Bonablast

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BONABLAST (BONABLAST)

Composition:

Active substance: ibandronic acid;

1 ml of concentrate contains sodium ibandronate monohydrate equivalent to 1 mg of ibandronic acid;

Excipients: sodium chloride; glacial acetic acid, sodium acetate trihydrate; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: Colorless clear solution, practically odorless, free from particles.

Pharmacotherapeutic group.

Drugs affecting bone structure and mineralization. Bisphosphonates. Ibandronic acid. ATC code M05B A06.

Pharmacological properties.

Pharmacodynamics.

Ibandronic acid is a bisphosphonate that acts specifically on bone tissue. It exerts a selective effect on bone tissue due to its high affinity for the mineral components of bone. It inhibits osteoclast activity, although the precise mechanism is not yet known.

In vivo, ibandronic acid prevents bone destruction induced experimentally by gonadal gland function blockade, retinoids, tumors, and tumor extracts. In kinetic studies with 45Ca, inhibition of endogenous bone resorption has also been documented, measured by the release of pre-administered radiolabeled tetracycline from bone tissue.

Ibandronic acid does not affect bone mineralization when administered at doses significantly exceeding pharmacologically effective levels.

Bone tissue resorption associated with malignancy is characterized by excessive bone resorption that is not balanced by corresponding bone formation. Ibandronic acid selectively inhibits osteoclast activity, thereby reducing bone resorption and consequently decreasing bone complications associated with malignancy.

Clinical studies in the treatment of tumor-induced hypercalcemia.

Clinical studies in hypercalcemia of malignancy have demonstrated that the inhibitory effect of ibandronic acid on tumor-induced osteolysis, and particularly on tumor-induced hypercalcemia, is characterized by a reduction in serum calcium levels and urinary calcium excretion.

Within the recommended dose range for treatment, clinical trials in patients with serum calcium corrected for serum albumin ≥ 3.0 mmol/L after adequate rehydration have shown the following response rates with corresponding confidence intervals.

Ibandronate acid, dose	% of patients with response	90% Confidence interval
2 mg	54	44‑63
4 mg	76	62‑86
6 mg	78	64‑88

For these patients and doses, the median time to achieve normocalcemia was 4–7 days. The median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/L) was 18–26 days.

Clinical studies on prevention of skeletal events in patients with breast cancer and bone metastases.

Clinical studies in patients with breast cancer and bone metastases have shown a dose-dependent inhibitory effect on bone osteolysis, as expressed by bone resorption markers, and a dose-dependent effect on skeletal damage.

Prevention of skeletal events in patients with breast cancer and bone metastases using intravenous administration of 6 mg of ibandronic acid was evaluated in one randomized, placebo-controlled Phase III study lasting 96 weeks. Patients with breast cancer and radiologically confirmed bone metastases were randomized to receive either placebo (158 patients) or 6 mg of ibandronic acid (154 patients). Results of this trial are summarized below.

Primary efficacy endpoints.

The primary endpoint of the trial was the Skeletal Morbidity Rate (SMPR). This was a composite endpoint with the following Skeletal Related Events (SREs) as subcomponents:

• Radiation therapy to bone for treatment of fractures/future fractures;
• Bone surgery for treatment of fractures;
• Vertebral fractures;
• Non-vertebral fractures.

The SMPR analysis was time-adjusted and considered that one or more events occurring within a single 12-week period could be potentially related. Therefore, for the purpose of analysis, multiple events were counted only once. Data from this study demonstrated a significant benefit of intravenous ibandronic acid 6 mg over placebo in reducing SREs, measured by time-corrected SMPR (p = 0.004). The number of SREs was also significantly reduced with 6 mg ibandronic acid, and the risk of SREs was reduced by 40% compared to placebo (relative risk 0.6, p = 0.003).

Secondary efficacy endpoints.

A statistically significant improvement in bone pain score was demonstrated for intravenous ibandronic acid 6 mg compared to placebo. Pain reduction remained consistently below baseline levels throughout the study and was accompanied by significantly reduced use of analgesics. Deterioration in quality of life was significantly less in patients receiving ibandronic acid compared to placebo.

