SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Actonel 30 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients with known effect

Each film-coated tablet contains 131.0 mg lactose monohydrate (equivalent to 124.45 mg lactose).

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets.

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of Paget’s disease of the bone.

4.2 Posology and method of administration Posology

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.

Method of administration

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 (see section 4.4).

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.

SPECIAL POPULATIONS

Elderly:

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

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) (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).

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 <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 Actonel (see section 4.5). In order to achieve the intended efficacy, strict adherence to dosing recommendations is necessary (see section 4.2).

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 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.

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.

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 medicinal product.

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 studies.

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.

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

Actonal 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 studies involving more than 15,000 patients. The majority of undesirable effects observed in clinical studies was mild to moderate in severity and usually did not require cessation of therapy.

Adverse experiences reported in phase III clinical studies 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: iritis¹

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 tests¹

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

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, 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).

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Bisphosphonates ATC Code: M05 BA07

Mechanism of action

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.

Clinical efficacy and safety

Paget’s disease of the bone: In the clinical programme Actonel was studied in patients with Paget’s disease. After treatment with Actonel 30 mg/day for 2 months the following was seen: ¹

• radiographs taken at baseline and after 6 months demonstrated a decrease in the extent of osteolytic lesions in both the appendicular and axial skeleton. No new fractures were observed.

The observed response was similar in pagetic patients regardless of whether they had previously received other treatments for Paget’s disease, or the severity of the disease.

53% of patients followed for 18 months after initiation of a single 2 month course of Actonel remained in biochemical remission.

In a trial comparing before-breakfast dosing and dosing at other times of the day in women with postmenopausal osteoporosis, lumbar spine BMD gains were statistically higher with before-breakfast dosing.

Paediatric population:

The safety and efficacy of risedronate sodium has been investigated in a 3-year study (a randomized, double-blind, placebo-controlled, multicenter, parallel group study of one year duration followed by 2 years of open-label treatment) in paediatric patients aged 4 to less than 16 years with mild to moderate osteogenesis imperfecta. In this study, patients weighing 1030 kg received risedronate 2.5 mg daily and patients weighing more than 30 kg received risedronate 5 mg daily.

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 patients with at least 1 new morphometric (identified by x-ray) vertebral fracture was found in the risedronate group compared to placebo. During the one-year double-blind period, the percentage of patients who reported clinical fractures was 30.9% in the risedronate group and 49.0% in the placebo group. In the open-label period when all patients received risedronate (month 12 to month 36), clinical fractures were reported by 65.3% of patients initially randomized to the placebo group and by 52.9% of patients initially randomized to the risedronate group. Overall, results do not support the use of risedronate sodium in paediatric patients with mild to moderate osteogenesis imperfecta.

5.2 Pharmacokinetic properties

Absorption:

Absorption after an oral dose is relatively rapid (t_max ~ 1 hour) and is independent of dose over the range studied (2.5 to 30 mg). 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 is 6.3 l/kg in humans. Plasma protein binding is about 24%.

Biotransformation

There is no evidence of systemic metabolism of risedronate sodium.

Elimination:

Approximately half of the absorbed 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.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:    Lactose monohydrate

Cellulose microcrystalline Crospovidone Magnesium stearate.

Film coating: Hypromellose Macrogol

Hydroxypropylcellulose Colloidal anhydrous silica Titanium dioxide E171.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

5 years.

6.4    Special precautions    for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Opaque PVC/aluminium foil blister cards of 14 tablets in cardboard carton, tablet count 28 (2 x 14) and tablet count 14 (1 x 14).

Sample pack - Opaque PVC/aluminium foil blister cards of 3 tablets in cardboard carton, tablet count 3 (1 x 3).

Not all pack sizes to be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Warner Chilcott UK Limited Old Belfast Road,

Millbrook Road, Larne,

County Antrim, BT40 2SH

8    MARKETING AUTHORISATION NUMBER(S)

PL 10947/0005

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/08/2009

10    DATE OF REVISION OF THE TEXT

11/11/2014

1

serum alkaline phosphatase normalised in 77% of patients compared to 11% in the control group (etidronate 400 mg/day for 6 months). Significant reductions were observed in urinary hydroxyproline/creatinine and urinary deoxypyridinoline/creatinine