Bisphosphonates

Risedronate sodium

Film-coated tablets. Oval white film-coated tablet with RSN on one side and 30 mg on the other.

Each film-coated tablet contains 30 mg risedronate sodium (equivalent to 27.8 mg risedronic acid).

Treatment of Paget's disease of the bone.

The recommended daily dose in adults is one 30 mg tablet orally for 2 months. If re-treatment is considered necessary (at least two months post-treatment), a new treatment with the same dose and duration of therapy could be given. The absorption of Actonel is affected by food, thus to ensure adequate absorption patients should take Actonel:

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, Actonel can be taken between meals or in the evening at the same time everyday, with strict adherence to the following instructions, to ensure Actonel is taken on an empty stomach:

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

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

The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach Actonel 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.

Physicians should consider the administration of supplemental calcium and vitamin D if dietary intake is inadequate, especially as bone turnover is significantly elevated in Paget's disease.

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 30 ml/min).

Safety and efficacy of Actonel have not been established in children and adolescents

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

• Hypersensitivity to risedronate sodium or to any of the excipients.
• Hypocalcaemia.
• 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) interfere with the absorption of bisphosphonates and should not be taken at the same time as Actonel. In order to achieve the intended efficacy, strict adherence to dosing recommendations is necessary.

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

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.

No formal interaction studies have been performed, however no clinically relevant interactions with other medicinal products were found during clinical trials.

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

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

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%)

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 phase III Paget's Disease clinical trial comparing risedronate vs. etidronate (61 patients in each group), the following additional adverse experiences considered possibly or probably drug related by investigators have been reported (incidence greater in risedronate than in etidronate): arthralgia (9.8% vs. 8.2%); amblyopia, apnoea, bronchitis, colitis, corneal lesion, cramps leg, dizziness, dry eye, flu syndrome, hypocalcaemia, myasthenia, neoplasm, nocturia, oedema peripheral, pain bone, pain chest, rash, sinusitis, tinnitus, and weight decrease (all at 1.6% vs. 0.0%).

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 and toxic epidermal necrolysis.

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.

Procter & Gamble/Aventis

(POM)

03 March 2010