4.1. Therapeutic indications

Iasibon is indicated in adults for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

4.2. Posology and method of administration

Iasibon therapy should only be initiated by physicians experienced in the treatment of cancer.

Posology

The recommended dose is one 50 mg film-coated tablet daily.

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Patients with renal impairment

No dose adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).

For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) a dosage adjustment to one 50 mg film-coated tablet every second day is recommended (see section 5.2).

For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

Elderly population (> 65 years)

No dose adjustment is necessary (see section 5.2).

Paediatric population

The safety and efficacy of Iasibon in children and adolescents below the age of 18 years have not been established. No data are available (see section 5.1 and 5.2).

Method of administration

For oral use.

Iasibon tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements (including calcium) should similarly be avoided prior to taking Iasibon tablets. Fasting should be continued for at least 30 minutes after taking the tablet. Water may be taken at any time during the course of Iasibon treatment (see section 4.5). Water with a high concentration of calcium should not be used. If there is 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.

- The tablets should be swallowed whole with a full glass of water (180 to 240 mL) while the patient is standing or sitting in an upright position.

- Patients should not lie down for 60 minutes after taking Iasibon.

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

- Water is the only drink that should be taken with Iasibon.

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

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Iasibon therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

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 Iasibon is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, 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 and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Iasibon 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.

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.

Osteonecrosis of the jaw

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

Renal function

Clinical studies have not shown any evidence of deterioration in renal function with long term Iasibon therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Iasibon.

Rare hereditary problems

Iasibon tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Patients with known hypersensitivity to other bisphosphonates

Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

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

Medicinal product -Food Interactions

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of Iasibon tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration.

Bioavailability was reduced by approximately 75% when Iasibon tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (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.

H2-antagonists or other medicinal products that increase gastric pH.

In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when Iasibon is administered with H2-antagonists or medicinal products that increase gastric pH.

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).

Aminoglycosides

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Fertility

There are no data on the effects of ibandronic acid in 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 Iasibon 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, and ocular inflammation (see paragraph “Description of selected adverse reactions” and section 4.4).

Treatment was most frequently associated with a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia.

Tabulated list of adverse reactions

Table 1 lists adverse reactions from 2 pivotal phase III studies (Prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with ibandronic acid 50 mg administered orally), and from post-marketing experience.

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 Drug Reactions Reported for Oral Administration of Ibandronate

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Anaemia

Immune system disorders

Hypersensitivity†, bronchospasm†, angioedema†, Anaphylactic reaction/shock†**

Asthma exacerbation

Metabolism and nutrition disorders

Hypocalcaemia**

Nervous system disorders

Paraesthesia, dysgeusia (taste perversion)

Eye disorders

Ocular inflammation†**

Gastrointestinal disorders

Oesophagitis, abdominal pain, dyspepsia, nausea

Haemorrage, duodenal ulcer, gastritis, dysphagia, dry mouth

Skin and subcutaneous tissue disorders

Pruritus

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

Musculoskeletal and connective tissue disorders

Atypical subtrochanteric and diaphyseal femoral fractures†

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

Renal and urinary disorders

Azotaemia (uraemia)

General disorders and administration site conditions

Asthenia

Chest pain, influenza-like illness, malaise, pain

Investigations

Blood parathyroid hormone increased

**See further information below

†Identified in post-marketing experience.

Description of selected adverse reactions

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

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

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 Website: 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 Iasibon. However, oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind Iasibon. Due to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.