4.4 Special warnings and precautions for use

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.

4.8 Undesirable effects

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).

 

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E- ail:medsafety@hpra.ie.

Section 9:

Date of first authorisation: 26th November 2010
Date of last renewal: 13th August 2013

Section 10:
September 2013

Section 5.1: Paediatric population:
The safety and effectiveness efficacy of risedronate sodium is being has been investigated in an 3 year on-going study (a randomized, double-blind, placebo-controlled, multicenter, parallel group study of one-year duration followed by 2 years of open-label treatment) in of paediatric patients aged 4 to less than 16 years with mild to moderate osteogenesis imperfecta. In this study, patients weighing 10-30 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 randomizsed, double-blind, placebo controlled period, 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. 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 randomised to the placebo group and by 52.9% of patients initially randomised to the risedronate group. Overall, results do not are insufficient to support the use of risedronate sodium in paediatric patients with mild to moderate osteogenesis imperfecta.

Section 2:
Excipient with known effect: 1.9 mg lactose in each tablet
For a full list of excipients see section 6.1.

Section 4.2:
Posology
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 Mylan Once a Week:

Section 4.3:
Hypersensitivity to risedronate sodium the active substance or to any of the excipients listed in section 6.1.

Section 4.4:
The evidence to support efficacy of bisphosphonates including risedronate sodium in the very elderly (>80 years) is limited (see section 5.1).

• If risedronate Risedronate Mylan Once a Week is given to patients with active or recent oesophageal or upper gastrointestinal problems (including known Barrett’s oesophagus).


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

Section 4.6:
Pregnancy
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.

Lactation
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.

Section 4.8:
The following additional adverse reactions have been reported during post-marketing use (frequency unknown):

frequency unknown:
Eye disorders:
iritis, uveitis

During post-marketing experience the following reactions have been reported (frequency rare):
Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Section 5.1:

Pharmaco-therapeutic group: Bisphosphonates, ATC Code: M05 BA07.
ATC Code: M05 BA07.

Mechanism of action

Section 10: Date of revision updated to July 2012.

Section 4.2:

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 Mylan Once a Week 35mg film-coated tablets on an individual patient basis, particularly after 5 or more years of use.

Section 4.4:

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.

Section 4.8:

frequency rare:

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

Section 4.8:

Section 4.2:

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

Section 5.1:

Paediatric population: The safety and effectiveness 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 period, 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.

Section 4.2:

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

Elderly:

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.

 

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).

 

Children:

Safety and efficacy of risedronate 35 mg have not been established in children and adolescents.

Section 4.4:

 

Efficacy of bisphosphonates in the treatment of osteoporosis is related to the presence of low bone mineral density 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.

Section 4.6

 

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.


Section 4.8:

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).

Muskuloskeletal and connective tissues disorders:

osteonecrosis of the jaw

 

Skin and subcutaneous tissue disorders:

hypersensitivity and skin reactions, including angioedema, generalised rash, urticaria, bullous skin reactions and leukocytoclastic vasculitis, 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.

Section 5.1:

 

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.

 

·         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 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 mg and 5 mg groups were 3.8%, placebo 7.4%).

 

None provided