactation (see section 4.3).

There are no adequate data from use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk to humans is unknown. Studies in animals indicate that a small amount of risedronate sodium pass into breast milk. Risedronate sodium must not be used during pregnancy or by breast-feeding women.

No effects on ability to drive and use machines have been observed.

Risedronate sodium:

Risedronate sodium has been studied in phase III clinical trials involving more than 15,000 patients. The majority of undesirable effects observed in clinical trials were mild to moderate in severity and usually did not require cessation of therapy.

Adverse experiences reported in phase III clinical trials in postmenopausal woman with osteoporosis treated for up to 36 months with risedronate sodium 5mg/day (n=5020)or placebo (n=5048) and considered possibly or probably related to risedronate sodium are listed below using the following convention (incidences versus placebo are shown in brackets): very common (1/10); common (1/100; <1/10); uncommon (1/1,000; <1/100); rare (1/10,000; <1/1,000); very rare (<1/10,000).

Nervous system disorders:

Common: headache (1.8% vs. 1.4%)

Eye disorders:

Uncommon iritis*

Gastrointestinal disorders:

Common: constipation (5.0% vs. 4.8%), dyspepsia (4.5% vs. 4.1%), nausea (4.3% vs. 4.0%), abdominal pain (3.5% vs. 3.3%), diarrhoea (3.0% vs. 2.7%)

Uncommon: gastritis (0.9% vs. 0.7%), oesophagitis (0.9% vs. 0.9%), dysphagia (0.4% vs. 0.2%), duodenitis (0.2% vs. 0.1%), oesophageal ulcer (0.2% vs. 0.2%)

Rare: glossitis (<0.1% vs. 0.1%), oesophageal stricture (<0.1% vs. 0.0%).

Musculoskeletal and connective tissues disorder:

Common: musculoskeletal pain (2.1% vs. 1.9%)

Investigations:

Rare: abnormal liver function tests*

* No relevant incidences from Phase III osteoporosis studies; frequency based on adverse event/laboratory rechallenge findings in earlier clinical trials.

In a one-year, double-blind, multicentre study comparing risedronate sodium 5 mg daily (n=480) and risedronate sodium 35 mg weekly (n=485) in postmenopausal women with osteoporosis, the overall safety and tolerability profiles were similar. The following additional adverse experiences considered possibly or probably drug related by investigators have been reported (incidence greater in risedronate sodium 35 mg than in risedronate sodium 5 mg group): gastrointestinal disorder (1.6% vs. 1.0%) and pain (1.2% vs. 0.8%).

Laboratory findings: Early, transient, asymptomatic and mild decreases in serum calcium and phosphate levels have been observed in some patients.

The following additional adverse reactions have been reported during post-marketing use (frequency unknown):

Eye disorders:

iritis, uveitis

Muskuloskeletal and connective tissues disorders:

osteonecrosis of the jaw

Skin and subcutaneous tissue disorders:

hypersensitivity and skin reactions, including angioedema, generalised rash, urticaria, and bullous skin reactions, some severe including isolated reports of Stevens-Johnson syndrome, toxic epidermal necrolysis and leukocytoclastic vasculitis.

hair loss

Immune system disorders:

anaphylactic reaction

Hepatobiliary disorders:

serious hepatic disorders. In most of the reported cases the patients were also treated with other products known to cause hepatic disorders.

During post-marketing experience the following reactions have been reported (frequency rare):

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

Calcium carbonate:

Adverse reactions are listed below, by system organ class and frequency: very common (1/10); common (1/100; <1/10); uncommon (1/1,000; <1/100); rare (1/10,000; <1/1,000); very rare (<1/10,000).

Metabolism and nutrition disorders:

Uncommon: hypercalcaemia and hypercalciuria.

Gastrointestinal disorders:

Rare: flatulence

Risedronate sodium:

No specific information is available on the treatment of acute overdose with risedronate sodium .

Decreases in serum calcium following substantial overdose may be expected. Signs and symptoms of hypocalcaemia may also occur in some of these patients.