In patients receiving ibandronic acid, a marked reduction in urinary markers of bone resorption (pyridinoline and deoxypyridinoline) was observed, which was statistically significant compared to placebo.

In a study of 130 patients with metastatic breast cancer, the safety of ibandronic acid administered over 1 hour versus 15 minutes was compared. No differences in renal function parameters were observed. The overall safety profile of ibandronic acid after 15-minute infusion was consistent with the known safety profile during longer infusion times, and no new safety concerns were identified with the 15-minute infusion.

The 15-minute infusion duration has not been studied in cancer patients with creatinine clearance < 50 ml/min. Pediatric patients.

The safety and efficacy of ibandronic acid in children and adolescents under 18 years of age have not been established. Data are lacking.

Pharmacokinetics.

After a 2-hour infusion at doses of 2 mg, 4 mg, and 6 mg, the pharmacokinetic parameters of ibandronic acid are dose-proportional.

Distribution.

Following initial systemic exposure, ibandronic acid rapidly binds to bone tissue or is excreted in urine. In humans, the apparent volume of distribution is at least 90 L, and approximately 40–50% of the circulating drug amount penetrates and accumulates in bone tissue. At therapeutic concentrations, approximately 85–87% of the drug is bound to plasma proteins; therefore, due to low displacement potential, the likelihood of interactions with other drugs is low. Metabolism.

There are no data on the metabolism of ibandronic acid in animals or humans.

Elimination.

The range of apparent elimination half-life is broad and depends on dose and assay sensitivity. The apparent terminal half-life generally ranges between 10 and 60 hours. However, the initial plasma drug concentration declines rapidly, reaching 10% of peak levels within 3 hours and 8 hours after intravenous and oral administration, respectively. With intravenous administration of ibandronic acid every 4 weeks over 48 weeks in patients with metastatic bone lesions, no systemic accumulation was observed.

Total clearance of ibandronic acid is low, averaging 84–160 ml/min. Renal clearance (approximately 60 ml/min in healthy postmenopausal women) accounts for 50–60% of total clearance and depends on creatinine clearance. The difference between apparent total and renal clearance reflects drug uptake by bone tissue.

Excretion pathways do not involve known acidic or basic transport systems involved in the elimination of other active substances. Furthermore, ibandronic acid does not inhibit major human hepatic P450 isoenzymes and does not induce the cytochrome P450 system in rats. Pharmacokinetics in special populations.

Gender.

Bioavailability and pharmacokinetic parameters of ibandronic acid are not influenced by gender. Race.

There are no data indicating clinically significant differences between Mongoloid and Caucasian patients regarding the distribution of ibandronic acid. Data on Negroid patients are insufficient.

Patients with renal impairment.

Renal clearance of ibandronic acid in patients with varying degrees of renal impairment is correlated with creatinine clearance. In patients with severe renal impairment (mean calculated creatinine clearance = 21.2 ml/min), the mean dose-normalized area under the concentration-time curve (AUC) from 0 to 24 hours increased by 110% compared to healthy volunteers. In the clinical pharmacology study WP18551, after intravenous administration of a single 6 mg dose (15-minute infusion), mean AUC increased by 14% and 86% in patients with mild (mean creatinine clearance – 68.1 ml/min) and moderate (mean creatinine clearance – 41.2 ml/min) renal impairment, respectively, compared to healthy volunteers (mean creatinine clearance – 120 ml/min). Mean maximum concentration (Cmax) did not increase in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. For patients with mild renal impairment (creatinine clearance ≥50 and <80 ml/min), dose adjustment is not required. For patients with breast cancer and metastatic bone disease with moderate renal impairment (creatinine clearance ≥30 and <50 ml/min) or severe renal impairment (creatinine clearance <30 ml/min) receiving treatment for prevention of skeletal events, dose adjustment is recommended (see section "Dosage and administration").

Patients with hepatic impairment (see section "Dosage and administration"). There are no data on the pharmacokinetics of ibandronic acid in patients with hepatic impairment. The liver plays a minor role in the clearance of ibandronic acid, which is not metabolized but eliminated via the kidneys and by uptake into bone tissue. Therefore, dose adjustment is not required in patients with hepatic impairment. Since plasma protein binding of ibandronic acid at therapeutic concentrations is low (approximately 87%), it is unlikely that hypoalbuminemia in severe liver disease would lead to a clinically significant increase in free drug concentration.

