Bondronat 2 Mg/2 Mℓ & 6 mg/6 mℓ Injection

BONDRONAT is indicated in:

• the treatment of tumour-induced hypercalcaemia with, or without, metastases.
• patients with breast cancer and bone metastases for the prevention of skeletal complications requiring radiotherapy.

Posology

Treatment of Metastatic Bone Disease

The recommended dose for metastatic bone disease is 6 mg i.v. given every 3 - 4 weeks. The dose should be infused over at least 15 minutes. For infusion, the contents of the ampoule/vial should be added to 100 mu2113 isotonic sodium chloride solution (or 100 mu2113 of 5 % dextrose solution). 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 mu2113/min. Refer to the section further below, u2018Patients with renal impairmentu2019, for recommendations on dosing and administration in this patient group.

Treatment of Tumour-Induced Hypercalcaemia

Adults and elderly: Consideration should be given to the severity of 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. Recommended single dose: Prior to treatment with BONDRONAT injection solution, the patient should be adequately rehydrated with 0,9 % sodium chloride. Warning: Overhydration should be avoided in patients at risk of cardiac failure/pulmonary oedema. Repeated treatment is possible in case of recurrent hypercalcaemia or insufficient efficacy. However, until adequate clinical experience has been gained, a cumulative dose of 6 mg should not be exceeded. BONDRONAT injection solution should be administered as an intravenous infusion. The contents of the ampoule/vials are to be added to 500 mu2113 isotonic sodium chloride solution (or 500 mu2113 of 5 % dextrose solution) and infused over 2 hours.

Albumin-corrected serum calcium* after adequate rehydration

Dose

• Severe hypercalcaemia > 3,5 mmol/u2113 (u2265 12 mg/du2113) 2 - 4 mg
• Moderate hypercalcaemia < 3,5 mmol/u2113 (< 12 mg/du2113) 1 - 2 mg

The highest dose used in clinical trials (for hypercalcaemia) 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/u2113) = serum calcium (mmol/u2113) - [0,02 x albumin (g/u2113)] + 0,8 Or Albumin-corrected serum calcium (mg/du2113) = serum calcium (mg/du2113) + 0,8 x [4 - albumin (g/du2113)] To convert the albumin-corrected serum calcium in mmol/u2113 value to mg/du2113, multiply by 4.

In most cases a raised serum calcium level can be reduced to the normal range within 7 days. Median time to relapse (re-increase of serum albumin corrected serum calcium above 3 mmol/u2113) was 18 - 19 days for the 2 mg and 4 mg doses, and 26 days for the 6 mg dose.

Special populations

Special Dosage instructions

Patients with hepatic impairment No dosage adjustment is expected to be necessary. See section 5.2, Pharmacokinetics in special populations.

Patients with renal impairment For patients with mild renal impairment (CLcr u2265 50 and < 80 mu2113/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr u2265 30 and < 50 mu2113/min) or severe renal impairment (CLcr < 30 mu2113/min), being treated for the treatment of skeletal events in breast cancer and metastatic bone disease, the following dosing recommendations should be followed.

Creatinine Clearance (mu2113/min) Dosage / Infusion time 1 Infusion Volume 2

• u2265 50 CLcr < 80 6 mg / 15 minutes 100 mu2113
• u2265 30 CLcr < 50 4 mg / 1 hour 500 mu2113
• < 30 2 mg / 1 hour 500 mu2113

1 Administration every 3 to 4 weeks

2 0,9 % sodium chloride solution or 5 % glucose solution

A 15 - minute infusion time has not been studied in cancer patients with CLcr < 50 mu2113/min.

Elderly No dose adjustment is necessary.

Paediatric population Safety and efficacy have not been established in patients less than 18 years old.

Method of administration

• For intravenous administration.
• The concentrate for solution for infusion is for single use only.
• Only clear solution without particles should be used.
• Unused solution should be discarded.

• Hypersensitivity to ibandronic acid, or other bisphosphonate or to any of the excipients listed in section 6.1.
• Hypocalcaemia, see section 4.4.
• BONDRONAT injection should not be used during pregnancy and lactation due to a lack of clinical experience (see section 4.6).

Administration failures

The inadvertent intra-arterial administration, as well as perivenous administration, is not recommended. This can lead to tissue damage. Ensure that BONDRONAT is only administered intravenously.

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting BONDRONAT 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.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with i.v. BONDRONAT. Appropriate medical support and monitoring measures should be readily available when BONDRONAT is administered intravenously. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the infusion 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 BONDRONAT 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 BONDRONAT in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patientu2019s 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 BONDRONAT. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to BONDRONAT 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 BONDRONAT 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).