Milk or antacids containing magnesium, calcium or aluminium should be given to bind risedronate sodium and reduce absorption of risedronate sodium. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed risedronate sodium.

Calcium carbonate:

Because of its limited intestinal absorption, overdosage with calcium carbonate is not likely. However, overdose can lead to hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polidipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias.

Treatment of hypercalcaemia: The treatment with calcium must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D and cardiac glycosides must also be discontinued. Emptying of the stomach in patients with impaired consciousness. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG and central venous pressure should be followed.

Pharmaco-therapeutic group: Bisphosphonates, combinations

ATC Code: M05BB02.

Risedronate sodium:

Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation is preserved. In preclinical studies risedronate sodium demonstrated potent anti-osteoclast and antiresorptive activity, and dose dependently increased bone mass and biomechanical skeletal strength. The activity of risedronate sodium was confirmed by measuring biochemical markers for bone turnover during pharmacodynamic and clinical studies. Decreases in biochemical markers of bone turnover were observed within 1 month and reached a maximum in 3-6 months. Decreases in biochemical markers of bone turnover were similar with risedronate sodium 35 mg weekly and risedronate sodium 5 mg daily at 12 months.

Treatment of Postmenopausal Osteoporosis:

A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.

Based on effects on mean change in lumbar spine BMD, risedronate sodium 35 mg weekly (n=485) was shown to be equivalent to risedronate sodium 5 mg daily (n=480) in a one-year, double-blind, multicentre study of postmenopausal women with osteoporosis.

The clinical programme for risedronate sodium administered once daily studied the effect of risedronate sodium on the risk of hip and vertebral fractures and contained early and late postmenopausal women with and without fracture. Daily doses of 2.5 mg and 5 mg were studied and all groups, including the control groups, received calcium and vitamin D (if baseline levels were low). The absolute and relative risk of new vertebral and hip fractures were estimated by use of a time-to-first event analysis.

• Two placebo-controlled trials (n=3661) enrolled postmenopausal women under 85 years with vertebral fractures at baseline. Risedronate sodium 5 mg daily given for 3 years reduced the risk of new vertebral fractures relative to the control group. In women with respectively at least 2 or at least 1 vertebral fractures, the relative risk reduction was 49% and 41% respectively (incidence of new vertebral fractures with risedronate sodium 18.1% and 11.3%, with placebo 29.0% and 16.3%, respectively). The effect of treatment was seen as early as the end of the first year of treatment. Benefits were also demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg daily also reduced the yearly height loss compared to the control group.

• Two further placebo controlled trials enrolled postmenopausal women above 70 years with or without vertebral fractures at baseline. Women 70-79 years were enrolled with femoral neck BMD T-score <-3 SD (manufacturer's range, i.e. -2.5 SD using NHANES III) and at least one additional risk factor. Women 80 years could be enrolled on the basis of at least one non-skeletal risk factor for hip fracture or low bone mineral density at the femoral neck. Statistical significance of the efficacy of risedronate sodium versus placebo is only reached when the two treatment groups 2.5 mg and 5 mg are pooled. The following results are only based on a-posteriori analysis of subgroups defined by clinical practise and current definitions of osteoporosis:

- In the subgroup of patients with femoral neck BMD T-score -2.5SD (NHANES III) and at least one vertebral fracture at baseline, risedronate sodium given for 3 years reduced the risk of hip fractures by 46% relative to the control group (incidence of hip fractures in combined risedronate sodium 2.5 and 5 mg groups 3.8%, placebo 7.4%);

- Data suggest that a more limited protection than this may be observed in the very elderly (80 years). This may be due to the increasing importance of non-skeletal factors for hip fracture with increasing age.

In these trials, data analysed as a secondary endpoint indicated a decrease in the risk of new vertebral fractures in patients with low femoral neck BMD without vertebral fracture and in patients with low femoral neck BMD with or without vertebral fracture.