Geriatric patients (see section "Dosage and administration").

Pharmacokinetic parameters studied in multivariate analysis do not depend on age. Since renal function declines with age, this is the only factor to consider (see section "Patients with renal impairment").

Children (see section "Dosage and administration").

There are no data on the use of Bonablast in children (under 18 years of age).

Clinical characteristics.

Indications.

The medicinal product is indicated for adult patients for:

• Prevention of skeletal events (pathological fractures, bone lesions requiring radiotherapy or surgical treatment) in patients with breast cancer and bone metastases.
• Treatment of hypercalcemia associated with malignant tumors with or without metastases.

Contraindications.

• Hypersensitivity to ibandronic acid or to any other component of the medicinal product (see section "Composition").
• Hypocalcemia.

Interaction with other medicinal products and other forms of interaction.

Metabolic interactions are considered unlikely, since ibandronic acid does not inhibit the major human hepatic CYP450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats (see section "Pharmacokinetics"). Ibandronic acid is eliminated via renal excretion and is not subject to biotransformation processes.

Use the medicinal product with caution in combination with aminoglycosides, since both substances may reduce serum calcium levels for a prolonged period. Also, hypomagnesemia should be monitored when these medicinal products are used concomitantly.

Special precautions for use.

Patients with disorders of bone and mineral metabolism.

Hypocalcemia and other disturbances of bone tissue metabolism and mineral balance should be corrected prior to initiating treatment with Bonablast for metastatic bone disease. Patients should receive adequate intake of calcium and vitamin D. If dietary intake of calcium and/or vitamin D is insufficient, supplementation with these nutrients should be provided.

Anaphylactic reaction/shock.

Cases of anaphylactic reactions/shock, including fatal cases, have been reported in patients receiving intravenous ibandronic acid. Appropriate medical support and monitoring measures should be readily available during intravenous administration of the medicinal product. If an anaphylactic or other severe hypersensitivity/allergic reaction occurs, the infusion should be immediately discontinued and appropriate treatment initiated.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw has been reported very rarely during post-marketing use of ibandronic acid in oncological indications (see section "Adverse reactions").

Initiation or resumption of treatment should be delayed in patients with non-healing open soft tissue lesions in the oral cavity. Prior to starting treatment, patients with concomitant risk factors should undergo a dental examination with appropriate preventive dental procedures and individual benefit-risk assessment. Factors to consider when assessing the risk of developing osteonecrosis of the jaw include:

• Potency of the bone resorption-inhibiting medicinal product (risk is higher with highly potent compounds), route of administration (risk is higher with parenteral administration), and cumulative dose of bone resorption therapy.
• Malignant neoplasms, concomitant medical conditions (e.g., anemia, coagulopathy, infection), and tobacco smoking.
• Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to the head and neck region.
• Poor oral hygiene, periodontal disease, ill-fitting dentures, dental history, and invasive dental procedures such as tooth extraction.

During treatment, all patients should be advised to maintain good oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as loose teeth, pain or swelling, or non-healing ulcers or discharge. Invasive dental procedures should only be performed after careful consideration during treatment. Such procedures should be avoided during and for some time after discontinuation of the medicinal product. Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration between the physician and a dentist or oral and maxillofacial surgeon experienced in managing osteonecrosis of the jaw. Consideration should be given to temporarily interrupting treatment with Bonablast until improvement occurs and, if possible, until concomitant risk factors are reduced.

Osteonecrosis of the external auditory canal.

Osteonecrosis of the external auditory canal has been reported with bisphosphonate use, primarily in association with long-term therapy. Potential risk factors for osteonecrosis of the external auditory canal include steroid hormone use, 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 femoral fractures.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, particularly in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur from slightly below the lesser trochanter to slightly above the supracondylar flare. These fractures occur following minimal or no trauma, and some patients experience thigh or groin pain, often associated with characteristic features of a stress fracture, for several weeks to months prior to the occurrence of a complete femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should also be evaluated in patients receiving bisphosphonate therapy who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Consideration should be given to discontinuing bisphosphonate therapy in patients with suspected atypical femoral fractures pending full assessment of the patient, taking into account individual benefit-risk evaluation.

