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

Posology:

The recommended dose is one 150 mg film-coated tablet once a month. The tablet should preferably be taken on the same date each month.

Ibandronic acid should be taken after an overnight fast (at least 6 hours) and 1 hour before the first food or drink (other than water) of the day (see section 4.5) or any other oral medicinal products or supplementation (including calcium).

In case a dose is missed, patients should be instructed to take one ibandronic acid 150 mg tablet the morning after the tablet is remembered, unless the time to the next scheduled dose is within 7 days. Patients should then return to taking their dose once a month on their originally scheduled date.

If the next scheduled dose is within 7 days, patients should wait until their next dose and then continue taking one tablet once a month as originally scheduled.

Patients should not take two tablets within the same week.

Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate (see sections 4.4 and 4.5).

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

Special populations

Patients with renal impairment

Ibandronic acid is not recommended for patients with a creatinine clearance below 30 ml/min due to limited clinical experience (see sections 4.4 and 5.2).

No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance 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 ibandronic acid in children below 18 years, and ibandronic acid was not studied in this population (see sections 5.1 and 5.2).

Method of administration:

For oral use.

• Tablets should be swallowed whole with a glass of water (180 to 240 ml) while the patient is sitting or standing in an upright position. Water with a high concentration of calcium should not be used. If there is a concern regarding potentially high levels of calcium in the tap water (hard water), it is advised to use bottled water with a low mineral content.

• Patients should not lie down for 1 hour after taking ibandronic acid.

• Water is the only drink that should be taken with ibandronic acid.

• Patients should not chew or suck the tablet, because of a potential for oropharyngeal ulceration.

4.3. Contraindications

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

• Hypocalcaemia.

• Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia.

• Inability to stand or sit upright for at least 60 minutes.

4.4. Special warnings and precautions for use

Hypocalcaemia

Existing hypocalcaemia must be corrected before starting ibandronic acid therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

Gastrointestinal irritation

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ibandronic acid is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse reactions such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention to and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue ibandronic acid and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Since Nonsteroidal Anti-Inflammatory medicinal products and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving ibandronic acid 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 ibandronic acid 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 ibandronic acid. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to ibandronic acid 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 ibandronic acid 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).

Renal impairment

Due to limited clinical experience, ibandronic acid is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).

Excipients

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

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

Medicinal product – food interaction

Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium, including milk, and other multivalent cations (such as aluminium, magnesium, iron), are likely to interfere with absorption of ibandronic acid, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking ibandronic acid and continue fasting for 1 hour following intake of ibandronic acid (see section 4.2).

Interactions with other medicinal products

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.

Calcium supplements, antacids and some oral medicinal products containing multivalent cations

Calcium supplements, antacids and some oral medicinal products containing multivalent cations (such as aluminium, magnesium, iron) are likely to interfere with the absorption of ibandronic acid. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking ibandronic acid and for 1 hour following intake of ibandronic acid.

Acetylsalicylic acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).

H2-blockers or proton pump inhibitors

Of over 1,500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens of ibandronic acid, 14 % and 18 % of patients used histamine (H2) blockers or proton pump inhibitors after one and two years, respectively. Among these patients, the incidence of upper gastrointestinal events in the patients treated with ibandronic acid 150 mg once monthly was similar to that in patients treated with ibandronic acid 2.5 mg daily.

In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine caused an increase in ibandronic acid bioavailability of about 20%, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of ibandronic acid, no dose adjustment is considered necessary when ibandronic acid is administered with H2-antagonists or other active substances which increase gastric pH.

4.6. Fertility, pregnancy and lactation

Pregnancy

Ibandronic acid is only for use in postmenopausal women and must not be taken by women of childbearing 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. Ibandronic acid should not be used during pregnancy.

Breastfeeding

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. Ibandronic acid should not be used during breast-feeding.

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 ibandronic acid 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 of the jaw, gastrointestinal irritation, 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 (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 1,251 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 a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of ibandronic acid 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse reaction, was 22.7% and 25.0% for ibandronic acid 150 mg once monthly after one and two years, respectively. Most cases 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) and 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 ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM_16549 and MF_4411 and in post-marketing experience.

System Organ Class

Frequency

Adverse reactions

Immune system disorders

Uncommon

Asthma exacerbation

Rare

Hypersensitivity reaction

Very rare

Anaphylactic reaction/shock *†

Metabolism and nutrition disorders

Uncommon

Hypocalcaemia†

Nervous system disorders

Common

Headache

Uncommon

Dizziness

Eye disorders

Rare

Ocular inflammation*†

Gastrointestinal disorders*

Common

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

Uncommon

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

Rare

Duodenitis

Skin and subcutaneous tissues disorders

Common

Rash

Rare

Angioedema, Face oedema, Urticaria

Very rare

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

Musculoskeletal, connective tissue and bone disorders

Common

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

Uncommon

Back pain

Rare

Atypical subtrochanteric and diaphyseal femoral fractures †

Very rare

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

Not known

Atypical fractures of long bones other than the femur

General disorders and administration site conditions

Common

Influenza like illness*

Uncommon

Fatigue

*See further information below.

†Identified in post-marketing experience.

Description of selected adverse reactions

Gastrointestinal adverse reactions

Patients with a previous history of gastrointestinal disease including patients with peptic ulcer without recent bleeding or hospitalisation, and patients with dyspepsia or reflux controlled by medication were included in the once monthly treatment study. For these patients, there was no difference in the incidence of upper gastrointestinal adverse events with the 150 mg once monthly regimen compared to the 2.5 mg daily regimen.

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, or bone pain.

Osteonecrosis of 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 on ONJ have been reported in the post marketing setting for ibandronic acid.

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is uncertain, 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 overdose with ibandronic acid.

However, based on a knowledge of this class of compounds, oral overdose may result in upper gastrointestinal adverse reactions (such as upset stomach, dyspepsia, oesophagitis, gastritis, or ulcer) or hypocalcaemia. Milk or antacids should be given to bind ibandronic acid, and any adverse reactions treated symptomatically. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.