• Risedronate sodium 5 mg daily given for 3 years increased BMD relative to control at the lumbar spine, femoral neck, trochanter and wrist and maintained bone density at the mid-shaft radius.

• In a one-year follow-up off therapy after three years treatment with risedronate sodium 5 mg daily there was rapid reversibility of the suppressing effect of risedronate sodium on bone turnover rate.

• Bone biopsy samples from postmenopausal women treated with risedronate sodium 5 mg daily for 2 to 3 years, showed an expected moderate decrease in bone turnover. Bone formed during risedronate sodium treatment was of normal lamellar structure and bone mineralisation. These data together with the decreased incidence of osteoporosis related fractures at vertebral sites in women with osteoporosis appear to indicate no detrimental effect on bone quality.

• Endoscopic findings from a number of patients with a number of moderate to severe gastrointestinal complaints in both risedronate sodium and control patients indicated no evidence of treatment related gastric, duodenal or oesophageal ulcers in either group, although duodenitis was uncommonly observed in the risedronate sodium group.

Calcium carbonate:

In case of calcium deficiency, oral intake of calcium supplementation supports the remineralisation of the skeleton.

Paediatric population: The safety and efficacy of risedronate sodium is being investigated in an on-going study of paediatric patients aged 4 to less than 16 years with osteogenesis imperfecta. After completion of its one-year randomized, double-blind, placebo controlled phase, a statistically significant increase in lumbar spine BMD in the risedronate group versus placebo group was demonstrated; however an increased number of at least 1 new morphometric (identified by x-ray) vertebral fracture was found in the risedronate group compared to placebo. Overall, results do not support the use of risedronate sodium in paediatric patients with osteogenesis imperfecta.

Risedronate sodium:

Absorption: Risedronate sodium absorption after an oral dose is relatively rapid (t_max ~1 hour) and 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 50 mg dosed weekly). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with food. Bioavailability was similar in men and women.

Distribution: The mean steady state volume of distribution of risedronate sodium is 6.3 l/kg in humans. Plasma protein binding is about 24%.

Metabolism: There is no evidence of systemic metabolism of risedronate sodium.

Elimination: Approximately half of the absorbed risedronate sodium dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine after 28 days. Mean renal clearance is 105 ml/min and mean total clearance is 122 ml/min, with the difference probably attributed to 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. Unabsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration the concentration-time profile shows three elimination phases with a terminal half-life of 480 hours.

Special Populations

Elderly: no dosage adjustment is necessary.

Acetyl salicylic acid/ NSAID users: Among regular acetyl salicylic acid or NSAID users (3 or more days per week) the incidence of upper gastrointestinal adverse events in risedronate sodium treated patients was similar to that in control patients.

Calcium carbonate:

Absorption: The amount of calcium absorbed through the gastrointestinal tract is approximately 30% of the swallowed dose.

Distribution and metabolism: 99% of the calcium in the body is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood-calcium content is in the physiologically active ionised form with approximately 10% being complexed to citrate, phosphate or other anions, the remaining 40% being bound to proteins, principally albumin.

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

Risedronate sodium:

In toxicological studies in rat and dog dose dependent liver toxic effects of risedronate sodium were seen, primarily as enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose related incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other bisphosphonates. Lower respiratory tract effects were also seen in longer term studies in rodents, although the clinical significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcemia and mortality in pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2mg/kg/day in rat and 10mg/kg/day in rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher doses. Studies on genotoxicity and carcinogenesis did not show any particular risks for humans.

Calcium carbonate:

There is no information of relevance to the safety assessment in addition to what is stated in other parts of the SPC.

Light-orange tablets:

Blue tablets:

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Clear PVC/aluminium foil blisters in a cardboard carton.

Blisters in packs containing 14, 28, 84, 112 tablets.

Not all pack sizes may be marketed.

No special requirements.

Warner Chilcott UK Limited

Old Belfast Road,

Millbrook,

Larne,

County Antrim,

BT40 2SH

PA 170/21/1

2004-08-13/2009-08-13

2011-08