During bisphosphonate therapy, patients should be advised to report new thigh, hip, or groin pain. All patients presenting with such symptoms should be evaluated for incomplete femoral fracture.

Atypical fractures of other long bones.

Atypical fractures of other long bones, such as the ulna and tibia, have been reported in patients receiving long-term bisphosphonate therapy. As with atypical femoral fractures, these fractures may occur following minor trauma or without trauma, and some patients experience prodromal pain prior to the occurrence of a complete fracture. In cases of ulnar fracture, this may be associated with repetitive stress due to prolonged use of walking aids (see section "Adverse reactions").

Renal impairment.

Clinical studies have not shown evidence of renal dysfunction with long-term ibandronic acid therapy. However, during treatment with Bonablast, renal function, as well as serum calcium, phosphate, and magnesium levels, should be monitored according to clinical assessment of each patient (see section "Dosage and administration").

Hepatic impairment.

Due to the lack of clinical data, dosage recommendations for patients with severe hepatic impairment cannot be provided (see section "Dosage and administration").

Heart failure.

Patients at risk of developing heart failure should avoid excessive hydration.

Important information on excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free."

Patients with hypersensitivity to other bisphosphonates.

Caution should be exercised in patients with hypersensitivity to other bisphosphonates.

Disposal of unused medicinal product or waste after expiry:

Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be carried out via a designated waste collection system, if available.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of ibandronic acid in pregnant women. Reproductive toxicity was observed in animal studies. The potential risk to humans is unknown. Bonablast should not be used during pregnancy.

Breastfeeding.

It is unknown whether ibandronic acid passes into human breast milk. Studies have demonstrated low levels of ibandronic acid in the milk of lactating rats following intravenous administration. Bonablast should not be used during breastfeeding.

Fertility.

There are no data on the effect of ibandronic acid in humans. In animal studies, ibandronic acid reduced fertility following oral administration and intravenous administration at high daily doses.

Ability to influence reaction speed when driving or operating machinery.

Given the pharmacodynamic characteristics, pharmacokinetic profile, and reported adverse reactions, ibandronic acid is expected to have no effect or a negligible effect on the ability to drive or operate machinery.

Administration and Dosage.

Treatment with Bonablast should only be prescribed by a physician experienced in the management of malignant diseases.

Dosage.

Skeletal event prevention in patients with breast cancer and bone metastases.

The recommended dose is 6 mg after prior dilution in 100 mL of 0.9% isotonic sodium chloride solution or 100 mL of 5% glucose solution. The medicinal product should be administered intravenously as an infusion over at least 15 minutes, once every 3–4 weeks. The shorter infusion duration (i.e., 15 minutes) should only be used in patients with normal renal function or mild renal impairment. There are no data on the use of shorter infusion durations in patients with creatinine clearance less than 50 mL/min. Dosage and administration recommendations for these patient groups are provided in the section "Special Patient Populations. Patients with Renal Impairment."

Treatment of hypercalcemia of malignancy.

Bonablast therapy should only be initiated after adequate hydration with 0.9% sodium chloride solution (9 mg/mL). The dose of the medicinal product depends on the severity of hypercalcemia and tumor type. Generally, lower doses are required for patients with osteolytic bone metastases compared to those with humoral hypercalcemia. For most patients with severe hypercalcemia (albumin-corrected serum calcium* ≥ 3 mmol/L or ≥ 12 mg/dL), a single dose of 4 mg is sufficient. A dose of 2 mg is effective in patients with moderate hypercalcemia (albumin-corrected serum calcium < 3 mmol/L or < 12 mg/dL). The highest dose used in clinical studies was 6 mg; however, administration of this dose did not result in enhanced efficacy.

*Serum albumin-corrected calcium concentration is calculated using the following formula:

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

or

albumin-corrected calcium = serum calcium (mg/dL) +
0.8 × [4 – albumin (g/dL)].

