4.1. Therapeutic indications

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures (see section 5.1).

Treatment of osteoporosis in men at high risk of fractures.(see section 5.1).

4.2. Posology and method of administration

The recommended dose in adults is one 35 mg tablet orally once a week. The tablet should 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 Risedronate sodium 35 mg:

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

Patients should be instructed that if a dose is missed, one Risedronate sodium 35 mg tablet should be taken on the day that the tablet is remembered. Patients should then return to taking one tablet once a week on the day the tablet is normally taken. Two tablets should not be taken on the same day.

The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach Risedronate sodium 35 mg 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).

Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.

Elderly patients: No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (>60 years of age) compared to younger subjects.

This has also been shown in the very elderly, 75 years old and above postmenopausal population.

Patients with renaliImpairment: 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 18 years of age due to insufficient data on its efficacy and safety (see also section 5.1).

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

4.3. Contraindications

Hypersensitivity to risedronate sodium or to any of the excipients listed in section 6.1.

Hypocalcaemia (see section 4.4).

Pregnancy and lactation.

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

4.4. Special warnings and precautions for use

Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) interfere with the absorption of bisphosphonates and should not be taken at the same time as Risedronate sodium 35 mg (see section 4.5). In order to achieve the intended efficacy, strict adherence to dosing recommendations is necessary (see section 4.2).

Efficacy of bisphosphonates in the treatment of osteoporosis is related to the presence of low bone mineral density (BMD T-score at hip or lumbar spine <-2.5 SD) and/or prevalent 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 in the very elderly (>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 (including known Barrett's oesophagus).

Prescribers should emphasise to patients the importance of paying attention to the dosing instructions and be alert to any signs and 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 Risedronate sodium 35 mg therapy. Other disturbances of bone and mineral metabolism (i.e. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Risedronate sodium 35 mg 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.

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 evaluation of the patient, based on an individual benefit risk assessment.

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

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.

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

4.5. Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed, 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 NSAID use was reported by 33% and 45% of patients respectively. In the Phase III once a week study in postmenopausal women, 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 (for women only).

Concomitant ingestion of medications containing polyvalent cations (e.g. calcium, magnesium, iron and aluminium) will interfere with the absorption of Risedronate sodium 35 mg (see section 4.4).

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

4.6. Fertility, pregnancy and lactation

There are no adequate data from the use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Studies in animal indicate that a small amount of risedronate sodium pass into breast milk.

Risedronate sodium 35 mg must not be used during pregnancy or by breast-feeding women.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 women with osteoporosis treated for up to 36 months with risedronate 5mg/day (n=5020) or placebo (n=5048) and considered possibly or probably related to risedronate 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 disorders:

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

Very rare: Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).

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 35 mg than in risedronate sodium 5 mg group): gastrointestinal disorder (1.6% vs. 1.0%) and pain (1.2% vs. 0.8%).

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.

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, and bullous skin reactions, some severe including isolated reports of Stevens-Johnson syndrome and 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)

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

No specific information is available on the treatment of 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 and reduce absorption of risedronate sodium. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed risedronate sodium.