4.1. Therapeutic indications

Treatment of osteoporosis in postmenopausal women at increased risk of fracture (see section 5.1).

A reduction in the risk of vertebral fractures has been demonstrated, efficacy on femoral neck fractures has not been established.

4.2. Posology and method of administration

Patients treated with Bonviva should be given the package leaflet and the patient reminder card.

Posology

The recommended dose of ibandronic acid is 3 mg, administered as an intravenous injection over 15 - 30 seconds, every three months.

Patients must receive supplemental calcium and vitamin D (see section 4.4 and section 4.5),

If a dose is missed, the injection should be administered as soon as convenient. Thereafter, injections should be scheduled every 3 months from the date of the last injection.

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 Bonviva on an individual patient basis, particularly after 5 or more years of use.

Special populations

Patients with renal impairment

Bonviva injection is not recommended for use in patients who have a serum creatinine above 200 μmol/l (2.3 mg/dl) or who have a creatinine clearance (measured or estimated) below 30 ml/min, because of limited clinical data available from studies including such patients (see section 4.4 and section 5.2).

No dose adjustment is necessary for patients with mild or moderate renal impairment where serum creatinine is equal or below 200 μmol/l (2.3 mg/dl) or where creatinine clearance (measured or estimated) is equal or greater than 30 ml/min

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Elderly population (>65 years)

No dose adjustment is required (see section 5.2).

Paediatric population

There is no relevant use of Bonviva in children below 18 years, and Bonviva was not studied in this population (see section 5.1 and 5.2).

Method of administration

For intravenous use over 15 - 30 seconds, every three months.

Strict adherence to the intravenous administration route is required (see section 4.4).

4.3. Contraindications

- Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1

- Hypocalcaemia

4.4. Special warnings and precautions for use

Administration failures

Care must be taken not to administer Bonviva injection via intra-arterial or paravenous administration as this could lead to tissue damage.

Hypocalcaemia

Bonviva, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values.

Existing hypocalcaemia must be corrected before starting Bonviva injection therapy. Other disturbances of bone and mineral metabolism should also be effectively treated before starting Bonviva injection therapy.

All patients must receive adequate supplemental calcium and vitamin D.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.

Appropriate medical support and monitoring measures should be readily available when Bonviva intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.

Renal impairment

Patients with concomitant diseases, or who use medicinal products which have potential for undesirable effects on the kidney, should be reviewed regularly in line with good medical practice during treatment.

Due to limited clinical experience, Bonviva injection is not recommended for patients with a serum creatinine above 200 μmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min (see section 4.2 and section 5.2).

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bonviva for osteoporosis (see section 4.8).

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth.

A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bonviva in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient's risk of developing ONJ:

- Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking

- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck

- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bonviva. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bonviva administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of Bonviva treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

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.

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 (see section 4.8).

Atypical fractures of other long bones

Atypical fractures of other long bones, such as the ulna and tibia have also been reported in patients receiving long-term treatment. As with atypical femoral fractures, these fractures occur after minimal, or no trauma and some patients experience prodromal pain prior to presenting with a completed fracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated with the long-term use of walking aids (see section 4.8).

Bonviva is essentially sodium free.

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

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.

4.6. Fertility, pregnancy and lactation

Pregnancy

Bonviva is only for use in postmenopausal women and must not be taken by women of child-bearing potential.

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Bonviva should not be used during pregnancy.

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bonviva should not be used during breastfeeding.

Fertility

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

4.7. Effects on ability to drive and use machines

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Bonviva has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis for the jaw and ocular inflammation (see paragraph “Description of selected adverse reactions” and section 4.4).

The most frequently reported adverse reactions are arthralgia and influenza-like symptoms. These symptoms are typically in association with the first dose, generally of short duration, mild or moderate in intensity, and usually resolve during continuing treatment without requiring remedial measures (please see paragraph “Influenza like illness”).

Tabulated list of adverse reactions

In table 1 a complete list of known adverse reactions is presented.

The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three-year fracture study (MF 4411).

In the pivotal two-year study in postmenopausal women with osteoporosis (BM16550), the overall safety of intravenous injection of Bonviva 3 mg every 3 months and oral ibandronic acid 2.5 mg daily were shown to be similar. The overall proportion of patients who experienced an adverse reaction was 26.0 % and 28.6 % for Bonviva 3 mg injection every 3 months after one year and two years, respectively. Most cases of adverse reactions did not lead to cessation of therapy.

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions occurring in postmenopausal women receiving Bonviva 3 mg injection every 3 months or ibandronic acid 2.5 mg daily in the phase III studies BM16550 and MF 4411, and in post-marketing experience.

System Organ Class

Common

Uncommon

Rare

Very rare

Not known

Immune system disorders

Asthma exacerbation

Hypersensitivity reaction

Anaphylactic reaction/shock*†

Metabolism and nutrition disorders

hypocalcaemia†

Nervous system disorders

Headache

Eye disorders

Ocular inflammation*†

Vascular disorders

Phlebitis/ thrombophlebitis

Gastrointestinal disorders

Gastritis, Dyspepsia, Diarrhoea, Abdominal pain, Nausea, Constipation

Skin and subcutaneous tissues disorders

Rash

Angioedema, Facial swelling/oedema, Urticaria

Stevens-Johnson Syndrome†, Erythema Multiforme†, Dermatitis Bullous†

Musculoskeletal and , connective tissue disorders

Arthralgia, Myalgia, Musculoskeletal pain, Back pain

Bone pain

Atypical subtrochanteric and diaphyseal femoral fractures†

Osteonecrosis of jaw*†

Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)†

Atypical fractures of long bones other than the femur

General disorders and administration site conditions

Influenza like illness*, Fatigue

Injection site reactions, Asthenia

*See further information below

†Identified in post-marketing experience.

Description of selected adverse reactions

Influenza-like illness

Influenza-like illness includes events reported as acute phase reaction or symptoms, including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is uncertain, consistent evidence from epidemiological studies suggests an increased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-term bisphosphonate therapy for postmenopausal osteoporosis, particularly beyond three to five years of use. The absolute risk of atypical subtrochanteric and diaphyseal long bone fractures (bisphosphonate class adverse reaction) remains very low.

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.

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 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 overdosage with Bonviva.

Based on knowledge of this class of compounds, intravenous overdosage may result in hypocalcaemia, hypophosphataemia, and hypomagnesaemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.