To convert serum albumin-corrected calcium values from mmol/L to mg/dL, multiply by 4.

In most cases, elevated serum calcium levels return to normal within 7 days. The median time to relapse (recurrent increase in serum albumin-corrected calcium concentration above 3 mmol/L) was 18–19 days with doses of 2 and 4 mg. The median time to relapse following administration of 6 mg was 26 days.

A limited number of patients (50 patients) received a second infusion due to hypercalcemia. Re-administration of the medicinal product may be considered in cases of hypercalcemia relapse or inadequate response.

Bonablast should be diluted in 500 mL of 0.9% isotonic sodium chloride solution or 500 mL of 5% glucose solution and administered as an intravenous infusion over 2 hours.

Special Patient Populations.

Patients with hepatic impairment.

Dose adjustment is not required (see section "Pharmacokinetics").

Patients with renal impairment.

For patients with mild renal impairment (creatinine clearance ≥50 and <80 mL/min), no dose adjustment is necessary.

For the prevention of skeletal events in patients with breast cancer and bone metastases who have moderate renal impairment (creatinine clearance ≥30 and <50 mL/min) or severe renal impairment (creatinine clearance <30 mL/min), the following additional recommendations must be followed (see section "Pharmacokinetics"):

Creatinine clearance (ml/min)	Dose	Volume1 and duration2 of infusion
≥ 50 to < 80	6 mg (6 ml concentrate for solution for infusion)	100 ml over 15 minutes
≥ 30 to < 50	4 mg (4 ml concentrate for solution for infusion)	500 ml over 1 hour
< 30	2 mg (2 ml concentrate for solution for infusion)	500 ml over 1 hour

1 0.9% sodium chloride solution or 5% glucose solution.

2 Administration once every 3–4 weeks.

The 15-minute infusion duration has not been studied in patients with malignancies and creatinine clearance less than 50 mL/min.

Elderly patients (aged 65 years and older).

Dose adjustment is not required (see section "Pharmacokinetics").

Special instructions for use

The concentrate for infusion solution is for single use only. Only clear, particle-free solutions should be used. Bonablast must be administered only as an intravenous infusion. The medicinal product must not be administered intraarterially or subcutaneously, as this may lead to tissue damage.

From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, storage time and conditions of the prepared solution are the responsibility of the user, provided that the diluted solution is stored no longer than 24 hours at 2–8 °C and only if dilution was carried out under controlled and validated aseptic conditions.

Children.

The safety and efficacy of Bonablast in children (under 18 years of age) have not been established. There is no available data.

Overdose.

Symptoms. There is no data on acute overdose with this medicinal product. Due to the potential toxic effects on the liver and kidneys when used at high doses, the function of these organs should be monitored.

Treatment. In case of hypocalcemia, treatment with intravenous calcium gluconate should be administered.

Adverse Reactions

The most serious adverse reactions reported are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, and ocular inflammation (see "Description of selected adverse reactions" and "Special warnings and precautions for use"). Treatment of malignancy-induced hypercalcaemia was most frequently associated with fever. Hypocalcaemia (decreased serum calcium levels below normal) was reported less frequently. In most cases, no specific treatment was required and symptoms resolved within several hours/days. When used for prevention of skeletal events in patients with breast cancer and bone metastases, treatment was most frequently associated with asthenia, accompanied by fever and headache.

The adverse reactions listed below were observed in pivotal Phase III clinical trials (treatment of malignancy-induced hypercalcaemia: 311 patients received ibandronic acid at a dose of 2 mg or 4 mg; prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients receiving ibandronic acid at a dose of 6 mg), as well as adverse reactions observed during post-marketing use.

Adverse reactions are listed below according to MedDRA (Medical Dictionary for Regulatory Activities) organ system classes and frequency categories. Frequencies are defined as follows: 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), frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Infections and infestations: common – infections; uncommon – cystitis, vaginitis, oral candidiasis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – benign skin neoplasms.

Blood and lymphatic system disorders: uncommon – anaemia, blood disorder.

