4.1. Therapeutic indications

Iasibon is indicated in adults for

- Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases

- Treatment of tumour-induced hypercalcaemia with or without metastases

4.2. Posology and method of administration

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

Posology

Prevention of skeletal events in patients with breast cancer and bone metastases

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterising the use of a shorter infusion time in patients with creatinine clearance below 50 mL/min. Prescribers should consult the section Patients with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this patient group.

Treatment of tumour-induced hypercalcaemia

Prior to treatment with Iasibon the patient should be adequately rehydrated with 9 mg/mL (0.9%) sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ≥3 mmol/L or ≥12 mg/dL) 4 mg is an adequate single dose. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/L or <12 mg/dL) 2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms of efficacy.

* Note albumin-corrected serum calcium concentrations are calculated as follows:

Albumin-corrected serum calcium (mmol/L) = serum calcium (mmol/L) - [0.02 x albumin (g/L)] + 0.8

or

Albumin-corrected serum calcium (mg/dL) =serum calcium (mg/dL) + 0.8 x [4 - albumin (g/dL)]

To convert the albumin-corrected serum calcium in mmol/L value to mg/dL, multiply by 4.

In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/L) was 18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

Iasibon concentrate for solution for infusion should be administered as an intravenous infusion over 2 hours.

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Patients with renal impairment

For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dose adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see section 5.2):

Creatinine Clearance (mL/min)

Dosage

Infusion Volume 1 and Time 2

≥50 CLcr <80

6 mg (6 mL of concentrate for solution for infusion)

100 mL over 15 minutes

≥30 CLcr <50

4 mg (4 mL of concentrate for solution for infusion)

500 mL over 1 hour

<30

2 mg (2 mL of concentrate for solution for infusion)

500 mL over 1 hour

1 0.9% sodium chloride solution or 5% glucose solution

2 Administration every 3 to 4 week

A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.

Elderly population (> 65 years)

No dose adjustment is required (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 section 5.2).

Method of administration

For intravenous administration.

The content of the ampoule is to be used as follows:

• Prevention of Skeletal Events - added to 100 mL isotonic sodium chloride solution or 100 mL 5% dextrose solution and infused over at least 15 minutes. See also dose section above for patients with renal impairment

• Treatment of tumour-induced hypercalcaemia - added to 500 mL isotonic sodium chloride solution or 500 mL 5% dextrose solution and infused over 2 hours

For single use only. Only clear solution without particles should be used.

Iasibon concentrate for solution for infusion should be administered as an intravenous infusion.

Care must be taken not to administer Iasibon concentrate for solution for infusion via intra-arterial or paravenous administration, as this could lead to tissue damage.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Hypocalcaemia

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 for metastatic bone disease.

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.

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 Iasibon intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.

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.

Patients with renal impairment

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 (see section 4.2).

Patients with hepatic impairment

As no clinical data are available, dose recommendations cannot be given for patients with severe hepatic insufficiency (see section 4.2).

Patients with cardiac impairment

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

Patients with known hypersensitivity to other bisphosphonates

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

Excipients with known effect

Iasibon contains less than 1 mmol sodium (23 mg) per ampoule, that is to say 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.

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 for the jaw, and ocular inflammation (see paragraph “description of selected adverse reactions” and section 4.4).

Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is reported. In most cases no specific treatment is required and the symptoms subside after a couple of hours/days.

In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is most frequently associated with asthenia followed by rise in body temperature and headache.

Tabulated list of adverse reactions

Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with ibandronic acid 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients treated with ibandronic acid 6 mg), 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 Reactions Reported for Intravenous Administration of Ibandronic Acid

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

Infection

Cystitis, vaginitis, oral candidiasis

Neoplasms benign, malignant, and unspecified

Benign skin neoplasm

Blood and lymphatic system disorders

Anaemia, blood dyscrasia

Immune system disorders

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

Asthma exacerbation

Endocrine disorders

Parathyroid disorder

Metabolism and nutrition disorders

Hypocalcaemia**

Hypophosphataemia

Psychiatric disorders

Sleep disorder, anxiety, affection lability

Nervous system disorders

Headache, dizziness, dysgeusia (taste perversion)

Cerebrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia

Eye disorders

Cataract

Ocular inflammation†**

Ear and labyrinth disorders

Deafness

Cardiac disorders

Bundle branch block

Myocardial ischaemia, cardiovascular disorder, palpitations

Respiratory, thoracic, and mediastinal disorders

Pharyngitis

Lung oedema, stridor

Gastrointestinal disorders

Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder

Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

Hepatobiliary disorders

Cholelithiasis

Skin and subcutaneous tissue disorders

Skin disorder, ecchymosis

Rash, alopecia

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

Musculoskeletal and connective tissue disorders

Osteoarthritis, myalgia, arthralgia, joint disorder, bone pain

Atypical subtrochanteric and diaphyseal femoral fractures†

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

Renal and urinary disorders

Urinary retention, renal cyst

Reproductive system and breast disorders

Pelvic pain

General disorders and administration site conditions

Pyrexia, influenza-like illness**, oedema peripheral, asthenia, thirst

Hypothermia

Investigations

Gamma-GT increased, creatinine increased

Blood alkaline phosphatase increase, weight decrease

Injury, poisoning and procedural complications

Injury, injection site pain

**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.

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

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

Up to now there is no experience of acute poisoning with Iasibon concentrate for solution for infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical studies with high doses, kidney and liver function should be monitored. Clinically relevant hypocalcaemia should be corrected by intravenous administration of calcium gluconate.