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. Prevention of osteoporosis in postmenopausal women with increased risk of osteoporosis (see section 5.1).

To maintain or increase bone mass in postmenopausal women undergoing long-term (more than 3 months), systemic corticosteroid treatment at doses ≥ 7.5 mg/day prednisone or equivalent.

4.2. Posology and method of administration

Posology

The recommended daily dose in adults is one 5 mg tablet orally.

Special populations

Elderly

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

Renal impairment

No dose 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 30 mL/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 safety and efficacy (see also section 5.1).

Method of administration

The absorption of risedronate sodium is affected by food, thus to ensure adequate absorption patients should take risedronate sodium:

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

In the particular instance that before breakfast dosing is not practical, risedronate sodium can be taken between meals or in the evening at the same time every day, with strict adherence to the following instructions, to ensure risedronate sodium is taken on an empty stomach:

• Between meals: Risedronate sodium should be taken at least 2 hours before and at least 2 hours after any food, medicinal product or drink (other than plain water).

• In the evening: Risedronate sodium should be taken at least 2 hours after the last food, medicinal product or drink (other than plain water) of the day. Risedronate sodium should be taken at least 30 minutes before going to bed.

If an occasional dose is missed, risedronate sodium can be taken before breakfast, between meals or in the evening according to the instructions above.

The tablets must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach risedronate sodium is to be taken while in an upright (standing or sitting) 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.

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 the active substance or to any of the excipients listed in section 6.1.

Hypocalcaemia (see section 4.4).

Pregnancy and lactation.

Severe renal impairment (creatinine clearance <30 ml/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 (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 postmenopausal 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 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 (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 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 risedronate sodium therapy. Other disturbances of bone and mineral metabolism (e.g. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting risedronate sodium 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 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.

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

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

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

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.

Concomitant ingestion of medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) interferes 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.

In the risedronate sodium Phase III osteoporosis studies, acetylsalicylic acid or NSAID use was reported by 33% and 45% of patients, respectively.

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

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 must not be used during pregnancy or by breast-feeding women.

4.7. Effects on ability to drive and use machines

Risedronate sodium has no or negligible influence on the ability to drive and use machines.

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 was 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 sodium 5 mg/day (n=5,020) or placebo (n=5,048) 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 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

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 tissue disorders:

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.

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

During post-marketing experience the following reactions have been reported:

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

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

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

Immune system disorders

anaphylactic reaction

Eye disorders

iritis, uveitis

Hepatobiliary disorders

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

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

Musculoskeletal and connective tissue disorders

osteonecrosis of the jaw

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 (website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

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.