Immune system disorders: very rare – hypersensitivity†, bronchospasm†, angioneurotic oedema†, anaphylactic reaction/shock†**; frequency not known – asthma exacerbation.

Endocrine disorders: common – parathyroid gland disorders.

Metabolism and nutrition disorders: common – hypocalcaemia**; uncommon – hypophosphataemia.

Psychiatric disorders: uncommon – sleep disorders, anxiety, emotional lability.

Nervous system disorders: common – headache, dizziness, dysgeusia (taste distortion); uncommon – cerebrovascular disorders, nerve root injury, amnesia, migraine, neuralgia, hypertension, hyperaesthesia, perioral paraesthesia, parosmia.

Eye disorders: common – cataract; rare – ocular inflammation†**.

Ear and labyrinth disorders: uncommon – deafness.

Cardiac disorders: common – bundle branch block; uncommon – myocardial ischaemia, cardiocirculatory disorders, palpitations.

Respiratory, thoracic and mediastinal disorders: common – pharyngitis; uncommon – pulmonary oedema, stridor.

Gastrointestinal disorders: common – diarrhoea, vomiting, dyspepsia, gastrointestinal pain, dental disorders; uncommon – gastroenteritis, gastritis, oral ulceration, dysphagia, cheilitis.

Hepatobiliary disorders: uncommon – cholelithiasis.

Skin and subcutaneous tissue disorders: common – skin disorders, ecchymoses; uncommon – rash, alopecia; very rare – Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis†.

Musculoskeletal and connective tissue disorders: common – osteoarthritis, myalgia, arthralgia, joint disorders, bone pain; rare – atypical subtrochanteric and diaphyseal femoral fractures†; very rare – osteonecrosis of the jaw†**, osteonecrosis of the external auditory canal (an adverse reaction typical of bisphosphonates as a class)†; frequency not known – atypical long bone fractures (excluding femur).

Renal and urinary disorders: uncommon – urinary retention, renal cysts.

Reproductive system and breast disorders: uncommon – pelvic pain.

General disorders and administration site conditions: common – pyrexia, influenza-like symptoms**, peripheral oedema, asthenia, thirst; uncommon – hypothermia.

Investigations: common – increased gamma-glutamyl transferase, increased creatinine; uncommon – increased alkaline phosphatase, weight decreased.

Injury, poisoning and procedural complications: uncommon – injury, injection site pain.** See below for details.

† Identified during post-marketing use.

Description of selected adverse reactions

Hypocalcaemia

Reduced renal excretion of calcium may be accompanied by decreased serum phosphate levels, which does not require therapeutic intervention. Serum calcium levels may decrease to hypocalcaemia.

Influenza-like illness

The influenza-like syndrome included symptoms such as fever, chills, and bone and/or muscle pain. In most cases, no specific treatment was required and symptoms resolved within several hours/days.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported, primarily in patients with malignancies receiving treatment with bone resorption inhibitors, including ibandronic acid (see section "Special warnings and precautions for use"). Cases of osteonecrosis of the jaw have also been reported during post-marketing use of ibandronic acid.

Atypical subtrochanteric and diaphyseal femoral fractures

Epidemiological data suggest an increased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-term bisphosphonate therapy for postmenopausal osteoporosis, particularly after three to five years of use, although the pathophysiology is not fully understood. The absolute risk of atypical subtrochanteric and diaphyseal fractures of long bones (a class effect of bisphosphonates) remains very low.

Ocular inflammation

Inflammatory eye disorders such as uveitis, episkleritis, and scleritis have been reported with the use of ibandronic acid. In some cases, these inflammatory disorders resolved only after discontinuation of bisphosphonates.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal cases, have been observed in patients receiving intravenous ibandronic acid.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorisation is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life

5 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of the reach and sight of children.

Incompatibilities

To avoid incompatibility, the medicinal product should be diluted only in 0.9% sodium chloride isotonic solution or 5% glucose solution.

The medicinal product must not be mixed with solutions containing calcium.

Packaging

6 ml in a vial; 1 vial in a cardboard carton.

Prescription status

Prescription only.

Manufacturer

FARMATEN S.A.

Manufacturer's address

Derivenakion 6, Pallini Attica, 15351, Greece