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term BONDRONAT therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that the renal function, serum calcium, phosphate, and magnesium should be monitored in patients treated with BONDRONAT (see section 4.2).

Patients with hepatic impairment

As no clinical data are available, dosage 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.

Paediatric population

BONDRONAT injection should not be used in children due to a lack of clinical experience (see section 4.2 and section 5.2).

Excipients with known effect

BONDRONAT is essentially sodium free.

BONDRONAT should not be mixed with calcium containing solutions.

Medicine interactions: When co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed. Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen). In relation to disposition, no medicine interactions of clinical significance are likely. BONDRONAT is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other medicines. In addition, BONDRONAT does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and BONDRONAT is therefore unlikely to displace other active substances. Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia. In clinical studies, BONDRONAT has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Interaction studies have only been performed in adults.

BONDRONAT injection should not be used during pregnancy and lactation due to a lack of clinical experience. See section 4.3.

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity. The potential risk for humans is unknown. Therefore, BONDRONAT 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. BONDRONAT should not be used during breastfeeding.

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.

Since undesirable effects such as dizziness and amnesia have been reported in patients receiving BONDRONAT, patients should not drive, use machinery, or perform any tasks that require concentration, until they are certain that BONDRONAT does not adversely affect their ability to do so (see section 4.8).

a) 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 u201cdescription of selected adverse reactionsu201d 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.

b) 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 BONDRONAT 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients treated with BONDRONAT 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 (u2265 1/100 to < 1/10), uncommon (u2265 1/1,000 to < 1/100), rare (u2265 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 BONDRONAT

System Organ Class Frequency Adverse reaction

Infections and infestations Common Infection Uncommon Cystitis, vaginitis, oral candidiasis

Neoplasms benign, malignant and unspecified Uncommon Benign skin neoplasm

Blood and lymphatic system disorders Uncommon Anaemia, blood dyscrasia

Immune system disorders Very rare Hypersensitivity u2020 , bronchospasm, angioedema u2020 , Anaphylactic reaction/shock u2020** Not Known Asthma exacerbation

Endocrine disorders Common Parathyroid disorder

Metabolism and nutrition disorders Common Hypocalcaemia** Uncommon Hypophosphataemia

Psychiatric disorders Uncommon Sleep disorder, anxiety, affection lability

Nervous system disorders Common Headache, dizziness, dysgeusia (taste perversion) Uncommon Cerebrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaesthesia, paraesthesia circumoral, parosmia

Eye disorders Common Cataract Uncommon Ocular inflammation u2020**

Ear and labyrinth disorders Uncommon Deafness

Cardiac disorders Common Bundle branch block Uncommon Myocardial ischaemia, cardiovascular disorder, palpitations

Respiratory, thoracic, and mediastinal disorders Common Pharyngitis Uncommon Lung oedema, stridor

Gastrointestinal disorders Common Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder Uncommon Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

Hepatobiliary disorders Uncommon Cholelithiasis

Skin and subcutaneous tissues disorders Common Skin disorder, ecchymosis Uncommon Rash, alopecia Very rare Stevens-Johnson Syndrome u2020 , Erythema multiforme u2020 , Dermatitis bullous u2020

Musculoskeletal and connective tissue disorders Common Osteoarthritis, myalgia, arthralgia, joint disorder, bone pain Rare Atypical subtrochanteric and diaphyseal femoral fracturesu2020 Very rare Osteonecrosis of jaw u2020** , Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) u2020 Not known Atypical fractures of long bones other than the femur

Renal and urinary disorders Uncommon Urinary retention, renal cyst

Reproductive system and breast disorders Uncommon Pelvic pain

General disorders and administration site conditions Common Pyrexia, influenza-like illness**, oedema peripheral, asthenia, thirst Uncommon Hypothermia

Investigations Common Gamma-GT increased, creatinine increased Uncommon Blood alkaline phosphatase increase, weight decrease

Injury, poisoning and procedural complications Uncommon Injury, injection site pain

**See further information below

u2020Identified in post-marketing experience.

c) 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 (ONJ)

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, 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Reporting can also be done directly to Adcock Ingram Limited at [email protected].

Up to now there is no experience of acute poisoning with BONDRONAT injection solution. Since both the kidney and the liver were found to be target organs for toxicity, kidney and liver function should be monitored. Clinically relevant hypocalcaemia should be corrected by i.v. administration of calcium gluconate. Standard haemodialysis procedures result in significant clearance of ibandronic acid.